Systemic Inflammatory Response Syndrome (SIRS)

Practice Essentials

Systemic inflammatory response syndrome (SIRS) is a clinical syndrome characterized by a systemic inflammatory response to an infectious or noninfectious trigger. It involves the release of proinflammatory mediators that can cause endothelial damage, microvascular thrombosis, and organ failure. The diagnostic criteria for SIRS include the presence of two or more of the following (see Presentation and Workup)^[1] :

• Body temperature >38°C (100.4°F) or < 36°C (96.8°F)
• Heart rate >90 beats/min
• Respiratory rate >20 breaths/min or arterial carbon dioxide tension (PaCO₂) < 32 mm Hg
• Abnormal white blood cell (WBC) count (>12,000/µL or < 4000/µL or >10% immature [band] forms)

The term Sepsis-2 refers to the definitions and criteria for sepsis and septic shock established by the Second International Consensus Definitions for Sepsis and Septic Shock in 2001.^[2] Sepsis-2 defined sepsis as a suspected or confirmed infection accompanied by two or more SIRS criteria.

In 2016, the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) led a task force to propose a new definition for sepsis: Sepsis-3, defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection."^{[3, 4]} This created a paradigm shift in the sepsis landscape.

The Sequential Organ Failure Assessment (SOFA), a nondiagnostic intensive care unit (ICU) mortality prediction score created in 1998^[5] that was largely not designed to predict mortality like the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Simplified Acute Physiology Score (SAPS), was recommended by the 2016 SCCM/ESICM Task Force, owing to its superior validity for predicting for in-hospital mortality as compared with SIRS.^{[3, 4]} In other words, SOFA was endorsed by the task force for identification of hospitalized patients at risk for death due to sepsis. The SOFA severity score comprises the following system assessments:

• Respiratory system - The ratio of arterial oxygen tension (PaO₂) to fraction of inspired oxygen (FiO₂)
• Cardiovascular system - Mean arterial pressure (MAP) and the need for vasopressors
• Hepatic system - Bilirubin level
• Coagulation system - Platelet count
• Neurologic system - Glasgow Coma Score (GCS)
• Renal system - Serum creatinine or urine output

SOFA as a clinical tool can be accessed here: SOFA Calculator.

Although the definition of Sepsis-3 does not use SIRS criteria for diagnosis, the pathophysiologic processes present in sepsis and noninfectious SIRS are similar (see Pathophysiology and Etiology), making a discussion of SIRS in critical illness appropriate. (See the image below.)

View Image

A Venn diagram of the systemic inflammatory response syndrome (SIRS). The diagram shows the overlap between infection, bacteremia, sepsis, SIRS, and m....

Bacteremia, sepsis, and septic shock

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 bloodstream, 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—though the term is no longer used—meets the aforementioned criteria and is associated with organ dysfunction, hypoperfusion, or hypotension. (See Etiology, Treatment, and Medication.)

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. Multiple organ dysfunction syndrome (MODS) is a state of physiologic derangements in which organ function is not capable of maintaining homeostasis. (See Pathophysiology.)

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Pathophysiology

Regardless of its etiology, SIRS 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^[1] best summarized the relationship between these complex interactions and SIRS, describing it in terms of the following three-stage process.

Stage I

Following an insult, cytokines are produced within immune effector cells de novo at the site. Local cytokine production incites a cellular inflammatory response, thereby promoting wound repair and recruitment of the reticular endothelial system. This process is essential for normal host defense homeostasis, and its absence is not compatible with life. Local inflammation (eg, in the skin and subcutaneous soft tissues) carries the classic description of rubor, tumor, dolor, calor and functio laesa:

• Rubor (redness) - This reflects local vasodilation caused by release of local vasodilating substances such as nitric oxide (NO) and prostacyclin
• Tumor (swelling) - This is due to vascular endothelial tight junction disruption and the local extravasation of protein-rich fluid into the interstitium, which also allows activated WBCs to pass from the vascular space into the tissue space to help clear infection and promote repair
• Dolor (pain) - This represents the impact inflammatory mediators have on local somatosensory nerves; presumably, the pain stops the host from trying to use this part of the body as it tries to repair itself
• Calor (heat) - The increased heat is due primarily to increased blood flow but also to increased local metabolism as WBCs become activated and localize to the injured tissue
• Functio laesa (loss of function) - This is a hallmark of inflammation and a common clinical finding of organ dysfunction when the infection is isolated to a specific organ (eg, pneumonia—acute respiratory failure; kidney—acute kidney injury).

