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 (see Presentation and Workup):

SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or several insults combined. Thus, SIRS is not always related to infection. Although sepsis has diverged from SIRS criteria for diagnosis and management in recent years, focusing more on infectious etiologies, the pathophysiologic processes present in sepsis and noninfectious SIRS are remarkably similar, making a discussion of SIRS in critical illness appropriate.(See Pathophysiology and Etiology.)

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Venn diagram showing overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

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

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.


Complications vary based on underlying etiology. Routine prophylaxis, including deep vein thrombosis (DVT) and stress ulcer prophylaxis, should be initiated when clinically indicated in severely ill bed-ridden patients, especially if they require mechanical ventilation. Long-term antibiotics, when clinically indicated, should be as narrow spectrum as possible to limit the potential for superinfection (suggested by a new fever, a change in the white blood cell [WBC] count, or clinical deterioration). Unnecessary vascular catheters and Foley catheters should be removed as soon as possible. (See Prognosis, Treatment, and Medication.)

Potential complications include the following:


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[1] best summarized the relationship between these complex interactions and SIRS as the following 3-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 if absent is not compatible with life. Local inflammation, such as in the skin and subcutaneous soft tissues, carries the classic description of rubor, tumor, dolor, calor and functio laesa.

Rubor or redness reflects local vasodilation caused by release of local vasodilating substances like nitric oxide (NO) and prostacyclin.

Tumor or swelling is due to vascular endothelial tight junction disruption and the local extravasation of protein-rich fluid into the interstitium, which also allows activated white blood cells to pass from the vascular space into the tissue space to help clear infection and promote repair.

Dolor is pain and represents the impact inflammatory mediators have on local somatosensory nerves. Presumably, this pain stops the host from trying to use this part of his or her body as it tries to repair itself.

Calor is the increased heat primarily due to increased blood flow but also increased local metabolism as white blood cells become activated and localize to the injured tissue.

Finally, functio laesa is loss of function, a hallmark of inflammation and a common clinical finding of organ dysfunction with 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 (eg, abscess) or cellular injury (eg, pus), which appear to be the necessary byproducts of an effective local inflammatory response.

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.

Multi-hit theory

Bone also endorsed a multi-hit theory behind the progression of SIRS to organ dysfunction and possibly multiple organ dysfunction syndrome (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.

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–alpha (TNF-α) and interleukin-1 (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-kB (NF-kB) inhibitor. Once the inhibitor is removed, NF-kB is able to initiate the production of messenger ribonucleic acid (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-α 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 that they 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. Of note, infection has been shown to induce a greater release of TNF-α —thus inducing a greater release of IL-6 and IL-8—than trauma does. 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 and the complement cascade and the release of nitric oxide, 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 and/or released passively by damaged cells. 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.[2] 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.[3] Therapeutic studies are under way to evaluate various mechanisms to block HMGB1, with hopes of improving outcomes in SIRS and sepsis syndromes.[2]

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.[4]


The correlation between inflammation and coagulation is critical to understanding the potential progression of SIRS. IL-1 and TNF-α 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-α via production of plasminogen activator inhibitor-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. Infection-related procoagulant activity is generally more severe than that produced by trauma.

SIRS versus 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 counter-inflammatory 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, like coagulation, anticoagulation, complement activation, and complement suppression.

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

The acute phase response also produces antagonists to TNF-α 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 helps determine a patient's outcome 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.


The etiology of systemic inflammatory response syndrome (SIRS) is broad and includes infectious and noninfectious conditions, surgical procedures, trauma, medications, and therapies. The inciting molecular stimuli inducing the above 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 partial list of the infectious causes of SIRS:

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


Occurrence in the United States

The true incidence of systemic inflammatory response syndrome (SIRS) is unknown but probably very high, owing to the nonspecific nature of its definition. 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,[6] any 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.[7] 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.[8] In comparison, the incidence in the intensive care unit (ICU) was 840 episodes per 1000 hospital days. It is not clear what percentage of patients with SIRS have a primary infectious etiology, allowing them to be classified as having sepsis. However, most likely the proportion of SIRS patients varies across patient and hospital groups, being highest for example in acute care settings and in those with immune deficiency.

