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Systemic Inflammatory Response Syndrome

Author: Steven D Burdette, MD, FIDSA; Chief Editor: Michael R Pinsky, MD, CM, FCCP, FCCM

OVERVIEW Background
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): Fever of more than 38C (100.4F) or less than 36C (96.8F) Heart rate of more than 90 beats per minute Respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension (PaCO 2) of less than 32mm Hg Abnormal white blood cell count (>12,000/L or < 4,000/L or >10% immature [band] forms) SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or several insults combined. Thus, SIRS is not always related to infection. (See Pathophysiology and Etiology.)

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. 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: Respiratory failure, acute respiratory distress syndrome (ARDS), and nosocomial pneumonia Renal failure Gastrointestinal (GI) bleeding and stress gastritis Anemia DVT Intravenous catheterrelated bacteremia Electrolyte abnormalities Hyperglycemia Disseminated intravesicular coagulation (DIC)

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.

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

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

Stage II
Small quantities of local cytokines are released into the 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.

Multihit theory
Bone also endorsed a multihit 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. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells are able to produce a multitude of cytokines. The cytokines tissue necrosis factor-a (TNF-a) and interleukin-1 (IL-1) are released first and initiate several cascades. The release of IL-1 and TNF-a (or the presence of endotoxin or exotoxin) leads to cleavage of the nuclear factor-kB (NF-kB) inhibitor. Once the inhibitor is removed, NF-kB is able to initiate the production of 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-a and IL-1 have been shown to be released in large quantities within 1 hour of an insult and have both local and systemic effects. In vitro studies have shown that these 2 cytokines given individually produce no significant hemodynamic response but that they cause severe lung injury and hypotension when given together. TNF-a and IL-1 are responsible for fever and the release of stress hormones (norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system). Other cytokines, especially IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP) and procalcitonin. Of note, infection has been shown to induce a greater release of TNF-athus inducing a greater release of IL-6 and IL-8than 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. Numerous proinflammatory polypeptides are found within the complement cascade. Protein complements C3a and C5a have been the most studied and are felt to contribute directly to the release of additional cytokines and to cause vasodilatation and increasing vascular permeability. Prostaglandins and leukotrienes incite endothelial damage, leading to multiorgan failure. Polymorphonuclear cells (PMNs) from critically ill patients with SIRS have been shown to be more resistant to activation than PMNs from healthy donors, but, when stimulated, demonstrate an exaggerated microbicidal response. This may represent an autoprotective mechanism in which the PMNs in the already inflamed host may avoid excessive inflammation, thus reducing the risk of further host cell injury and death. [2] Coagulation The correlation between inflammation and coagulation is critical to understanding the potential progression of SIRS. IL-1 and TNF-a directly affect endothelial surfaces, leading to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby promoting coagulation, and is a proinflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF-a via production of plasminogen activator inhibitor-1. Proinflammatory cytokines also disrupt the naturally occurring anti-inflammatory 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 counter inflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF-a, IL-1, IL-6, and IL-8.

The acute phase response also produces antagonists to TNF-a and IL-1 receptors. These antagonists either bind the cytokine, and thereby inactivate it, or block the receptors. Comorbidities and other factors can influence a patient's ability to respond appropriately. The balance of SIRS and CARS determines a patient's prognosis after an insult. Some researchers believe that, because of CARS, many of the new medications meant to inhibit the proinflammatory mediators may lead to deleterious immunosuppression.

The etiology of systemic inflammatory response syndrome (SIRS) is broad and includes infectious and noninfectious conditions, surgical procedures, trauma, medications, and therapies. The following is partial list of the infectious causes of SIRS: Bacterial sepsis; Burn wound infections; Candidiasis; Cellulitis; Cholecystitis; Community-acquired pneumonia[3]; Diabetic foot infection; Erysipelas; Infective endocarditis; Influenza; Intraabdominal infections - Eg, diverticulitis, appendicitis; Gas gangrene; Meningitis; Nosocomial pneumonia; Pseudomembranous colitis; Pyelonephritis; Septic arthritis; Toxic shock syndrome; Urinary tract infections (male and female) The following is a partial list of the noninfectious causes of SIRS: Acute mesenteric ischemia; Adrenal insufficiency; Autoimmune disorders; Burns; Chemical aspiration; Cirrhosis; Cutaneous vasculitis; Dehydration; Drug reaction; Electrical injuries; Erythema multiforme; Hemorrhagic shock; Hematologic malignancy; Intestinal perforation; Medication side effect - Eg, from theophylline; Myocardial infarction; Pancreatitis[4]; Seizure; Substance abuse - Stimulants such as cocaine and amphetamines; Surgical procedures; Toxic epidermal necrolysis; Transfusion reactions; Upper gastrointestinal bleeding; Vasculitis

Occurrence in the United States
The true incidence of systemic inflammatory response syndrome (SIRS) is unknown. However, because SIRS criteria are nonspecific and occur in patients who present with conditions ranging from influenza to cardiovascular collapse associated with severe pancreatitis,[4] such incidence figures would need to be stratified based on SIRS severity. Rangel-Fausto et al published a prospective survey of patients admitted to a tertiary care center that revealed 68% of hospital admissions to surveyed units met SIRS criteria.[5] 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.[6] In comparison, the incidence in the intensive care unit (ICU) was 840 episodes per 1000 hospital days. 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. [7] Another cohort of patients demonstrated that 62% of patients who presented to the emergency department with SIRS had a confirmed infection, while 38% did not. Within the same cohort of patients, 38% of infected patients did not present with SIRS.[8] 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.[9] 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 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.[8] Prognosis depends on the etiologic source of SIRS, as well as on associated comorbidities. The mortality rates in the previously mentioned Rangel-Fausto study were 7% (SIRS), 16% (sepsis), 20% (severe sepsis), and 46% (septic shock).[5] The median time interval from SIRS to sepsis was inversely related to the number of SIRS criteria (2, 3, or all 4) met. Morbidity is related to the causes of SIRS, complications of organ failure, and the potential for prolonged hospitalization. Pittet et al showed that control patients had the shortest hospital stay, while patients with SIRS, sepsis, and severe sepsis, respectively, required progressively longer hospital stays. [6] A study by Shapiro et al evaluated mortality in patients with suspected infection in the emergency department and found the following inhospital mortality rates[10] : Suspected infection without SIRS - 2.1% Sepsis - 1.3% Severe sepsis - 9.2% Septic shock - 28% In the study, the presence of SIRS criteria alone had no prognostic value for either inhospital 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.[11] In the aforementioned Heffner 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). [7]


