DEFINITION:
Systemic Inflammatory Response Syndrome (SIRS) is characterized by one or more of the following clinical features.1
• Body temperature less than 36°C or greater than 38°C
• Heart rate greater than 90 beats per minute
• Tachypnea (high respiratory rate), with greater than 20 breaths per minute; or, an arterial partial pressure of carbon dioxide less than 4.3 kPa (32 mmHg)
• White blood cell count less than 4000 cells/mm³ (4 x 109 cells/L) or greater than 12,000 cells/mm³ (12 x 109 cells/L); or the presence of greater than 10% immature neutrophils (band forms).2,3,4,5.
In children, the SIRS criteria are modified in the following fashion:7
• Heart rate > 2 standard deviations above normal for age in the absence of stimuli such as pain and drug administration. Body temperature obtained orally, rectally, from Foley catheter probe, or from central venous catheter probe > 38.5 °C or < 36 °C.
• Respiratory rate > 2 standard deviations above normal for age OR the requirement for mechanical ventilation not related to neuromuscular disease or the administration of anesthesia.

CLASSIFICATION:
SIRS is one of several conditions related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm, in which there is abnormal regulation of various cytokines. SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection.1,2,3
• Tachypnea (high respiratory rate), with greater than 20 breaths per minute; or, an arterial partial pressure of carbon dioxide less than 4.3 kPa (32 mmHg)
• White blood cell count less than 4000 cells/mm³ (4 x 109 cells/L) or greater than 12,000 cells/mm³ (12 x 109 cells/L); or the presence of greater than 10% immature neutrophils (band forms)
• Respiratory rate > 2 standard deviations above normal for age OR the requirement for mechanical ventilation not related to neuromuscular disease or the administration of anesthesia.
• White blood cell count elevated or depressed for age not related to chemotherapy, Note that SIRS criteria are very non-specific,8 and must be interpreted carefully within the clinical context.
Bacteremia is the presence of bacteria within the blood stream, but this condition does not always lead to SIRS. 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.
PATHOPHYSIOLOGY:
SIRS independent of the etiology, has the same pathophysiologic properties, with minor differences in inciting cascades. Many consider the syndrome a self-defense mechanism. Inflammation is the body’s response to nonspecific insults that arise from chemical, traumatic, or infectious stimuli. The inflammatory cascade is a complex process that involves humoral and cellular responses, complement, and cytokine cascades. Bone best summarized the relationship between these complex interactions and SIRS as the following 3-stage process:
• Stage I: Following an insult, local cytokine is produced with the goal of inciting an inflammatory response, thereby promoting wound repair and recruitment of the reticular endothelial system.
• Stage II: Small quantities of local cytokines are released into circulation to improve the local response. This leads to growth factor stimulation and the recruitment of macrophages and platelets. This acute phase response is typically well controlled by a decrease in the pro inflammatory 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.
The key to preventing the multiple hits is adequate identification of the cause of SIRS and appropriate resuscitation and therapy.
Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells are able to produce a multitude of cytokines. The cytokines tissue necrosis factor (TNF) and interleukin (IL)–1 are released first 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 B (NF-B) inhibitor. Once the inhibitor is removed, NF- B is able to initiate the production of mRNA, which induces the production other pro inflammatory cytokines.
IL-6, IL-8, and interferon gamma are the primary pro inflammatory mediators induced by NF- B. In vitro research suggests that glucocorticoids may function by inhibiting NF- B. 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. In vitro studies have shown that these 2 cytokines given individually produce no significant hemodynamic response but cause severe lung injury and hypotension when given together. TNF and IL-1 are responsible for fever and the release of stress hormones (norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system).
Other cytokines, like IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP). Of note, infection has been shown to induce a greater release of TNF than trauma, which induces a greater release of IL-6 and IL-8. This is suggested to be the reason higher fever is associated with infection rather than trauma.
The pro inflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade, complement cascade, and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes. Numerous pro inflammatory 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.
The correlation between inflammation and coagulation is critical to understanding the potential progression of SIRS. IL-1 and TNF directly affect endothelial surfaces, leading to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby promoting coagulation, and is a pro inflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF via production of plasminogen activator inhibitor-1. Pro inflammatory cytokines also disrupt the naturally occurring anti-inflammatory mediator’s antithrombin and activated protein-C (APC). If unchecked, this coagulation cascade leads to complications of microvascular thrombosis, including organ dysfunction. The complement system also plays a role in the coagulation cascade. Infection-related procoagulant activity is generally more severe than that produced by trauma.
The cumulative effect of this inflammatory cascade is an unbalanced state with inflammation and coagulation dominating. To counteract the acute inflammatory response, the body is equipped to reverse this process via counter inflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF, 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. Comorbidities and other factors can influence a patient’s ability to respond appropriately. The balance of SIRS and CARS determines a patient’s prognosis after an insult. Some researchers believe that, because of CARS, many of the new medications meant to inhibit the pro inflammatory mediators may lead to deleterious immunosuppression.
CAUSES:
• The causes of SIRS are broadly classified as infectious or noninfectious. As above, when SIRS is due to an infection, it is considered sepsis.
• The following is partial list of the infectious causes of SIRS:
o Bacterial sepsis
o Burn wound infections
o Candidiasis
o Cellulitis
o Cholecystitis
o Community-acquired pneumonia
o Diabetic foot infection
o Erysipelas
o Infective endocarditis
o Influenza
o Intraabdominal infections (eg, diverticulitis, appendicitis)
o Gas gangrene
o Meningitis
o Nosocomial pneumonia
o Pseudomembranous colitis
o Pyelonephritis
o Septic arthritis
o Toxic shock syndrome
o Urinary tract infections (both male and female)

