Systemic Inflammatory Response Syndrome 

In 1992, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) introduced definitions for systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS).^[1] The idea behind defining SIRS was to define a clinical response to a nonspecific insult of either infectious or noninfectious origin. SIRS is defined as 2 or more of the following variables:

• Fever of more than 38°C or less than 36°C
• Heart rate of more than 90 beats per minute
• Respiratory rate of more than 20 breaths per minute or a PaCO2 level of less than 32 mm Hg
• Abnormal white blood cell count (>12,000/µL or < 4,000/µL or >10% bands)

SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or a combination of several insults. SIRS is not always related to infection. Infection is defined as "a microbial phenomenon characterized by an inflammatory response to the microorganisms or the invasion of normally sterile tissue by those organisms."

Bacteremia is the presence of bacteria within the blood stream, but this condition does not always lead to SIRS or sepsis. Sepsis is the systemic response to infection and is defined as the presence of SIRS in addition to a documented or presumed infection. Severe sepsis meets the aforementioned criteria and is associated with organ dysfunction, hypoperfusion, or hypotension. Sepsis-induced hypotension is defined as "the presence of a systolic blood pressure of less than 90 mm Hg or a reduction of more than 40 mm Hg from baseline in the absence of other causes of hypotension." Patients meet the criteria for septic shock if they have persistent hypotension and perfusion abnormalities despite adequate fluid resuscitation. MODS is a state of physiological derangements in which organ function is not capable of maintaining homeostasis.

Although not universally accepted terminology, severe SIRS and SIRS shock are terms that some authors have proposed. These terms suggest organ dysfunction or refractory hypotension related to an ischemic or inflammatory process rather than to an infectious etiology.

Systemic inflammatory response syndrome (SIRS), independent of the etiology, has the same pathophysiologic properties, with minor differences in inciting cascades. Many consider the syndrome a self-defense mechanism. Inflammation is the body's response to nonspecific insults that arise from chemical, traumatic, or infectious stimuli. The inflammatory cascade is a complex process that involves humoral and cellular responses, complement, and cytokine cascades. Bone best summarized the relationship between these complex interactions and SIRS as the following 3-stage process:

• Stage I: Following an insult, local cytokine is produced with the goal of inciting an inflammatory response, thereby promoting wound repair and recruitment of the reticular endothelial system.
• Stage II: Small quantities of local cytokines are released into circulation to improve the local response. This leads to growth factor stimulation and the recruitment of macrophages and platelets. This acute phase response is typically well controlled by a decrease in the proinflammatory mediators and by the release of endogenous antagonists. The goal is homeostasis.
• Stage III: If homeostasis is not restored, a significant systemic reaction occurs. The cytokine release leads to destruction rather than protection. A consequence of this is the activation of numerous humoral cascades and the activation of the reticular endothelial system and subsequent loss of circulatory integrity. This leads to end-organ dysfunction.

Bone also endorsed a multihit theory behind the progression of SIRS to organ dysfunction and possibly MODS. In this theory, the event that initiates the SIRS cascade primes the pump. With each additional event, an altered or exaggerated response occurs, leading to progressive illness. The key to preventing the multiple hits is adequate identification of the cause of SIRS and appropriate resuscitation and therapy.

Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells are able to produce a multitude of cytokines. The cytokines tissue necrosis factor-a (TNF-a) and interleukin (IL)–1 are released first and initiate several cascades. The release of IL-1 and TNF-a (or the presence of endotoxin or exotoxin) leads to cleavage of the nuclear factor-kB (NF-kB) inhibitor. Once the inhibitor is removed, NF-kB is able to initiate the production of mRNA, which induces the production other proinflammatory cytokines.

IL-6, IL-8, and interferon gamma are the primary proinflammatory mediators induced by NF-kB. In vitro research suggests that glucocorticoids may function by inhibiting NF-kB. TNF-a and IL-1 have been shown to be released in large quantities within 1 hour of an insult and have both local and systemic effects. In vitro studies have shown that these 2 cytokines given individually produce no significant hemodynamic response but cause severe lung injury and hypotension when given together. TNF-a and IL-1 are responsible for fever and the release of stress hormones (norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system).

Other cytokines, especially IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP) and procalcitonin. Of note, infection has been shown to induce a greater release of TNF-a than trauma, which induces a greater release of IL-6 and IL-8. This is suggested to be the reason higher fever is associated with infection rather than trauma.

The proinflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade, complement cascade, and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes. Numerous proinflammatory polypeptides are found within the complement cascade. Protein complements C3a and C5a have been the most studied and are felt to contribute directly to the release of additional cytokines and to cause vasodilatation and increasing vascular permeability. Prostaglandins and leukotrienes incite endothelial damage, leading to multiorgan failure.