Importantly, on a local level, this cytokine and chemokine release by attracting activated leukocytes to the region may cause local tissue destruction  or cellular injury.

Stage II

Small quantities of local cytokines are released into the circulation, improving 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. At this stage, some minimal malaise and low-grade fever may become manifest.

Stage III

If homeostasis is not restored and if the inflammatory stimuli continue to seed into the systemic circulation, 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.

Multiple-hit theory

Bone also endorsed a multiple-hit theory behind the progression of SIRS to organ dysfunction and possibly to MODS. In this theory, the event that initiates the SIRS cascade primes the pump, and 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 followed by appropriate resuscitation and therapy.

Inflammatory cascade

Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. Initially, a proinflammatory activation occurs, but almost immediately thereafter, a reactive suppressing anti-inflammatory response occurs. This SIRS usually manifests itself as increased systemic expression of both proinflammatory and anti-inflammatory species. 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 (TNF)-α and interleukin (IL)-1 are released first and initiate several cascades.

The release of IL-1 and TNF-α (or the presence of endotoxin or exotoxin) leads to cleavage of the nuclear factor (NF)-κB inhibitor. Once the inhibitor is removed, NF-κB is able to initiate the production of messenger RNA (mRNA), which induces the production other proinflammatory cytokines.

IL-6, IL-8, and interferon gamma are the primary proinflammatory mediators induced by NF-κB. In-vitro research suggests that glucocorticoids may function by inhibiting NF-κB. TNF-α and IL-1 have been shown to be released in large quantities within 1 hour of an insult and to exert both local and systemic effects. In-vitro studies have shown that these two cytokines produce no significant hemodynamic response when given individually but cause severe lung injury and hypotension when given together. TNF-α 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. It is noteworthy that infection has been shown to induce a greater release of TNF-α—and consequently a greater release of IL-6 and IL-8—than trauma does. This is suggested to be the reason why a higher fever is associated with infection as compared with trauma.

The proinflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade and the complement cascade and the release of NO, platelet-activating factor, prostaglandins, and leukotrienes.

High mobility group box 1 (HMGB1) is a protein present in the cytoplasm and nuclei in a majority of cell types. In response to infection or injury, as is seen with SIRS, HMGB1 is secreted by innate immune cells, released passively by damaged cells, or both. Thus, elevated serum and tissue levels of HMGB1 would result from many of the causes of SIRS.

HMGB1 acts as a potent proinflammatory cytokine and is involved in delayed endotoxin lethality and sepsis.^[6] In an observational study of patients with traumatic brain injury, multivariate analysis selected plasma HMGB1 level as an independent predictor for 1-year mortality and unfavorable outcome.^[7] Therapeutic studies are under way to evaluate various mechanisms for blocking HMGB1, with hopes of improving outcomes in SIRS and sepsis syndromes.^[6]

Numerous proinflammatory polypeptides are found within the complement cascade. The protein complements C3a and C5a have been the most studied and are believed 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.

Studies have shown that polymorphonuclear cells (PMNs) from critically ill patients with SIRS are 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, thereby reducing the risk of further host cell injury and death.^[8]

Coagulation

The correlation between inflammation and coagulation is critical for understanding the potential progression of SIRS. IL-1 and TNF-α directly affect endothelial surfaces, leading to the expression of tissue factor (TF). TF initiates the production of thrombin, thereby promoting coagulation, and is a proinflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF-α via production of plasminogen activator inhibitor (PAI)-1. Proinflammatory cytokines also disrupt the naturally occurring anti-inflammatory mediators 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. Procoagulant activity related to infection is generally more severe than that produced by trauma.

SIRS vs CARS

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 the counterinflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF-α, IL-1, IL-6, and IL-8. In fact, this proinflammatory and anti-inflammatory activation mirrors other homeostatic processes, such as coagulation, anticoagulation, complement activation, and complement suppression.

The normal homeostatic processes attempt to keep these highly toxic inflammatory processes in check. Inflammation is an essential component of host defense and serves a strongly positive survival function in suppressing and then eliminating local infection and tissue injury. It is only when this localized aggressive process gains access to the whole body through the bloodstream and lymphatic vessels that SIRS develops.

The acute-phase response also produces antagonists to TNF-α and IL-1 receptors. These antagonists either bind the cytokine, thereby inactivating it, or block the receptors. Comorbidities and other factors can influence a patient's ability to respond appropriately.

The balance between SIRS and CARS helps determine a patient's outcome after an insult. It is possible that because of CARS, medications meant to inhibit the proinflammatory mediators may lead to deleterious immunosuppression.

