Systemic Inflammatory Response Syndrome (SIRS)

Authors: Steven D. Burdette, M.D.


In 1992, the American College of Chest Physicians (ACCP) / Society of Critical Care Medicine (SCCM) introduced definitions for systemic inflammatory response syndrome (SIRS) as well as sepsis, severe sepsis, septic shock and MODS (multiple organ dysfunction syndrome) (Table 1). The introduction of SIRS was intended to define a clinical response to a non-specific insult, either infectious or non-infectious in origin (Table 2). SIRS is defined as 2 or more of the following:

                    1. Fever >38◦C or < 36◦C

                    2. Heart rate >90 beats per minute

                    3. Respiratory rate >20 breaths per minute or PaCO2 <32 mm Hg

                    4. Abnormal white blood cell count (>12,000/mm3 or <4,000/ mm3 or >10% bands)

SIRS can be incited by ischemia, inflammation, trauma, infection or a combination of several “insults”. SIRS is not always associated with infection. While not universally accepted, some have proposed the terms “severe SIRS” and “SIRS shock” to describe serious clinical syndromes that are not infectious in nature and thus cannot be labeled according to the various sepsis definitions (Table 1). These terms suggest organ dysfunction or refractor hypotension not related to an infectious etiology, but rather an ischemic, traumatic or inflammatory process. The goal of this monograph is to review SIRS. Sepsis will be covered elsewhere.

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SIRS, independent of the etiology, has the same pathophysiology with minor differences in inciting cascades. Many consider the syndrome as a self defense mechanism, which uses inflammation as the body’s response to nonspecific insults that arise from chemical, traumatic or infectious stimuli. The inflammatory cascade is complex and involves humoral and cellular responses, complement and the cytokine cascades. The relationship between these complex interactions and SIRS was best summarized by Dr. RC Bone as a 3 stage process.

Stage I: Following an insult, there is local cytokine production with the goal of inciting an inflammatory response thereby promoting wound repair and recruitment of the reticular endothelial system.

Stage II: Small quantities of local cytokines are released into circulation to improve the local response. This leads to growth factor stimulation and the recruitment of macrophages and platelets. This acute phase response is typically well controlled by a decrease in the proinflammatory mediators and by the release of endogenous antagonists. The goal is homeostasis.

Stage III: If homeostasis is not restored, a significant systemic reaction occurs. The cytokine release leads to destruction rather than protection. A consequence of this is the activation of numerous humoral cascades and the activation of the reticular endothelial system and subsequent loss of circulatory integrity. This leads to end organ dysfunction.

Dr. Bone also endorsed a multi-hit theory behind the progression of SIRS to organ dysfunction and possibly MODS. In this theory, the event that initiates the SIRS cascade “primes the pump.” With each additional event, an altered or exaggerated response occurs, leading to progressive illness. The key to preventing the multiple hits is adequate identification of the cause of SIRS and appropriate resuscitation and therapy. Depending on the inciting factors, many SIRS states resolve without specific intervention.

Trauma, inflammation or infections lead to the activation of the inflammatory cascade. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets and endothelial cells are able to produce a multitude of cytokines. Cytokines Tissue Necrosis Factor-α (TNF) and interleukin 1 (IL-1) are first released and initiate several cascades. The release of IL-1 and TNF (or the presence of endotoxin or exotoxin) leads to cleavage of the Nuclear Factor Kappa B (NF-κB) inhibitor. Once the inhibitor is removed, NF-κB is able initiate the production of mRNA that will induce the production other pro-inflammatory cytokines. Interleukins 6 (IL-6) and 8 (IL-8) and Interferon-gamma are the primary pro-inflammatory mediators induced by NF-κB. TNF 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. They are responsible for fever and the release of stress hormones (norepinephrine, vasopressin and activation of the renin-angiotensin-aldosterone system). Other cytokines, especially IL-6, stimulate the release of acute phase reactants such as C-reactive protein. Infection has been shown to induce a greater release of TNF than does trauma, which therefore leads to a  greater release of IL-6 and IL-8. This is suggested to be why there is higher fever associated with infection than trauma.

The cumulative effect of this inflammatory cascade is an unbalanced state with inflammation and coagulation dominating. To counteract the acute inflammatory response, the body is equipped to reverse this process via counter inflammatory response syndrome (CARS). Interleukin 4 (IL-4) and 10 (IL-10) are cytokines responsible for decreasing the production of TNF, IL-1, IL-6 and IL-8. The acute phase response also produces antagonists to TNF and IL-1 receptors. These antagonists either bind the cytokine and thereby inactivate it or block the receptors. The balance of SIRS and CARS is a critical factor in determining a patients outcome.