The etiology of patients admitted with severe sepsis from a community emergency department was evaluated by Heffner et al, who determined that 55% of patients had negative cultures and that 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.[9]

Another study 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.[10]

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.[11] The real incidence of SIRS, therefore, must be much higher and likely depends somewhat on the rigor with which the definition is applied.

International occurrence

No difference in the frequency of SIRS exists based on world geography.

Sex-related demographics

The sex-based mortality risk of severe SIRS is unknown. Females tend to have less inflammation from the same degree of proinflammatory stimuli because of the mitigating aspects of estrogen. The reasons for this are not completely known, but estrogen sustains adrenergic receptor activity in inflammation, when, in its absence, adrenergic receptor down-regulation occurs. Thus, premenopausal females tend to have less vasoplegia and respond more vigorously to resuscitation efforts. This equates to women having a 10-year age benefit over men. 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-related demographics

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 the counter-inflammatory response syndrome [CARS]). Young people have better outcomes for equivalent diagnoses.


Comstedt et al, in a study of systemic inflammatory response syndrome (SIRS) in acutely hospitalized medical patients, demonstrated a 6.9 times higher 28-day mortality in SIRS patients than in non-SIRS patients. Most deaths occurred in SIRS patients with an associated malignancy.[10]

Prognosis depends on the etiologic source of SIRS, as well as on associated comorbidities. The mortality rates in the previously mentioned Rangel-Fausto et al study were 7% (SIRS), 16% (sepsis), 20% (severe sepsis), and 46% (septic shock).[7] 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, the large retrospective study of all of Australia and New Zealand ICU care from 2000-2012 demonstrated a clear progressive decline in severe sepsis and septic shock mortality from 35% to 18% over this period, with equal trends across all age groups and treatment settings.[12] These data suggest that attention to detail, using best practices and overall quality care, has nearly halved mortality from severe sepsis independent of any specific treatment. Thus, attention to overall patient status and use of proven risk reduction approaches (eg, stress ulcer prophylaxis, DVT prophylaxis, daily awakening, and weaning trials in ventilator-dependent patients) are central to improving outcome from severe sepsis.

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.[8]

A study by Shapiro et al evaluated mortality in patients with suspected infection in the emergency department and found the following in-hospital mortality rates[13] :

In the 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, rather than SIRS criteria, was a better predictor of mortality.

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. The occurrence of SIRS was characterized by a significantly elevated release of IL-6 and IL-8, with subsequent increase in the leukocyte count, C-reactive protein (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.[14]

In the aforementioned Heffner et al study, patients without an identified infection had a lower hospital mortality rate than did patients with an infectious etiology for their SIRS (9% vs 15%, respectively).[9]

Patient Education

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


Despite having a relatively common physiologic pathway, systemic inflammatory response syndrome (SIRS) has numerous triggers, and patients may present in various manners. The clinician's history should be focused around 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 to 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, a physician should 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.

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 bleeding.

With the exception of white blood cell count abnormalities (>12,000/µL or < 4,000/µL or >10% immature [band] forms), the criteria for SIRS are based on vital signs, as follows:

Careful review of initial vital signs is an integral component of the diagnosis. Reassessing the vital signs periodically during the initial evaluation period is necessary, as multiple factors (eg, stress, anxiety, exertion of walking to the examination room) may lead to a false diagnosis of SIRS.

Key points associated with physical examination are as follows:

Approach Considerations

At minimum, a complete evaluation for systemic inflammatory response syndrome (SIRS) requires a complete blood cell (CBC) count with differential, to evaluate for leukocytosis or leukopenia. A white blood cell count of greater than 12,000/µL or less than 4,000/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.[15]

Routine screenings often also include a basic metabolic profile. Other laboratory tests should be individualized based on patient history and physical examination findings. Measuring every possible measurable marker of inflammation, injury, and infection in all patients is discouraged. Since infectious SIRS etiologies have a high mortality if not treated effectively, and since effective treatment for infection often requires bacteriologic identification of the inciting organism, priority for bacteriological cultures in the diagnostic workup needs to be stressed.  Although one can measure almost anything, tests to consider include the following:

Interleukin 6

Patients who meet SIRS criteria and have increased interleukin 6 (IL-6) levels (>300 pg/mL) have been shown to be at increased risk for complications such as pneumonia, multiple organ dysfunction syndrome (MODS), and death.[16] In addition, a decrease in IL-6 by the second day of antibiotic treatment has been shown to be a marker of effectiveness of therapy and a positive prognostic sign in those patients with an infectious etiology for their SIRS.[17]