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Etiology

The etiology of SIRS is broad and includes the following:

• Infectious and noninfectious conditions
• Surgical procedures
• Trauma
• Medications
• Other therapies

The inciting molecular stimuli inducing this generalized inflammatory reaction fall into two broad categories: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs become present when infection of foreign cell lysis releases these foreign molecules intrinsic to their structure into the circulation, whereas DAMPs arise when cellular injury occurs at rates that overwhelm local clearance mechanisms. Thus, it can be seen that generalized bacteremia, severe pneumonia (viral or bacterial), severe trauma with tissue injury, and pancreatitis all share common inflammatory activation pathways.

The following is a partial list of infectious causes of SIRS:

• Bacterial sepsis
• Burn wound infections
• Candidiasis
• Cellulitis
• Cholecystitis
• Community-acquired pneumonia^[9]
• Diabetic foot infection
• Erysipelas
• Infective endocarditis
• Influenza
• Intra-abdominal infections (eg, diverticulitis, appendicitis)
• Gas gangrene
• Meningitis
• Nosocomial pneumonia
• Pseudomembranous colitis
• Pyelonephritis
• Septic arthritis
• Toxic shock syndrome
• Urinary tract infections (male and female)
• Total joint arthroplasty infection^[10]

The following is a partial list of noninfectious causes of SIRS:

• Acute mesenteric ischemia
• Adrenal insufficiency
• Autoimmune disorders
• Burns
• Chemical aspiration
• Cirrhosis
• Cutaneous vasculitis
• Dehydration
• Drug reaction
• Electrical injuries
• Erythema multiforme
• Hemorrhagic shock
• Hematologic malignancy
• Intestinal perforation
• Medication side effect (eg, from theophylline)
• Myocardial infarction
• Pancreatitis^[11]
• Seizure
• Substance abuse - Stimulants such as cocaine and amphetamines
• Surgical procedures
• Toxic epidermal necrolysis
• Transfusion reactions
• Upper gastrointestinal (GI) bleeding
• Vasculitis

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Epidemiology

US and international statistics

The true incidence of SIRS is not known. Not all patients with SIRS require hospitalization or have diseases that progress to serious illness. Indeed, patients with a seasonal head cold due to rhinovirus usually fulfill the criteria for SIRS. Because SIRS criteria are nonspecific and occur in patients who present with conditions ranging from influenza to cardiovascular collapse associated with severe pancreatitis,^[11] any incidence figures would need to be stratified according to SIRS severity.

In a prospective survey of patients admitted to a tertiary care center, Rangel-Fausto et al determined that 68% of hospital admissions to surveyed units met SIRS criteria.^[12] 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.

A hospital survey of SIRS performed by Pittel et al revealed an overall in-hospital incidence of 542 episodes per 1000 hospital days.^[13] In comparison, the incidence in the ICU was 840 episodes per 1000 hospital days. It is not clear what percentage of patients with SIRS have a primary infectious etiology that allows them to be classified as having sepsis. It is most likely, however, that the proportion of SIRS patients varies across patient and hospital groups—for example, being highest in acute care settings and in those with immune deficiency.

The etiology in patients admitted with severe sepsis from a community emergency department (ED) was evaluated by Heffner et al, who determined that 55% of patients had negative cultures and 18% were diagnosed with noninfectious causes that mimicked sepsis (SIRS).^[14] Many of the noninfectious etiologies (eg, pulmonary embolism, myocardial infarction, and pancreatitis) required urgent alternative disease-specific therapy. In the SIRS patients without infection, the clinical characteristics were similar to those in the patients with positive cultures.

Another study demonstrated that 62% of patients who presented to the ED with SIRS had a confirmed infection, whereas 38% did not.^[15] Within the same cohort of patients, 38% of infected patients did not present with SIRS.

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.^[16] The real incidence of SIRS, therefore, must be much higher and likely depends to some degree on the rigor with which the definition is applied.

Internationally, no geography-based differences in the frequency of SIRS have been defined.

Age- and sex-related demographics

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

The sex-based mortality risk of severe SIRS is unknown. Because of the mitigating aspects of estrogen, females tend to have less inflammation from the same degree of proinflammatory stimuli. The reasons are not completely known, but estrogen sustains adrenergic receptor activity in inflammation, when, in its absence, adrenergic receptor downregulation occurs. Thus, premenopausal females tend to have less vasoplegia and to respond more vigorously to resuscitation. This equates to women having a 10-year age benefit over men. Mortality in women with severe sepsis is similar to that in men 10 years younger; however, whether this protective effect applies to women with noninfectious SIRS is unknown.