• Noninfectious causes of SIRS include trauma, burns, pancreatitis, ischemia, and hemorrhage.1
• The following is a partial list of the noninfectious causes of SIRS:
o Acute mesenteric ischemia
o Autoimmune disorders
o Burns
o Chemical aspiration
o Cirrhosis
o Dehydration
o Drug reaction
o Electrical injuries
o Erythema multiforme
o Hemorrhagic shock
o Intestinal perforation
o Medication side effect (eg, theophylline)
o Myocardial infarction
o Pancreatitis
o Substance abuse (stimulants such as cocaine and amphetamines)
o Surgical procedures
o Toxic epidermal necrolysis
o Transfusion reactions
o Upper gastrointestinal bleeding
o Vasculitis

Other causes are:
• Complications of surgery
• Adrenal insufficiency
• Pulmonary embolism
• Complicated aortic aneurysm
• Cardiac tamponade
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.
Clinical History
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 both 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 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 based on initial history, a complete review of systems is indicated to try an undercover potential diagnosis.
• Patients’ medications should be reviewed. Medication side effects or pharmacologic properties may either induce or mask SIRS (ie, 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.
• Careful review of initial vital signs is an integral component to making the diagnosis. Repeating the review of vital signs periodically during the initial evaluation period is necessary, as multiple other factors (eg, stress, anxiety, exertion of walking to the examination room) may lead to a false diagnosis of SIRS.

• Extreme of ages (both young and old) may not manifest as typical criteria for SIRS; therefore, clinical suspicion may be required to diagnosis a serious illness (either infectious or noninfectious).
• Patients receiving a beta-blocker or a calcium channel blocker are likely unable to elevate their heart rate and, therefore, tachycardia may not be present.
• Although blood pressure is not one of the four criterias, it is still an important marker. If the blood pressure is low, the establishment of intravenous access and fluid resuscitation is of 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.
COMPLICATIONS:
• Complications vary based on underlying etiology. Routine prophylaxis including deep vein thrombosis (DVT) and stress ulcer prophylaxis should be initiated when clinically indicated. Long-term antibiotics, when clinically indicated, should be as narrow spectrum as possible to limit potential for superinfection (suggested by a new fever, change in white blood cell count, or clinical deterioration). Unnecessary vascular catheters and Foley catheters should be removed as soon as possible.
• Other potential complications include the following:
o Respiratory failure, acute respiratory distress syndrome (ARDS) and pneumonia
o Renal failure
o GI bleeding and stress gastritis
o Anemia
o DVT
o Intravenous catheter–related bacteremia
o Electrolyte abnormalities
o Hyperglycemia
o Disseminated intravesicular coagulation (DIC)