Blood lactate levels are often measured in critically ill patients. These are thought to be indicators of anaerobic metabolism associated with tissue dysoxia. Although a reasonable presumption in patients presenting in circulatory shock and trauma, in septic patients they reflect more the inflammatory burden rather than level of tissue hypoperfusion and, as such, usually do not decrease, if elevated, in response to fluid resuscitation. Levels are commonly elevated from increased peripheral intraorgan production, reduced hepatic uptake, and reduced renal elimination. Numerous studies have found that lactate levels correlate strongly with mortality.

Imaging studies

No diagnostic imaging studies exist for SIRS. The selection of imaging studies depends on the etiology that required hospital and intensive care unit (ICU) admission.

Special concerns

Patients at the extremes of age, patients with immunosuppression, and patients with diabetes may present with sepsis or other complications of infection without meeting SIRS criteria.

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.


A significant amount of research has evaluated the use of acute-phase reactants to help differentiate infectious from noninfectious causes of systemic inflammatory response syndrome (SIRS). Several studies have found plasma procalcitonin (PCT) levels to be useful in this regard.[18]

In an observational, prospective study in a pediatric ICU, Arkader et al showed that PCT levels could be used to differentiate between infectious and noninfectious SIRS, while C-reactive protein (CRP) levels could not. 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.[19]

A review of PCT and CRP, as well as 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. 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, versus 16.8 ng/mL in patients with sepsis.[20]

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.[21] Hohn et al recently demonstrated, in the ICU, that sepsis protocols using PCT to determine antibiotic utilization was associated with decreased duration of antibiotic therapy without compromising patient outcomes.[22]

Caution must be used in interpreting PCT results in elderly patients. Lai et al demonstrated that PCT is useful in predicting bacteremia in elderly patients but was not an independent marker for local infections.[23] There is also current debate regarding appropriate cut-off levels for PCT at which they are significant.

PCT is becoming increasingly available to physicians as a point-of-care test. Currently, availability of this assay will vary by medical center.


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–alpha (TNF-α ) levels. Using serum leptin levels with a cutoff of 38 µg/L, 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.[24, 25]

Approach Considerations

SIRS is a syndrome, not a disease. Treatment of SIRS should focus on possible inciting causes. As the causes of SIRS include a wide range of disorders (eg, acute myocardial infarction, community-acquired pneumonia,[5] pancreatitis), the appropriate interventions will likewise differ from patient to patient.

Studies of tumor necrosis factor–alpha (TNF-α) and interleukin 1 (IL-1) receptor antagonists, antibradykinin, platelet-activating factor 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 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 intravenous access and commonly require 2 large-bore intravenous lines or a central venous catheter. For further details on the management of hypotension, please refer to Septic Shock.


The details of surgical management 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 acute surgical issues (eg, ruptured appendix, cholecystitis) that cause SIRS should be treated with appropriate surgical measures. Prosthetic devices should be removed in a timely manner, when clinically feasible.


Enteral feedings supplemented with arginine and omega-3 fatty acids have been shown to be beneficial (decreased infectious complications, hospital days, and duration of mechanical ventilation) in critically ill patients. The ability to feed a patient and the route of nutrition vary based on the etiology of SIRS.


Because of the causative illness, many patients are bed bound. Therefore, deep venous thrombosis (DVT) and gastrointestinal stress ulcer prophylaxis should be considered to help prevent complications. Patients who are otherwise clinically stable and without contraindications to mobility should be permitted to perform activities as tolerated.


Requirements for patient transfer depend on a facility's capabilities and the comfort level of the admitting physicians for managing different medical conditions. The availability of specialists also affects transfer.

Antimicrobial Therapy

Antibiotic therapy

Empiric antibiotics are not indicated for all patients with systemic inflammatory response syndrome (SIRS). Indications for antibiotic therapy include the following:

When feasible, culture specimens should always be obtained prior to initiating antibiotic therapy. 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 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 exposure to antibiotics (typically within 3 months) must be considered when choosing empiric regimens, because recent antibiotic therapy increases the risk for resistant pathogens.