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Prognosis

Comstedt et al, in a study focusing on SIRS in acutely hospitalized medical patients, found 28-day mortality to be 6.9 times higher in SIRS patients than in non-SIRS patients.^[15] Most deaths occurred in SIRS patients with an associated malignancy.

Prognosis depends on the etiologic source of SIRS, as well as on associated comorbidities. The mortality figures in the previously mentioned study by Rangel-Fausto et al were 7% for SIRS, 16% for sepsis, 20% for severe sepsis, and 46% for septic shock.^[12] The median time interval from SIRS to sepsis was inversely related to the number of SIRS criteria met. Morbidity is related to the causes of SIRS, complications of organ failure, and the potential for prolonged hospitalization.

However, a large retrospective study of Australia and New Zealand ICU care over the period 2000-2012 found a clear progressive decline in severe sepsis and septic shock mortality, from 35% to 18%, with equal trends across all age groups and treatment settings.^[17] These data suggest that attention to detail, using best practices and overall quality care, has nearly halved mortality from severe sepsis, independently of any specific treatment. Thus, attention to overall patient status and use of proven risk reduction approaches (eg, stress ulcer prophylaxis, deep vein thrombosis [DVT] prophylaxis, daily awakening, and weaning trials in ventilator-dependent patients) are central to improving outcomes.

Pittet et al showed that control patients had the shortest hospital stay, whereas patients with SIRS, sepsis, and severe sepsis required progressively longer hospital stays.^[13]

A study by Shapiro et al evaluated mortality in patients with suspected infection in the ED and found the following in-hospital death rates^[18] :

• Suspected infection without SIRS - 2.1%
• Sepsis - 1.3%
• Severe sepsis - 9.2%
• Septic shock - 28%

In this study, 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 was a better predictor of mortality than SIRS criteria were.

Sinning et al evaluated the SIRS criteria in patients who underwent transcatheter aortic valve implantation (TAVI) and found that SIRS appeared to be a strong predictor of mortality.^[19] The occurrence of SIRS was characterized by a significantly elevated release of IL-6 and IL-8, with subsequent increases in the leukocyte count, CRP, and procalcitonin. The occurrence of SIRS was related to 30-day and 1-year mortality (18% vs 1.1% and 52.5% vs 9.9%, respectively) and independently predicted 1-year mortality risk.

In the aforementioned Heffner et al study, in-hospital mortality was lower in SIRS patients without an identified infection than in patients with an infectious etiology for their SIRS (9% vs 15%).^[14]

McConnell et al found that nearly 10% of patients with infections of a total knee or hip arthroplasty developed SIRS that led to increases in duration of hospitalization, ICU admissions, and 2-year reoperation and death rates.^[10]

The reformulated definitions by the 2016 SCCM/EISCM task force specified that (1) sepsis requires organ dysfunction and (2) the concepts of SIRS and severe sepsis are eliminated. Furthermore, the task force recommended SOFA as the tool to assess severity of organ dysfunction in potentially septic patients, on the grounds that SOFA has superior predictive validity for in-hospital mortality as compared with SIRS.^[4]

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Patient Education

Education should ideally target the patient's family. Family members need to understand the fluid nature of immune responsiveness and to realize that SIRS is a potential harbinger of other more dire syndromes.

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History

Systemic inflammatory response syndrome (SIRS) can be caused by numerous triggers, and patients' clinical presentations may vary broadly. The clinician's history should focus on the chief symptom, with a pertinent review of systems being performed. Patients should be questioned regarding constitutional symptoms of fever, chills, and night sweats. This may help differentiate infectious from noninfectious etiologies. The timing of symptom onset may also guide a differential diagnosis toward an infectious, traumatic, ischemic, or inflammatory etiology.

Pain, especially when it can be localized, may guide a physician in differential diagnosis and necessary evaluation. Although providing a differential for pain in the various body parts is beyond the scope of this article, it is important that the physician carefully obtain information on the duration, location, radiation, quality, and exacerbating factors associated with the pain to help establish a thorough differential diagnosis.

In patients for whom a diagnosis cannot be made on the basis of the initial history, a complete review of systems is indicated to try to uncover a potential diagnosis.

The patient's medications should be reviewed. Medication side effects or pharmacologic properties may either induce or mask SIRS (eg, beta blockers prevent tachycardia). Recent changes in medications should be addressed to rule out drug-drug interactions or a new side effect. Allergy information should be gathered, and the specifics of the reaction should be obtained.