TREATMENT:
The initial medical care should include prompt initiation of pertinent laboratory testing and imaging studies after obtaining a history and performing a physical examination. Treatment should then be focused based on possible inciting causes of systemic inflammatory response syndrome (SIRS; eg, appropriate treatment of acute myocardial infarction differs from the treatment of community-acquired pneumonia or pancreatitis).
• Empiric antibiotics are not indicated for all patients with SIRS. Indications for antibiotic therapy include
(1) suspected or diagnosed infectious etiology (eg, urinary tract infection [UTI], pneumonia, cellulitis)
(2) hemodynamic instability
(3) neutropenia (or other immunocompromised states)
(4) asplenia (due to the potential for overwhelming postsplenectomy infection [OPSI]).
When feasible, culture data should always be obtained prior to initiating antibiotic therapy. 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. Once bacteriologic diagnosis is obtained, narrowing the antibiotic spectrum to the most appropriate therapy is critical.
• 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.
o With the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the community, vancomycin or another anti-MRSA therapy should be considered.
o Gram-negative coverage with either cefepime or a quinolone is reasonable.
o Recent exposure to antibiotics must be considered when choosing empiric regimens because recent antibiotic therapy increases the risk for resistant pathogens.
o Care must be made not to use an antibiotic to which the patient is allergic. This may be a second hit and lead to worsening SIRS.
o Because of the high prevalence of patients with penicillin allergy, a quinolone or aztreonam is reasonable alternatives for gram-negative coverage.
o Antiviral therapy has no role in SIRS.
o 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.
o Although empiric antibiotics may be reasonable in many situations, the key is to stop antibiotics when infection is ruled out or narrow the antibiotic spectrum once a pathogen is found.
o Proper culture data must be obtained prior to any antibiotic therapy. Antibiotics prior to culturing a patient may be a cause of sterile sepsis.
• TNF and IL-1 receptor antagonists, antibradykinin, platelet-activating factor receptor antagonists, and anticoagulants (antithrombin III) have been studied without showing statistically significant benefits in SIRS (with variable results for sepsis and septic shock). These medications have no role in treating patients who meet criteria for SIRS only.
• Drotrecogin alfa, a recombinant form of APC, warrants further comment. APC reduces microvascular dysfunction by reducing inflammation and coagulation and increasing fibrinolysis.
o The Patients in the Recombinant Human Activated Protein-C Worldwide Evaluation in Severe Sepsis (PROWESS) study demonstrated its ability to reduce 28-day all-cause mortality following severe sepsis. Further studies have demonstrated that it is best used in patients with gram-negative septic shock. In the PROWESS study, no clinical benefit was found in patients with acute physiology and chronic health evaluation (APACHE) scores of less than 25, and further studies have demonstrated worse outcomes in patients with lower APACHE scores.8
o Therefore, APC has no role in most SIRS cases unless the clinical presentation is consistent with septic shock. APC has strict inclusion and exclusion criteria that must be considered in all patients prior to initiating therapy. The greatest benefit of APC has been demonstrated when this medication is initiated early in the inflammatory cascade.
• Steroids for sepsis and septic shock have been extensively studied, but no SIRS-specific studies have been performed to date.
o 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 d) improved survival and the reversal of shock in vasopressor-dependent patients.
o As mentioned above, the inflammatory mediators and receptors associated with infectious insults (ie, septic shock) are the same as those of noninfectious insults (ie, trauma, inflammatory conditions, ischemia). Therefore, in patients with severe or progressive SIRS, even without an obvious infectious insult, low steroids could be considered.
o Current data do not support using ACTH stimulation testing to determine patients who should receive steroid therapy. Patients receiving steroids require careful monitoring for hyperglycemia.

• Patients who are hypotensive should receive intravenous fluids, and, if still hypotensive after adequate resuscitation, vasopressor agents should be administered while carefully monitoring hemodynamic status. 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 the eMedicine article Septic Shock.

• Hyperglycemia, a common laboratory finding in SIRS, even in individuals without diabetes, has numerous deleterious systemic effects.
o An increase of 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, and TNF) and other secondary mediators (NF B) have all been implicated as causes of cellular injury, tissue damage, and organ dysfunction in patients with hyperglycemia.
o 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%.9 The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus.

• Supplemental oxygen should be provided to any patient that demonstrates an increased oxygen requirement or decreased oxygen availability. Oxygen can be provided via nasal canula or mask, or, 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 their 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).
Surgical Care
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.
Consultations
Consultations vary depending on the admitting physician’s training and the cause of SIRS (ie, 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 room, early in the course of illness.10
• 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, HIV, AIDS, malignancy, solid organ transplantation). They 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.11
Diet
Enteral feedings 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.
Activity
Because of the causative illness, many patients are bed-bound.11,12 Therefore, deep venous thrombosis (DVT) and GI 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 do activity as tolerated.
Medication
No drugs of choice exist for this entity. Medication prescriptions target specific diagnoses, preexisting comorbidities, and prophylaxis regimens for complications. No pharmacologic agents have been demonstrated to improve the systemic inflammatory response syndrome (SIRS) outcome. Broad-spectrum antibiotics, insulin therapy (in patients with hyperglycemia), and steroids should be considered in patients who meet criteria for SIRS.
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.
Special Concerns
• Pregnant patients require intensive evaluation because of the presence of 2 patients, as well as the propensity of uncontrolled inflammation to lead to preterm labor.
• 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.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Conclusions
In SAH patients, SIRS on admission reflected the extent of tissue damage at onset and predicted further tissue disruption, producing clinical worsening and, ultimately, a poor outcome.