Gram-negative coverage with cefepime, piperacillin-tazobactam, carbapenem (imipenem, meropenem, or doripenem), 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.

Three FDA-approved antibiotics, oritavancin (Orbactiv), dalbavancin (Dalvance), and tedizolid (Sivextro), can be used for the treatment of acute bacterial skin and skin structure infections. These agents are active against Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MSSA, MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), among others.

For complete drug information, including dosing, see the following monographs:

Antiviral and antifungal therapy

Antiviral therapy has no role in SIRS unless the patient is immunocompromised or presents for evaluation during influenza season and the clinical picture is consistent with influenza infection.

Empiric antifungal therapy (fluconazole or an echinocandin) 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.


The inflammatory mediators and receptors associated with infectious insults (ie, septic shock) are the same as those linked to noninfectious insults (ie, trauma, inflammatory conditions, ischemia).

Steroids for sepsis and septic shock have been extensively studied, but no investigations specific to systemic inflammatory response syndrome (SIRS) have been performed to date.

The initial research in sepsis and septic shock showed a trend toward worse outcomes when treating with high doses of steroids (methylprednisolone sodium succinate 30 mg/kg every 6 h for 4 doses) compared with placebo. However, research into low-dose steroids (200-300 mg of hydrocortisone for 5-7 days) improved survival and the reversal of shock in vasopressor-dependent patients.

Low-dose steroids should be considered on an individual basis for patients with refractory hypotension (ie, septic shock) despite adequate fluid resuscitation and appropriate vasopressor administration.[26] Prior to initiating steroid therapy, however, physicians must consider the potential risks of steroids, such as stress ulcers and hyperglycemia.[27]

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

Current 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.

Glucose Control

Hyperglycemia, a common laboratory finding in systemic inflammatory response syndrome (SIRS), even in individuals without diabetes, has numerous deleterious systemic effects.[28, 29]

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 direct inhibitory action on the immune system. Oxidative stress and endothelial cell dysfunction, along with proinflammatory cytokines (IL-6, IL-8, TNF-α) and other secondary mediators (NF-kB) have all been implicated as causes of cellular injury, tissue damage, and organ dysfunction in patients with hyperglycemia.

Intensive control of blood glucose levels has been shown to diminish in-hospital morbidity and mortality in the surgical and medical intensive care setting. 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 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 rates 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 rate for hypoglycemia and hypokalemia complicate its effects. Presently, the Surviving Sepsis guidelines recommend keeping glucose levels at less than 180 mg/dL.[26]

Supplemental Oxygen

Supplemental oxygen should be provided to any patient who demonstrates an increased oxygen requirement or decreased oxygen availability. Oxygen can be provided via nasal cannula or mask, although 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 in 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).


Consultations vary depending on the admitting physician's training and the cause of systemic inflammatory response syndrome (SIRS); for example, cardiology consultation for acute myocardial infarction or gastroenterology 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.

Consider consultation with an intensivist, if one is available. If organ dysfunction develops, the intensivist or a consultant specialist 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, human immunodeficiency virus [HIV] infection, acquired immunodeficiency syndrome [AIDS], malignancy, solid organ transplantation). This specialist can also provide guidance in situations in which patients are not responding to standard antibiotic therapy, have multiple drug allergies, or are infected with multidrug-resistant organisms or when a diagnosis is still uncertain.

Medication Summary

No drugs of choice exist for systemic inflammatory response syndrome (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.

Because of increasing bacterial resistance, when an infectious cause for SIRS is a concern but no specific infection has been diagnosed, broad-spectrum antibiotics should be administered. Therapy for methicillin-resistant Staphylococcus aureus (MRSA) should be considered, owing to the rising prevalence of MRSA in the community.

Insulin therapy (in patients with hyperglycemia) and steroids should also be considered in patients who meet criteria for SIRS.

Cefepime (Maxipime)

Clinical Context:  Cefepime, a fourth-generation cephalosporin, is used for the treatment of Pseudomonas infections. Its gram-negative coverage is comparable to that of ceftazidime, and cefepime has better gram-positive coverage. Cefepime is a zwitter ion that rapidly penetrates gram-negative cells. It is the best beta-lactam antibiotic for intramuscular (IM) administration. Cefepime's poor capacity to cross the blood-brain barrier precludes the drug's use for meningitis treatment.