Polymorphonuclear cells (PMNs) from critically ill patients with SIRS have been shown to be more resistant to activation than PMNs from healthy donors, but, when stimulated, demonstrate an exaggerated microbicidal response. This may represent an autoprotective mechanism in which the PMNs in the already inflamed host may avoid excessive inflammation, thus reducing the risk of further host cell injury and death.^[2]

The correlation between inflammation and coagulation is critical to understanding the potential progression of SIRS. IL-1 and TNF-a directly affect endothelial surfaces, leading to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby promoting coagulation, and is a proinflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF-a via production of plasminogen activator inhibitor-1. Proinflammatory cytokines also disrupt the naturally occurring anti-inflammatory mediator's antithrombin and activated protein-C (APC). If unchecked, this coagulation cascade leads to complications of microvascular thrombosis, including organ dysfunction. The complement system also plays a role in the coagulation cascade. Infection-related procoagulant activity is generally more severe than that produced by trauma.

The cumulative effect of this inflammatory cascade is an unbalanced state with inflammation and coagulation dominating. To counteract the acute inflammatory response, the body is equipped to reverse this process via counter inflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF-a, IL-1, IL-6, and IL-8. The acute phase response also produces antagonists to TNF-a and IL-1 receptors. These antagonists either bind the cytokine, and thereby inactivate it, or block the receptors. Comorbidities and other factors can influence a patient's ability to respond appropriately. The balance of SIRS and CARS determines a patient's prognosis after an insult. Some researchers believe that, because of CARS, many of the new medications meant to inhibit the proinflammatory mediators may lead to deleterious immunosuppression.

Frequency

United States

The true incidence of systemic inflammatory response syndrome (SIRS) is unknown. However, because SIRS criteria are nonspecific and occur in patients who present with conditions that range from influenza to cardiovascular collapse associated with severe pancreatitis, such incidence figures would need to be stratified based on SIRS severity.

Rangel-Fausto et al published a prospective survey of patients admitted to a tertiary care center that revealed 68% of hospital admissions to surveyed units met SIRS criteria.^[3] The incidence of SIRS increased as the level of unit acuity increased. The following progression of patients with SIRS was noted: 26% developed sepsis, 18% developed severe sepsis, and 4% developed septic shock within 28 days of admission.

Pittet et al performed a hospital survey of SIRS that revealed an overall in-hospital incidence of 542 episodes per 1000 hospital days.^[4] In comparison, the incidence in the ICU was 840 episodes per 1000 hospital days.

The etiology of patients admitted with severe sepsis from a community emergency department was recently evaluated by Heffner et al. Fifty-five percent of patients had negative cultures, while 18% were diagnosed with noninfectious causes that mimicked sepsis (SIRS). Many of the noninfectious etiologies required urgent alternate disease specific therapy (eg, pulmonary embolism, myocardial infarction, pancreatitis). Of the SIRS patients without infection, the clinical characteristics were similar to those with positive cultures.^[5] Another cohort of patients demonstrated that 62% of patients who presented to the emergency department with SIRS had a confirmed infection, while 38% did not. Within the same cohort of patients, 38% of infected patients did not present with SIRS.^[6]

Still, Angus et al found the incidence of severe SIRS associated with infection to be 3 cases per 1,000 population, or 2.26 cases per 100 hospital discharges.^[7] The real incidence of SIRS, therefore, must be much higher and likely depends somewhat on the rigor with which the definition is applied.

International

No difference in frequency exists based on world geography.

Mortality/Morbidity

The mortality rates in the previously mentioned Rangel-Fausto study were 7% (SIRS), 16% (sepsis), 20% (severe sepsis), and 46% (septic shock).^[3] The medial time interval from SIRS to sepsis was inversely related to the number of SIRS criteria (2, 3, or all 4) met. Morbidity is related to the causes of SIRS, complications of organ failure, and the potential for prolonged hospitalization. Pittet et al showed that control patients had the shortest hospital stay, while patients with SIRS, sepsis, and severe sepsis, respectively, required progressively longer hospital stays.^[4]

A study by Shapiro et al evaluated mortality in patients with suspected infection in the emergency department.^[8] The in-hospital mortality rates were as follows: 2.1% had a suspected infection without SIRS, 1.3% had sepsis, 9.2% had severe sepsis, and 28% had septic shock. The presence of SIRS criteria alone had no prognostic value for either in-hospital mortality or 1-year mortality. Each additional organ dysfunction increased the risk of mortality at 1 year. The authors concluded that organ dysfunction, rather than SIRS criteria, was a better predictor of mortality.

Patients without an identified infection, according to the Heffner study, had a lower hospital mortality rate than those with an infectious etiology for their SIRS (9% v 15%; p=0.03).^[5] Comstedt et al, in a study of SIRS in acutely hospitalized medical patients, demonstrated a 6.9 times higher 28-day mortality in SIRS patients as compared with non-SIRS patients. Most deaths occurred in SIRS patients with an associated malignancy.^[6]

Race

No racial predilection exists for this disease entity.

Sex

Using the same logic as expressed in Frequency, the sex-based mortality risk of severe SIRS is also unknown. Females tend to have less inflammation for the same degree of proinflammatory stimuli because of the mitigating aspects of estrogen. The mortality rate among women with severe sepsis is similar to that of men who are 10 years younger; however, whether this protective effect applies to women with noninfectious SIRS is unknown.

Age

Extremes of age (young and old) and concomitant comorbidities probably negatively affect the outcome of SIRS. Young people may be able to mount a more exuberant inflammatory response to a challenge than older people and yet may be able to better modify the inflammatory state (via CARS). Young people have better outcomes of equivalent diagnoses.