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Physical Examination

A focused physical examination based on a patient's symptoms is adequate in most situations. Under certain circumstances, if no obvious etiology is obtained during the history or laboratory evaluation, a complete physical examination may be indicated. Patients who cannot provide any history should also undergo a complete physical examination, including a rectal examination, to rule out an abscess or gastrointestinal (GI) bleeding, among other disorders.

With the exception of white blood cell (WBC) count abnormalities (>12,000/µL or < 4000/µL or >10% immature [band] forms), the criteria for SIRS are based on vital signs, as follows:

• Temperature >38°C (100.4°F) or < 36°C (96.8°F)
• Heart rate >90 beats/min
• Respiratory rate >20 breaths/min or arterial carbon dioxide tension (PaCO₂) < 32 mm Hg

Careful review of initial vital signs is an integral component of the diagnosis. Vital signs must be reassessed periodically during the initial evaluation period because multiple factors (eg, stress, anxiety, or the exertion of walking to the examination room) may lead to a false diagnosis of SIRS.

Patients at the extremes of age (both young and old) may not manifest typical criteria for SIRS; therefore, clinical suspicion may be required to diagnosis a serious illness (either infectious or noninfectious).

Patients receiving drugs that slow the cardiac rhythm may be unable to elevate their heart rate; therefore, tachycardia may not be present.

Although low blood pressure is not a criterion for SIRS, it is still an important marker. If blood pressure is low, establishment of intravenous (IV) access and initiation of fluid resuscitation are of the utmost importance. Frank hypotension associated with SIRS is uncommon unless the patient is septic or severely dehydrated (hypotension may lead to the patient being admitted or transferred to a higher-acuity unit)

Respiratory rate may be the most sensitive marker of the severity of illness.

The clinical examination should also seek to identify whether respiratory failure is imminent (signs of high work of breathing) and whether tissue perfusion is impaired.

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Complications

Complications vary according to the underlying etiology. Potential complications include the following:

• Respiratory failure, acute respiratory distress syndrome (ARDS), and nosocomial pneumonia
• Renal failure
• Stress ulcers
• Superinfection
• GI bleeding and stress gastritis
• Anemia
• Deep vein thrombosis (DVT)
• IV catheter–related bacteremia
• Electrolyte abnormalities
• Hyperglycemia
• Disseminated intravascular coagulation (DIC)

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Approach Considerations

In the workup for suspected systemic inflammatory response syndrome (SIRS), it must be kept in mind that patients at the extremes of age, patients with immunosuppression, and patients with diabetes may present with sepsis or other complications of infection without meeting the criteria for SIRS.

In addition, pregnant patients require intensive evaluation because of the presence of two patients, as well as the propensity of uncontrolled inflammation to lead to preterm labor.

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Laboratory Studies

At a minimum, a complete evaluation for systemic inflammatory response syndrome (SIRS) requires a complete blood count (CBC) with differential to evaluate for leukocytosis or leukopenia. A white blood cell (WBC) count higher than 12,000/µL or lower than 4000/µL or with greater than 10% immature (band) forms on the differential is a criterion for SIRS. An increased percentage of bands is associated with an increased incidence of infectious causes of SIRS.^[20]

Routine screenings often also include a basic metabolic profile. Other laboratory tests should be individualized on the basis of the patient history and the findings from physical examination. measurement of every possible measurable marker of inflammation, injury, and infection in all patients is discouraged. Because infectious SIRS etiologies have a high mortality if not treated effectively, and because effective treatment of infection often requires bacteriologic identification of the inciting organism, bacteriologic cultures should be a priority in the diagnostic workup.

Although one can measure almost anything, tests to consider include the following:

• Blood cultures
• Urinalysis and culture (even in asymptomatic patients)
• Sputum Gram stain and culture (if respiratory symptoms are present)
• Cardiac enzymes
• Amylase
• Lipase
• Cerebrospinal fluid (CSF) analysis
• Liver profiles
• Serum lactate
• Venous or arterial blood gases (for assessment of acid-base status)

Lactate

Lactate levels are often measured in critically ill patients. These are thought to be indicators of anaerobic metabolism associated with tissue dysoxia. Levels are elevated from increased peripheral intraorgan production, reduced hepatic uptake, and reduced renal elimination. Numerous studies have found that lactate levels correlate strongly with mortality.