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A hospital survey of patients with SIRS done by Pittet et al revealed an overall in-hospital incidence of 542 episodes/1000 hospital days. In comparison, the incidence in the ICU was 840 episodes / 1000 hospital days. Rangel-Frausto et al published a prospect survey of patients admitted to a tertiary care center that revealed 68% of hospital admissions to surveyed units met criteria for SIRS. The incidence of SIRS increased as the level of unit acuity increased. Progression of SIRS was noted to be: 26% developed sepsis, 18% developed severe sepsis and 4% developed septic shock within 28 days of admission. The mortality rates were 7% (SIRS), 16% (sepsis), 20% (severe sepsis) and 46% (septic shock). The medial time interval from SIRS to sepsis was inversely related to the number of SIRS criteria (2, 3 or all 4) met. Pittet et al also demonstrated that control patients had the shortest hospital stay, while patients with SIRS, sepsis and severe sepsis respectively required progressively longer hospital stays.
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Clinical Examination

Despite having a relatively common physiologic pathway, numerous triggers exists for SIRS and patients present in a variety of manners. A thorough history is critical in determining the proper evaluation of the patient with SIRS as the differential diagnosis is extremely broad (Table 2). The clinician’s history should be focused around the chief complaint with a pertinent review of systems. Patients should be questioned regarding constitutional symptoms of fever, chills and night sweats which may help differentiate infectious from noninfectious etiologies. The timing of symptom onset may also guide a differential diagnosis towards either an infectious, traumatic, ischemic or inflammatory etiology.

Pain, especially when localizable, may guide a health care worker in both differential diagnosis and the necessary evaluation. While it is beyond the scope of this chapter to provide a differential for pain in the various body parts, a physician should carefully obtain the duration, location, radiation, quality and exacerbating factors associated with the pain to help establish a thorough differential diagnosis.

Patients’ medications should be reviewed. Medication side effects or pharmacologic properties may either induce or mask SIRS (i.e. Beta Blockers will 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 specifics of reaction should be obtained.

Careful review of initial vital signs is an integral component to making the diagnosis. Repeating of vital signs periodically during the initial evaluation period is necessary as multiple other factors (stress, anxiety, exertion of walking to the examination room, etc) may lead to a false diagnosis of SIRS. A focused physical examination based on a patient’s complaints is adequate in most situations. Evaluation for evidence of hypoperfusion (skin mottling, mental status changes, delayed capillary refill and decreased urinary output) should be performed in all patients. Those that are unable to provide any history should also undergo a complete physical examination including a rectal examination to rule out a perirectal abscess or gastrointestinal bleeding.

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Laboratory Evaluation

In order to completely assess SIRS, a minimum of a complete blood cell count with differential to evaluate for leukocytosis or leucopenia in required. Routine laboratory tests will often times include a basic metabolic profile while other lab tests should be individualized based on history and physical examination findings (Table 3). Patients being seen in an outpatient physician’s office or emergency room will require a different evaluation than a currently hospitalized patient with new onset SIRS. The selection of imaging studies depends on the differential diagnosis that is being entertained.

Sedimentation rates and C-reactive proteins are not sensitive in distinguishing between causes of SIRS but may be helpful in certain circumstances. The lack of specificity significantly diminishes the clinical role of acute phase reactants in narrowing the differential diagnosis, but when elevated, may have a role in monitoring response to treatment. Procalcitonin levels have shown variable clinical utility in differentiating infectious from noninfectious causes and their lack of routine availability in most hospitals limits their usefulness. Research is currently being conducted to evaluate other potentially useful acute phase reactants.

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There is no drug of choice for the treatment of SIRS. Medications target specific diagnosis, preexisting comorbidities and prophylaxis regimens for prevention of complications. Medical care includes the prompt initiation of pertinent laboratory testing and imaging studies (Table 3) after obtaining a history and performing a physical examination. Treatment should be focused on possible inciting causes of SIRS (i.e. appropriate treatment of acute myocardial infarction will differ from the treatment of community acquired pneumonia or pancreatitis, etc.). Hypotensive patients should receive adequate resuscitation with intravenous fluids and if still hypotensive, vasopressor agents should be administered with carefully hemodynamic monitoring. All patients should have adequate intravenous access and often require 2 large bore IV’s or a central venous catheter.