Clinical Context:  Vancomycin is used to treat enterococcal infections when ampicillin is contraindicated because of significant penicillin allergy and when strains are resistant to ampicillin but susceptible to vancomycin. Target levels of 30-50 µg/mL (peak) and 10-15 µg/mL (trough) for endocarditis and other serious infections. Patients with SIRS often require increased dosages to achieve target concentrations, especially patients with higher creatinine clearances.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin, a second-generation quinolone, acts by interfering with deoxyribonucleic acid (DNA) gyrase in bacterial cells. A bactericidal drug, levofloxacin is highly active against gram-negative and gram-positive organisms, including Pseudomonas aeruginosa.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. The 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 narrow the antibiotic spectrum once a pathogen is found.

Hydrocortisone sodium succinate or phosphate (Cortef, Solu-Cortef)

Clinical Context:  This is the drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. It has glucocorticoid and mineralocorticoid properties. The biologic half-life is 8-12 hours. The easiest way to set up an infusion is to have the pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9% saline.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune system to diverse stimuli. The initial research in sepsis and septic shock showed a trend toward worse outcomes when treating with high doses of steroids (methylprednisolone sodium succinate 30 mg/kg every 6 h for 4 doses) compared with placebo. However, research into low-dose steroids (200-300 mg of hydrocortisone for 5-7 days) improved survival and the reversal of shock in vasopressor-dependent patients.

Insulin regular human (Humulin, Novolin, Humalog)

Clinical Context:  This is an ultra–short-acting insulin analog. Insulin suppresses hepatic glucose output and enhances glucose uptake by peripheral tissues. Insulin also suppresses ketogenesis and lipolysis, stimulates proper use of glucose by the cells, and reduces blood sugar levels.

Class Summary

These agents are used to treat hyperglycemia. A reduction of in-hospital mortality rates by 34% has been reported with intensive insulin therapy (maintenance of blood glucose at 80-110 mg/dL.

Fluconazole (Diflucan)

Clinical Context:  Fluconazole is a synthetic triazole antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol. It is used to treat mild-to-moderate infections or severe or life-threatening infections in patients intolerant of amphotericin B. Metabolic clearance is prolonged in renal dysfunction.

Caspofungin (Cancidas)

Clinical Context:  Caspofungin is the first of a new class of antifungal drugs (glucan synthesis inhibitors). It inhibits synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall. It is used to treat refractory invasive aspergillosis.

Class Summary

Empiric antifungal therapy (fluconazole or an echinocandin) 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.


Lewis J Kaplan, MD, FACS, FCCM, FCCP, Associate Professor of Surgery, Division of Trauma, Surgical Critical Care, and Emergency Surgery, Perelman School of Medicine, University of Pennsylvania; Section Chief, Surgical Critical Care, Philadelphia Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr(HC), FCCP, MCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Masimo, Edwards Lifesciences, Cheetah Medical<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED for board membership; Received honoraria from Edwards Lifesciences for consulting; Received honoraria from Masimo, Inc for board membership.


Heatherlee Bailey, MD Assistant Program Director, Assistant Professor, Department of Emergency Medicine, Division of Critical Care, Medical College of Pennsylvania Hahnemann University

Heatherlee Bailey, MD is a member of the following medical societies: American Academy of Emergency Medicine, Association for Surgical Education, Society for Academic Emergency Medicine, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Steven D Burdette, MD, FIDSA Associate Professor of Medicine, Program Director, Infectious Diseases Fellowship, Wright State University, Boonshoft School of Medicine; Infectious Disease Advisor to Transplant Program, Miami Valley Hospital; Medical Director of Infectious Diseases, Green Memorial Hospital

Steven D Burdette, MD, FIDSA is a member of the following medical societies: Alpha Omega Alpha, American Society for Microbiology, American Society of Transplantation, Infectious Diseases Society of America, and Transplantation Society

Disclosure: Cubist Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching

Joseph F John Jr, MD, FACP, FIDSA, FSHEA Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Klaus-Dieter Lessnau, MD, FCCP Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Miguel A Parilo, MD, FACP Associate Clinical Professor of Medicine, Department of Medicine, Wright State University, Boonshoft School of Medicine; Medical Director, The Bull Family Diabetes Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment


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Venn diagram showing overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

Venn diagram showing overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.