Procalcitonin

A significant amount of research has evaluated the use of acute-phase reactants to help differentiate infectious from noninfectious causes of SIRS. Several studies have found plasma procalcitonin (PCT) levels to be useful in this regard.^[21]

In an observational prospective study in a pediatric intensive care unit (ICU), Arkader et al showed that PCT levels could be used to differentiate between infectious and noninfectious SIRS, whereas C-reactive protein (CRP) levels could not.^[22] In this study, PCT levels were increased at admission (median, 9.15 ng/mL) in all 14 patients with bacterial sepsis, whereas CRP levels were increased in only 11 of the 14. In addition, PCT levels, but not CRP levels, subsequently decreased in most patients who progressed favorably.

A review of PCT and CRP, as well as interleukin (IL)-6 and protein complement 3a (C3a), by Selberg et al showed that PCT, IL-6, and C3a were more reliable in distinguishing SIRS from sepsis.^[23] Plasma concentrations of PCT, C3a, and IL-6 obtained up to 8 hours after clinical onset of sepsis or SIRS were significantly higher in septic patients; the median PCT was 3.0 ng/ml in patients with SIRS, compared with 16.8 ng/mL in patients with sepsis.

A study by Balci et al confirmed that PCT is a better indicator of early septic complications than CRP is in complex populations, such as patients with multiple trauma.^[24] Hohn et al demonstrated that sepsis protocols using PCT to determine antibiotic utilization in the ICU were associated with decreased duration of antibiotic therapy without compromising patient outcomes.^[25]

Caution must be exercised in interpreting PCT results in elderly patients. Lai et al found that PCT was useful for predicting bacteremia in elderly patients but was not an independent marker for local infections.^[26]  There remains some debate regarding the appropriate cutoff levels at which PCT results should be considered significant.

PCT is increasingly available to physicians as a point-of-care test, though its availability continues to vary from one medical center to another.

Leptin

Leptin, a hormone generated by adipocytes that acts centrally on the hypothalamus to regulate body weight and energy expenditure, is an emerging marker that correlates well with serum IL-6 and tumor necrosis factor (TNF)-α levels. Using a cutoff value of 38 µg/L for serum leptin levels, researchers have been able to differentiate sepsis from noninfectious SIRS with a sensitivity of 91.2% and a specificity of 85%. This test is not yet readily available for clinical practice in the United States.^{[27, 28]}

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Imaging Studies

No specific diagnostic imaging studies exist for SIRS. Selection of imaging studies depends on the infectious or noninfectious cause that necessitated hospital and ICU admission.

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Approach Considerations

Systemic inflammatory response syndrome (SIRS) is a syndrome, not a disease. Accordingly, treatment of SIRS should focus on the underlying condition causing the syndrome. Because the possible causes of SIRS include a wide range of disorders (eg, acute myocardial infarction, community-acquired pneumonia,^[9]  pancreatitis), the appropriate interventions will necessarily differ from patient to patient.^[29]

No drugs of choice exist for SIRS. Medication prescriptions target specific diagnoses, preexisting comorbidities, and prophylaxis regimens for complications. No pharmacologic agents have been demonstrated to improve the outcome of SIRS. (See Medication.)

Insulin therapy^[30] (in patients with hyperglycemia) and steroids^{[31, 32]} should be considered in patients who meet criteria for SIRS.

Early care to treat sepsis is critical in patients suspected of infection and hemodynamic instability.

Studies of tumor necrosis factor (TNF)-α and interleukin (IL)-1 receptor antagonists, antibradykinin, platelet-activating factor (PAF) receptor antagonists, and anticoagulants (antithrombin III) have not shown statistically significant benefits in SIRS. Variable results for sepsis and septic shock have been reported. These medications have no role in treating patients who meet criteria for SIRS only.

Patients who are hypotensive should receive intravenous (IV) fluids. In patients who are still hypotensive after adequate resuscitation, vasopressor agents should be administered while hemodynamic status is carefully monitored. All patients should have adequate IV access; commonly, two large-bore IV lines or a central venous catheter will be required. (For further details on the management of hypotension, see Septic Shock.)

Requirements for patient transfer depend on a facility's capabilities and on the admitting physicians' comfort level with managing different medical conditions. Transfer is also affected by the availabilty of specialists with the relevant expertise.

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Antimicrobial Therapy

Antibiotic therapy

Empiric antibiotics are not indicated for all patients with SIRS. Indications for antibiotic therapy include the following:

• Suspected or diagnosed infectious etiology (eg, urinary tract infection [UTI], pneumonia, or cellulitis)
• Hemodynamic instability
• Neutropenia or other immunocompromised states
• Asplenia (because of the potential for overwhelming postsplenectomy infection [OPSI])

When feasible, culture specimens should always be obtained before antibiotic therapy is initiated. Antibiotics administered prior to culturing may be a cause of sterile sepsis.