Empiric antibiotics are not indicated for all patients with SIRS (Table 4). Fever is not an indication for antibiotics. Indications for antibiotic therapy includes: suspected or diagnosed infection (UTI, pneumonia, cellulitis, etc), hemodynamic instability, neutropenia (or other immunocompromised states) and asplenia (due to the potential for overwhelming postsplenectomy infection i.e. OPSI). Empiric antibiotic therapy should be guided by available guidelines (most infectious disease syndromes are covered elsewhere in this manual) and knowledge of the local antibiotic antibiograms. One must also take into account the patient’s risk factors for resistant pathogens (antibiotic exposures, nursing home stay, and hospitalization) and allergies. Once a bacteriologic diagnosis is obtained, it is critical to narrow the antibiotic spectrum to the most appropriate therapy. If an infectious disease workup is negative, discontinuation of antibiotics may be indicated.

Proper culture data must be obtained prior to any antibiotic therapy when feasible to prevent “sterile sepsis". Due to increasing bacterial resistance, when concern exist for an infectious cause of SIRS but no specific infectious diagnosis is initially identified; broad spectrum antibiotics may be considered. With the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the community, vancomycin or another anti-MRSA therapy may be reasonable. Gram-negative coverage may include either a 3rd or 4th generation cephalosporin or a fluoroquinolone. Recent exposure to antibiotics must be considered when choosing empiric regimens as recent antibiotic therapy increases the risk for resistant pathogens. It is recommended to avoid an antibiotic class to which a patient has recently been exposed. Care must be made not to use an antibiotic for which the patient is allergic. This may be a “second hit” and lead to worsening SIRS. Aztreonam is a reasonable alternative for gram negative bacteria in patients with significant penicillin allergies. Antiviral therapy has no role in SIRS. Empiric antifungal therapy (fluconazole or an echinocandin) may be considered in hemodynamically unstable patients who have already been treated with antibiotics, are neutropenic, receiving TPN or who have long term central venous access in place. While empiric antibiotics may be reasonable in many situations, the key is to discontinue antibiotics when infection is ruled out or to narrow the antibiotic spectrum once a pathogen is isolated. Drotrecogin alfa, a recombinant form of activated protein-C (APC) has no role in SIRS. It utility is limited septic shock. Steroids for sepsis and septic shock have been extensively studied, but no SIRS specific studies have been done to date.

Intensive control of blood glucose levels has been shown to diminish in-hospital morbidity and mortality in both the surgical and medical intensive care setting. Various trials have shown 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 (2006) reported a reduction of in-hospital mortality rates with intensive insulin therapy (maintenance of blood glucose at 80-110 mg/dL) by 34%. The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus.

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Complications will vary based on underlying etiology (Table 5). Routine prophylaxis including DVT and stress ulcer prophylaxis should be initiated when clinically indicated. An extended course of antibiotics, when clinically indicated, should be as narrow spectrum as possible to limit the potential for superinfection such as Clostridium difficile associated diarrhea.


SIRS is a clinical response to a non-specific insult which may be either infectious or non-infectious in etiology. When evaluating a patient with SIRS, a careful history, physical and laboratory evaluation is critical for identifying the cause and will impact initial therapy. Initiation of antibiotic therapy, if indicated, should be discontinued if a non-infectious etiology is found.

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1. Baue AE: Multiple organ failure, multiple organ dysfunction syndrome, and systemic inflammatory response syndrome. Why no magic bullets? Arch Surg 1997;132: 703-7.[PubMed]

2. Bone RC: Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med 1996;24:163-72. [PubMed]

3. Bone RC: Systemic inflammatory response syndrome: a unifying concept of systemic inflammation. In: Fein A, Abraham A, et al. Sepsis and Multiorgan Failure. Philadelphia, Pa: Lippencott, Williams, & Wilkins; 1997:1-10.

4. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-1655. [PubMed]

5. Davies MG and Hagen PO. Systemic inflammatory response syndrome. Br J of Surg 1997;84:920-935.[PubMed]

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7. Dellinger RP. Inflammation and coagulation: implications for the septic patient. CID 2003;36:1259-1264.[PubMed]

8. Fry DE: Sepsis syndrome. Am Surg 2000;66:126-32. [PubMed]

9. Gebay C, Kushner I. Acute-phase proteins and other systemic inflammatory responses to inflammation. NEJM 1999;340:448-454. [PubMed]

10. Jeschke MG, Klein D, Herndon DN. Insulin treatment improves systemic inflammatory reaction to severe trauma. Ann Surg 2004;239:553-560 . [PubMed]

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13. Minneci PC, Deans KJ, Banks SM, Eichaker PQ, Natanson C. Meta-Analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47-57. [PubMed]

14. Muckart DJ, Bhagwanjee S. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients. Crit Care Med 1997;25:1789-1795. [PubMed]