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 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.

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. Three of the 4 criteria for SIRS are based on the following vital signs: Fever of more than 38C (100.4F) or less than 36C (96.8F) Heart rate of more than 90 beats per minute Respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension (PaCO 2) of less than 32mm Hg Abnormal white blood cell count (>12,000/L or < 4,000/L or >10% immature [band] forms) 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 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: 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 4 criteria for SIRS, 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) Respiratory rate is the most sensitive marker of the severity of illness

Diagnostic Considerations
Conditions to consider in the differential diagnosis of systemic inflammatory response syndrome (SIRS) include the following: Abdominal abscess; Diverticulitis; Electrical injuries; Erythema multiforme (Stevens-Johnson Syndrome); Gas gangrene; Posttransplantation infections; Infective endocarditis; Influenza; Intestinal perforation; Meningitis; Meningococcemia; Multisystem organ failure of sepsis; Myocardial Infarction; Nosocomial pneumonia; Acute pancreatitis[4]; Perioperative pulmonary management; Community-acquired pneumonia[3]; Pseudomembranous colitis; Pulmonary embolism; Acute pyelonephritis; Respiratory failure; Bacterial sepsis; Septic arthritis; Septic shock; Toxic epidermal necrolysis; Toxic shock syndrome; Transfusion reactions; Upper gastrointestinal bleeding; Female urinary tract infection; Male urinary tract infection; Autoimmune disorders; Chemical aspiration; Cutaneous adverse drug reaction; Dehydration; Medication effects; Pulmonary contusions; Substance abuse Stimulants such as cocaine and amphetamines; Surgical procedures; Viral infections

Differential Diagnoses
Acute Coronary Syndromes; Acute Mesenteric Ischemia; Burn Wound Infections; Candidiasis; Cardiogenic Shock; Cellulitis; Cholecystitis; Cirrhosis; Diabetic Foot Infections; Hypersensitivity Reactions, Immediate

WORK-UP Approach Considerations

Laboratory tests to consider include the following: Blood cultures Urinalysis and culture Cardiac enzymes Amylase Lipase spinal fluid Liver profiles In order to completely evaluate for systemic inflammatory response syndrome (SIRS), a minimum of a complete blood count (CBC) with differential to evaluate for leukocytosis or leukopenia is required. Routine screenings often also include a basic metabolic profile. Other laboratory tests should be individualized based on patient history and physical examination findings.

Patients who meet SIRS criteria and have increased 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. [12]

Blood lactate assessments are often performed in critically ill patients. These are felt to be indicators of anaerobic metabolism associated with tissue dysoxia. levels are commonly elevated from increased peripheral intraorgan production, reduced hepatic uptake, and reduced renal elimination. Based on numerous studies, 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 ICU and hospital 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 2 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). [13] In an observational, prospective study in a pediatric ICU, Arkader et al showed that procalcitonin (PCT) was able to differentiate between infectious and noninfectious SIRS, while C-reactive protein (CRP) was not.[14] Selberg et al reviewed procalcitonin (PCT) and C-reactive protein (CRP), in addition to looking at IL-6 and the protein complement C3a, and showed that PCT, IL-6, and C3a were more reliable in distinguishing infectious from noninfectious causes.[15] 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.[16] 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. [17] PCT is becoming increasingly available to physicians as a point-of-care test. Currently, availability of this assay will vary by medical center.

TREATMENT Approach Considerations

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[3] or pancreatitis. TNF-a 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. 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 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: Suspected or diagnosed infectious etiology - Eg, urinary tract infection (UTI), pneumonia, cellulitis Hemodynamic instability Neutropenia or other immunocompromised states Asplenia - Due to the potential for overwhelming postsplenectomy infection (OPSI) When feasible, culture data should always be obtained prior to initiating antibiotic therapy. Antibiotics prior to culturing a patient 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 methicillinresistant Staphylococcus aureus (MRSA) in the community, vancomycin or another anti-MRSA therapy should be considered. Gram-negative coverage with cefepime, piperacillin-tazobactam, carbapenem (imipenem, meropenem, or doripenem), or a quinolone is reasonable. 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. Care must be taken not to use an antibiotic to which the patient is allergic. This may be a second hit and lead to worsening SIRS. Because of the high prevalence of patients with penicillin allergy, a quinolone or aztreonam is a reasonable alternative for gram-negative coverage in patients with a penicillin allergy. If aztreonam is used, grampositive coverage (with an agent such as vancomycin) should be initiated as well, until culture data are available.

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. [20] Prior to initiating steroid therapy, however, physicians must consider the potential risk of steroids (such as stress ulcers and hyperglycemia).[21] 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. [22, 23] 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-a) 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 inhospital 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 inhospital mortality rates with intensive insulin therapy (maintenance of blood glucose at 80-110mg/dL) by 34%.[24] The greatest reduction in mortality involved deaths due to multipleorgan failure with a proven septic focus.

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

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