Empiric antibiotic therapy should be guided by available practice guidelines and knowledge of the local antibiogram, as well as the patient's risk factors for resistant pathogens and allergies. The key is to stop antibiotics when infection is ruled out or to narrow the antibiotic spectrum once a pathogen is found.

Because of increasing bacterial resistance, broad-spectrum antibiotics should be initiated when an infectious cause for SIRS is a concern but no specific infection is diagnosed. With the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the community, vancomycin or another anti-MRSA therapy should be considered. Recent (typically ≤ 3 mo) exposure to antibiotics must be taken into account in the selection of an empiric regimen because recent antibiotic therapy increases the risk microbial resistance.

Gram-negative coverage with cefepime, piperacillin-tazobactam, a carbapenem (imipenem or meropenem), or a quinolone is reasonable. Care must be taken not to use an antibiotic to which the patient is allergic, which may be a second hit and lead to worsening SIRS; penicillin allergy is a particular concern, given its prevalence. A quinolone or aztreonam is a reasonable choice for gram-negative coverage in patients with a penicillin allergy. If aztreonam is used, gram-positive coverage (with an agent such as vancomycin) should be initiated as well, until culture results are available. (See Medication.)

The antibiotics oritavancin, dalbavancin, and tedizolid are approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections. (See Medication.) These agents are active against Staphylococcus aureus (including both MRSA and methicillin-susceptible S aureus [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (which includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), among others.

Antiviral and antifungal therapy

Antiviral therapy is indicated for patients with SIRS in whom viral infections have been detected. Polymerase chain reaction (PCR)-based testing has become a common form of detecting potential viral infections, especially in the respiratory tract and bloodstream.

Empiric antifungal therapy (eg, with fluconazole or an echinocandin; see Medication) can be considered in patients who have already been treated with antibiotics, patients who are neutropenic, patients who are receiving total parenteral nutrition (TPN), or patients who have central venous access in place. Newer tests of markers of fungal infection have emerged (1,3-beta-D-glucan, T2 candida panel, galactomanna assays) that may improve the diagnosis of clincially significant fungal infections.

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Steroid Therapy

The inflammatory mediators and receptors associated with infectious insults (eg, septic shock) are the same as those associated with noninfectious insults (eg, trauma, inflammatory conditions, and ischemia). Steroids for sepsis and septic shock have been extensively studied, but no investigations specific to SIRS have been performed to date.

The initial research in sepsis and septic shock showed a trend toward worse outcomes for high-dose steroid therapy (methylprednisolone sodium succinate 30 mg/kg q6hr for 4 doses) as compared with placebo. However, research into low-dose steroid therapy (hydrocortisone 200-300 mg for 5-7 d) showed improved survival and the reversal of shock in vasopressor-dependent patients. 

A meta-analysis of 45 random controlled trials concluded that corticosteroids likely reduce short-term mortality and increase shock reversal at 7 days, but that the use of corticosteroids also increases the risk of hyperglycemia and hypernatremia and may increase the risk of neuromuscular weakness.^[33] The analysis found that the optimal regimen for reducing mortality was hydrocortisone at approximately 260 mg/day.

Current guidelines have recommended low-dose steroids for patients with septic shock.^[31] Before initiating steroid therapy, however, physicians must consider the potential risks associated with steroid use, including stress ulcers and hyperglycemia.^[34]  Increasing evidence has suggested that adding fludrocortisone to hydrocortisone may be beneficial for septic shock patients.^[32]

Similarly, in critically ill vasoplegic patients (ie, patients who remain hypotensive despite fluid resuscitation and vasopressor therapy), the use of vasopressin (0.01-0.02 μg/kg/h) may be beneficial in decreasing vasopressor requirements without causing more ischemia. Its effects on mortality have not been proved.

The available data do not support using adrenocorticotropic hormone (ACTH) stimulation testing to determine which patients should receive steroid therapy. Patients receiving steroids require careful monitoring for hyperglycemia.

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Glucose Control

Hyperglycemia, a common laboratory finding in SIRS patients, even those who do not have diabetes, has numerous deleterious systemic effects.^{[35, 36]}

An increase in counterregulatory hormones—namely, cortisol and epinephrine—and relative hypoinsulinemia lead to increased hepatic glucose production, increased peripheral insulin resistance, and increased circulating free fatty acids. This has a direct inhibitory action on the immune system. Oxidative stress and endothelial cell dysfunction, along with proinflammatory cytokines (eg, IL-6, IL-8, and TNF-α) and other secondary mediators (eg, nuclear factor [NF]-κB) have all been implicated as causes of cellular injury, tissue damage, and organ dysfunction in patients with hyperglycemia.