15. Nystrom PO. The systemic inflammatory response syndrome: definitions and etiology. J Antimicrob Chemo 1998; 41: 1-7. [PubMed]

16. Pittet D, Rangel-Fausto MS, Li N, Tarara D, Costigan M, Rempe L, Jebson P, Wenzel RP. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients. Int Care Med 1995;21:302-309. [PubMed]

17. Rangel-Fausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wnzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995; 273: 117-123. [PubMed]

18. Talmor M, Hydo L, Barie PS. Relationship of systemic inflammatory response syndrome to organ dysfunction, length of stay, and mortality in critical surgical illness: effect of intensive care unit resuscitation. Arch Surg 1999;134: 81-87. [PubMed]

19. Van der Poll T, Opal, S. Host-pathogen Interactions in Sepsis. The LANCET Infectious Diseases 2008; Vol.8, Issue 1, 32-42.

20. Van den Berghe G, Wilmer A, Hermans G. Intensive insulin therapy in the medical ICU. N Eng J Med. 2006; 354:449-61.

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Table 1:  Definitions

A. SIRS: 2 or more of the following variables:

1.      Fever >38◦C or < 36◦C

2.      Heart rate >90 beats per minute

3.      Respiratory rate >20 breaths per minute or PaCO2 <32 mm Hg

4.      Abnormal white blood cell count (>12,000/mm3 or <4,000/ mm3 or >10% bands)

B. Bacteremia: bacteria within the blood stream (SIRS or sepsis) 

C. Sepsis: SIRS plus a documented or presumed infection.

D. Severe sepsis: aforementioned sepsis criteria with associated organ dysfunction, hypoperfusion or hypotension. 

E. Sepsis induced hypotension: presence of a systolic BP <90 mmHg or a reduction of > 40 mmHg from baseline in the absence of other causes of hypotension.” 

F. Septic shock: Persistent hypotension and perfusion abnormalities despite adequate fluid resuscitation. 

G. Multiorgan dysfunction syndrome (MODS): state of physiological derangements in which organ function is not capable of maintaining homeostasis.

Table 2:  Differential Diagnosis for patients who meet criteria for SIRS

Infectious causes

Noninfectious causes


Bacterial Sepsis



Community-Acquired Pneumonia

Diabetic Foot Infection


HIV (acute retroviral syndrome)

Infective endocarditis


Intra-abdominal infections


Necrotizing fasciitis

Nosocomial Pneumonia

Pelvic inflammatory disease


Pseudomembranous colitis (Clostridium difficile)


Septic arthritis

Toxic Shock Syndrome

Urinary Tract Infection

Viral syndrome

Acute Mesenteric Ischemia

Alcohol withdrawal



Connective Tissue Disease

Deep venous thrombosis



Drug overdose

Drug reaction

Electrical Injuries

Erythema multiforme

Gastrointestinal Bleeding


Hemorrhagic Shock

Intestinal Perforation


Myocardial Infarction


Peripheral ischemia

Pulmonary embolism

Toxic Epidermal Necrolysis

Transfusion reactions


Table 3:  Laboratory and imaging studies to consider in a patient with SIRS

Primary Laboratory Testing

   Complete blood count with differential

   Comprehensive metabolic panel



Secondary Laboratory Testing


    Blood cultures

    Cardiac enzymes and EKG

    C-reactive protein and ESR

    Influenza nasal swab (November-March)

    Lactic acid level

    Legionella urine antigen

    Pneumococcal urine antigen

    Spinal fluid analysis

    Sputum culture (if suspecting  


    Urine cultures

Primary Radiographic Testing

   Chest radiograph

   Abdominal radiograph

   Soft tissue radiographs


Secondary Radiographic Testing

   CT of abdomen and pelvis

   CT of chest

   CT or MRI of the brain

   CT or MRI  of soft tissue

   Lower extremity ultrasound

   Right upper quadrant ultrasound

Table 4:  Definitive indications for empiric antibiotics in the patient with SIRS


Documented or presumed infection (UTI, pneumonia, cellulitis, etc.)

Hemodynamic instability

Immunocompromised state



Table 5Potential complications of SIRS



Cardiovascular decompensation

Deep venous thrombosis


Electrolyte abnormalities

GI Bleeding and stress gastritis


IV catheter related bacteremia

Renal failure

Respiratory failure


Van der Poll, T. and Opal, S. Host-pathogen Interactions in Sepsis. The LANCET Infectious Diseases 2008; Vol.8, Issue 1, 32-42.

No longer recommended? Steroids and insulin for septic shock. N Engl J Med 2008.

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