INTRODUCTION

Systemic inflammatory response syndrome (SIRS) is a term introduced by the American College of Chest Physicians and Society of Critical Care Medicine consensus conference in 1992 to acknowledge the importance of systemic activation of inflammation as a contributor to organ failure in sepsis.¹ The inherent heterogeneity of patients with sepsis and the observation of similar clinical courses in disease states lacking an infectious cause led to the breakdown of sepsis into a trigger (bacterial invasion) and a response to that trigger (the inflammatory response). From this realization emerged the concept of SIRS, or a systemic response to an insult that is infectious or noninfectious in origin.

Although SIRS is most commonly associated with sepsis, other disease states known to cause widespread release of endogenous mediators and subsequent systemic inflammation in people include trauma, burns, major surgery, and pancreatitis.² These insults can progress to multiple organ failure, shock, and death due to the magnitude of the inflammatory response alone (and in the absence of infection).^2,3 SIRS describes a clinical state rather than a disease entity. Proposed criteria for diagnosis consist of two out of the following four clinical signs: (1) hypothermia or hyperthermia, (2) leukocytosis or leukopenia, (3) tachycardia, and (4) tachypnea.¹ Studies relating the magnitude of the inflammatory response to outcome highlight the importance of early recognition of systemic inflammation and treatment of the underlying disease process.⁴

SYSTEMIC INFLAMMATION

Systemic inflammation may be triggered by products of both gram-positive and gram-negative bacteria. Factors known to stimulate macrophages and monocytes include lipopolysaccharide (from gram-negative bacteria), lipoteichoic acid (gram-positive bacteria), peptidoglycan and flagellin (gram-positive and gram-negative bacteria), and mannan (fungi). Normally leukocyte activation resulting from exposure to these proteins, and subsequent release of tumor necrosis factor-α (TNF-α), lead to an inflammatory response designed to protect the host. Excessive activation of inflammation, however, may contribute to multiple organ failure and death.

Although the release of mediators such as TNF-α, interleukin (IL)-1, IL-6, prekallikreins, bradykinin, platelet activating factor, and others in response to leukocyte activation has been well characterized, this proinflammatory response is accompanied by activation of antiinflammatory measures designed to counteract the proinflammatory state. This compensatory antiinflammatory response syndrome (CARS) is characterized by the release of antiinflammatory mediators, including IL-10, transforming growth factor-β (TGF-β), and IL-13; production of soluble receptors and receptor antagonists for cytokines such as TNF-α; and reduction of B and T lymphocyte production. Although clearly beneficial in its ability to control the proinflammatory state, excessive stimulation of the compensatory antiinflammatory response may contribute to immunoparalysis and increased susceptibility to nosocomial infections seen in the late stages of sepsis.^5-7

CONSEQUENCES OF SYSTEMIC INFLAMMATION

Disruptions in homeostasis caused by production of proinflammatory mediators include loss of vascular tone, disruption of the endothelial permeability barrier, and stimulation of coagulation (see Chapter 107, Septic Shock). Loss of vascular tone is thought to occur secondary to excessive inducible nitric oxide synthase (iNOS) production, the precursor to nitric oxide release, and possibly a deficiency of vasopressin (a potent vasoconstrictor hormone). Disruption of the endothelial permeability barrier is a direct result of cytokine production.^8,9

A hypercoagulable state, induced by cytokine-mediated tissue factor expression on the surface of leukocytes, leads to fibrin deposition in the microvasculature and is thought to contribute to organ failure in proinflammatory states. Endogenous anticoagulant systems such as antithrombin, protein C, and tissue factor pathway inhibitor are overwhelmed in states of systemic inflammation. Interestingly, studies have supported a close relationship between inflammation and coagulation.^10,11 Thrombin resulting from the activation of coagulation stimulates leukocyte activation and further cytokine production.

TNF-α downregulates the activation of protein C, which is known to have antiinflammatory properties in addition to its role as an anticoagulant. Administration of drotrecogin-α, or recombinant human activated protein C, significantly improved survival in humans with sepsis.¹² Studies suggest, however, that the beneficial effect of protein C may be due to its antiinflammatory effect rather than its anticoagulant properties.¹³

SIRS AND SEPSIS

Although SIRS has been identified as an important component of sepsis, it can occur in the absence of infection, yet have a clinical course resembling that of sepsis. Parameters such as body temperature, heart rate, and respiratory rate are useful to identify systemic inflammation, but they lack sensitivity and specificity for the diagnosis of sepsis. The time required to obtain culture results precludes their usefulness in differentiating nonseptic SIRS from septic SIRS in most clinical situations. This need to differentiate sepsis from SIRS of noninfectious origin has led to the search for biologic markers that would identify the presence (or lack of) bacterial infection in patients with clinical signs of SIRS. C-reactive protein (CRP) and procalcitonin (PCT) have both been studied extensively in humans. Additionally, use of the PIRO (predisposition, insult or infection, response, and organ dysfunction) acronym was adopted following the 2001 Sepsis Definitions conference to more accurately stage sepsis and describe the clinical manifestations of the infection and the host response (see Chapter 106, Sepsis).

MARKERS OF SEPSIS

CRP is an acute phase protein produced by hepatocytes in response to inflammatory cytokine release, including TNF-α and IL-1β. CRP release peaks 36 to 50 hours following secretion and it has a half-life of 19 hours. Although studies support a rise in CRP in humans with sepsis,¹⁴ elevations have also been documented secondary to other inflammatory processes such as trauma, surgery, acute pancreatitis, and myocardial infarction.¹⁵ Some studies have also suggested that CRP levels reflect the severity of the inflammatory process, but these levels have not been shown to differ between survivors and nonsurvivors.¹⁶ Because of the prolonged half-life and lack of specificity, CRP is not considered the ideal marker for the diagnosis of sepsis.

PCT, the precursor molecule to calcitonin, has also been investigated as a potential marker of sepsis. Normally produced by the thyroid gland, PCT during sepsis is thought to originate from mononuclear leukocytes following endotoxin and cytokine stimulation.¹⁷ PCT is released hours after endotoxin release, and peak levels persist for up to 24 hours. Although the exact role of PCT in sepsis is still unknown, it is known to increase iNOS–mediated nitric oxide release and therefore may play a role in amplification of the inflammation.¹⁸

Studies have documented elevated PCT levels in bacterial infections complicated by systemic inflammation and little to no change in PCT in localized infections or in infections of viral etiology. These findings support the use of PCT to differentiate between bacterial sepsis and SIRS of nonbacterial origin in humans.¹⁹ In some studies, PCT levels correlate with disease severity and may have prognostic value for sepsis and septic shock. Overall, PCT is thought to represent a superior marker of sepsis than CRP in humans.