Control of blood glucose levels has been shown to diminish in-hospital morbidity and mortality in the surgical and medical intensive care settings. Various trials have demonstrated that glycemic control with insulin improves patient outcomes (including renal function and acute renal failure), reduces the need for red blood cell (RBC) transfusions, reduces the number of days in the ICU, lowers the incidence of critical-illness polyneuropathy, and decreases the need for prolonged mechanical ventilation.

Van den Berghe et al reported a reduction of in-hospital mortality with intensive insulin therapy (maintenance of blood glucose at 80-110 mg/dL) by 34%.^[30] The greatest reduction in mortality involved deaths due to multiple organ failure with a proven septic focus. Subsequent studies by this group and others have failed to demonstrate distinct outcome benefit from such tight glucose control, mainly because the complication rates for hypoglycemia and hypokalemia obscure its effects.

The 2021 guidelines from the Surviving Sepsis Campaign recommended keeping glucose levels between 140 and 180 mg/dL.^[29]

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Supplemental Oxygen

Supplemental oxygen should be provided to any patient who demonstrates an increased oxygen requirement or decreased oxygen availability. Oxygen can usually be provided via nasal cannula or mask, though in certain situations, ventilator support may be required to maximize oxygen delivery.

Supplying supraphysiologic oxygen has shown mixed results in a multitude of studies. Providing too much oxygen to a patient with severe chronic obstructive pulmonary disease (COPD) should be avoided, because it can depress the respiratory drive.

Patients who do not respond to increased oxygen supply have a poor prognosis. Patients with associated respiratory failure who require mechanical ventilation should be treated with low–tidal volume mechanical ventilation (6 mL/kg).

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Surgical Care

The details of surgical management in the setting of SIRS are site-specific and are beyond the scope of this article. In general, however, abscesses or drainable foci of infection should be drained expeditiously to increase the efficacy of antibiotic therapy and to allow for adequate culture data. Patients with an acute surgical issue (eg, ruptured appendix or cholecystitis) that causes SIRS should be treated with appropriate surgical measures. Prosthetic devices should be removed in a timely manner, when clinically feasible.

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Diet

Enteral feedings supplemented with arginine and omega-3 fatty acids have been shown to be beneficial for critically ill patients, leading to decreases in infectious complications, length of hospitalization, and duration of mechanical ventilation. The ability to feed a patient and the route of nutrition vary according to the etiology of SIRS.

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Activity

Because of the causative illness, many patients are bed-bound. Accordingly, deep venous thrombosis (DVT) and gastrointestinal (GI) stress ulcer prophylaxis should be considered to help prevent complications. Patients who are otherwise clinically stable and have no contraindications for mobility should be permitted to perform activities as tolerated.

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Consultations

Consideration of consultations varies, depending on the admitting physician's training and on the cause of SIRS. For example, a cardiology consultation may be warranted for acute myocardial infarction or a gastroenterology consultation for acute GI bleeding. Patients with potential surgical issues should undergo a surgical evaluation, often in the emergency department, early in the course of their illness.

Consultation with an intensivist, if one is available, should be considered. If organ dysfunction develops, the intensivist or a consultant who specializes in that organ system should be involved.

Early consultation with an expert in infectious diseases is particularly helpful for patients who are immunocompromised, regardless of the cause (eg, HIV infection, AIDS, malignancy, or solid-organ transplantation). This specialist can also provide guidance in situations where patients are unresponsive to standard antibiotic therapy, have multiple drug allergies, are infected with multidrug-resistant organisms, or have not yet received a definite diagnosis.

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Imipenem/cilastatin (Primaxin)

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Meropenem (Merrem IV)

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Cefepime (Maxipime)

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Vancomycin (Firvanq, Vancocin)

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Oritavancin (Kimyrsa, Orbactiv)

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Dalbavancin (Dalvance)

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Levofloxacin (Levaquin, Levofloxacin Systemic)

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Piperacillin/tazobactam (Zosyn)

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Tedizolid (Sivextro)

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Aztreonam (Azactam)

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Fluconazole (Diflucan)

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Caspofungin (Cancidas)

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Hydrocortisone (AHydrocort (DSC), Alkindi Sprinkle, Alphosyl (DSC))

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Fludrocortisone (Florinef, Florinef Acetate)

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Insulin regular human (Humulin R, Humulin R U-500, Novolin R)

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