Several large population-based studies have examined the incidence of sepsis and its associated mortality. Dombrovsky and colleagues conducted a trend analysis from the years 1993 to 2003 that studied hospitalization rates for patients with severe sepsis, and subsequent mortality and case fatality rates.¹ Data were collected by the Nationwide Inpatient Sample (NIS), a 20% stratified sample of all United States community hospitals. Analysis of data revealed that hospital admissions for patients with severe sepsis nearly doubled from 1993 to 2003. The mortality rate from the same time period also significantly increased. Despite the overall increase in the number of cases, a decrease was seen in the case fatality rate. Hospitalization and mortality rates were higher for men compared with women; but, interestingly, the case fatality rate was higher for women. The most common site of infection was the respiratory tract.

An observational cohort pan-European study was subsequently conducted regarding the incidence of sepsis in ICUs in 24 European countries, and used the same operational definitions as the study by Dombrovsky.⁴ Over 3,000 patients, admitted with a diagnosis of sepsis over a two-week study period, were included in the study. The diagnosis of sepsis was noted in more than 35% of patients admitted to an ICU. In units with a high incidence of admissions secondary to sepsis, a higher mortality rate was also noted. Variables associated with a higher mortality rate included: a more severe degree of organ failure, advanced age, and other medical conditions such as cirrhosis or an excessive positive fluid balance. The responsible microorganism was identified in only 60% of patients in the study. Gram-negative and gram-positive microorganisms were found in cultures with similar frequency. As in the study by Dombrovsky, the most frequent site of infection was the lung.

Multiple studies have addressed sepsis during pregnancy. Mabie and colleagues reported results from their study of a series of 18 pregnant women diagnosed with sepsis collected over a ten-year period.³ They estimated the incidence to be 1 in 8,338 deliveries. In their series, the causes of sepsis were pyelonephritis (6), chorioamnionitis (3), toxic shock (2), postpartum endometritis (2), septic abortion (1), ruptured appendix (1), ruptured ovarian abscess
(1), necrotizing fasciitis (1), and bacterial endocarditis (1). The mortality rate was 28%. Escherichia coli, group A beta-hemolytic Streptococcus, and group B Streptococcus were the organisms most often identified. In 2003, Kankuri and colleagues reported results from a study of pregnant women with sepsis which included 43,483 deliveries that occurred between the years 1990 and 1998.⁵ They calculated the incidence of sepsis with bacteremia to be 1 in 1,060. Variables most often associated with sepsis, in the setting of documented bacteremia, included obesity, primiparous status, preterm delivery, and Cesarean delivery. Of the 41 women who had sepsis with bacteremia, 1 developed septic shock. No deaths were reported.

A review article on sepsis in pregnancy by Fernandez-Perez and colleagues reported that sepsis in pregnancy was a rare event; the incidence of sepsis in their review declined from 0.6% in 1979 to 0.3% in 2000.⁶ However, they concluded that when sepsis did occur in pregnancy, the potential for maternal mortality was significant. Such trend analyses are possible in part because of international consensus on the definition of sepsis.

The pathophysiology of sepsis, the role of the immune system in sepsis, and the individual response of the

host are not completely understood. These concepts are the focus of research and continue to generate debate. Historically, antimicrobial therapy was the mainstay for treatment of sepsis. However, despite the widespread use of antibiotics and pharmacologic advances, mortality rates have remained essentially unchanged. The lack of a favorable impact of antibiotics on mortality rates has prompted further study into the role of the immune system in sepsis. A prevalent hypothesis attributes the pathophysiologic alterations of sepsis to immune system dysfunction or maladaptation. The degree of immune dysfunction is likely related to multiple factors, including the virility of the pathogen, the health status of the host, the genetic response of the host to infection, and the severity of the infection.⁹

A thorough discussion of the immune system is beyond the scope of this chapter; however, a review of key concepts is presented in order to facilitate understanding of the pathogenesis of sepsis. The goals of the immune system are to prevent and fight infection; however, the process is not completely understood. In addition, the ability of an individual’s immune system to respond to pathogens may be unique and subsequently play a role in the course infection takes in that person.

After epithelial penetration, the first line of immune defense is white blood cells such as granulocytes, macrophages, and monocytes. Surface receptors called toll-like receptors (TLRs), located on antigen-presenting
cells including granulocytes, macrophages, and monocytes, recognize specific patterns on the surface of microorganisms (pathogen-associated molecular patterns or PAMPs). TLRs react with the pathogen and release substances that activate the immune system.¹⁰ Specific TLRs recognize specific groups of microorganisms. For example, TLR4 recognizes the lipopolysaccharide of gram-negative bacteria, while TLR3 recognizes viruses. As a group, TLRs provide early detection and response to invading pathogens. However, the specific activation of individual TLRs may in part explain the variety of courses different infections often take. Further study may reveal methods to measure TLR response, which may facilitate identification of the pathogen, enhance prediction of complications, and determine treatment to optimize the immune response, especially in cases where the individual response is either too aggressive or absent.¹¹

If these immune mechanisms are insufficient to control the pathogen, a second form of immunity, called adaptive immunity, is activated. Adaptive immunity is triggered by a specific antigen and has memory for that antigen; this permits rapid response following subsequent exposures. This response is mediated by the release of signaling molecules called cytokines. Cytokines mediate the processes of inflammation, including but not limited to vasodilation, vasopermeability, activation of adhesion molecules, and coagulation. An overview of the inflammatory response is depicted in Figure 18-1. Cytokine release can lead to damage of healthy endothelium, resulting in pathologic vasodilation and vasopermeability. This may also include activation of the coagulation cascade and depression of fibrinolysis. Increased vasopermeability and vasodilation ultimately lead to the clinical syndrome termed distributive shock, manifested by hypotension and decreased systemic vascular resistance (SVR). Subsequently, oxygen transport is impaired and the risk of end-organ dysfunction or failure is increased. Activation of the coagulation cascade results in the formation of thrombi in the microcirculation,
which results in the mechanical obstruction of oxyhemoglobin reaching distal capillaries. This further interferes with oxygen delivery to tissues.⁹

Although dysfunction or maladaptation of the immune system likely facilitates pathophysiologic changes associated with sepsis, therapies developed to counteract pro-inflammatory mediators have yielded mixed results in clinical trials. It is clear that the cascade of inflammatory mediators involved in the development of sepsis is complex. In the future, purposeful manipulation of cytokine activity may be therapeutic; however, the physiologic effects of cytokines must first be better understood.^12,13

Genetic polymorphism also likely plays a role in an individual’s inflammatory response and susceptibility to infection. A polymorphism is a common variation in a gene or DNA sequence. These alterations may or may not have a noticeable effect on gene function. Polymorphisms of cytokine or cytokine receptor genes can, however, result in an imbalance in the anti-inflammatory and pro-inflammatory responses to microorganisms. Inflammatory maladaptation may decrease survival in patients with sepsis. Polymorphisms that affect the ability of immune cells to identify specific microorganisms may also alter the disease course. Continued research may provide evidence regarding why different patients with sepsis have different systemic responses, under what seem to be similar clinical circumstances.¹⁴

The pathophysiologic events described above lead to alterations in hemodynamic function.¹⁵ A thorough discussion of clinical concepts related to hemodynamic and oxygen transport, including critical concepts related to interpretation of data obtained via invasive central hemodynamic monitoring during pregnancy, is presented in Chapter 4 of this text. Select concepts will be presented in the description of treatment strategies for the patient with sepsis.

The Surviving Sepsis Campaign (SSC) divides sepsis into three stages; each stage is described in the portion of their document that includes definitions.¹⁶ However, sepsis has generally been divided into two stages—early and late—largely distinguished by the patient’s cardiovascular function. This conceptual framework may facilitate clinical decision-making. In the early stage of sepsis, inflammatory mediators produce endothelial damage. This causes capillary damage and subsequent increased vascular permeability. In turn, colloid osmotic pressure (COP) values decrease; a result of the loss of serum proteins across capillary membranes. Subsequently, interstitial fluid volume increases while intravascularvolume decreases. Hemodynamic alterations during this stage include central hypovolemia; specifically, decreased preload that refers to a reduction in ventricular end-diastolic volume. When preload decreases, the potential for decreased cardiac output and oxygen transport increases. Compensatory mechanisms to these hemodynamic alterations include increased ventricular contractility and increased heart rate. Selective vasoconstriction may also occur, in order to increase perfusion of available blood, oxygen, and nutrients to the most essential organ systems. If central mixed-venous oxygen saturation (SvO₂) via a fiberoptic pulmonary artery catheter (PAC) is continually assessed, or a central mixed-venous blood gas sample is intermittently obtained, the SvO₂

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