Systemic Inflammatory Response Syndrome

Systemic inflammatory response syndrome (SIRS) is an exaggerated defense response of the body to a noxious stressor, which can include infection, trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy, aimed at localizing and then eliminating the endogenous or exogenous source of the insult. This response involves the release of acute-phase reactants, which are direct mediators of widespread autonomic, endocrine, hematological, and immunological alterations in the subject. Even though the purpose is defensive, the dysregulated cytokine storm can cause a massive inflammatory cascade leading to reversible or irreversible end-organ dysfunction and even death.

Objectively, SIRS is defined by the presence of any 2 of the following criteria:

1. Body temperature >100.4 °F (38 °C) or <96.8 °F (36 °C)

2. Heart rate >90 bpm

3. Respiratory rate >20 breaths/minute or PaCO₂ <32 mm Hg (4.3 kPa)

4. Leukocyte count >12,000/μL, <4,000/μL, or >10% immature forms (bands)

Sepsis, Septic Shock, and Multiple Organ Dysfunction Syndrome

SIRS with a suspected infectious source is termed sepsis. Culture confirmation is not required early in diagnosis. Historically, "severe sepsis" described sepsis with organ dysfunction; however, the Sepsis-3 task force removed this category in 2016, consolidating it under the revised definition of sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection. This distinction is no longer used clinically but may appear in older literature. Septic shock represents the most severe form, marked by circulatory, cellular, and metabolic abnormalities that persist despite adequate fluid resuscitation. Together, sepsis and septic shock are considered a continuum of worsening host response to infection.

The American College of Chest Physicians/Society of Critical Care Medicine-sponsored sepsis definitions consensus conference also identified the entity of multiple organ dysfunction syndrome (MODS) as the presence of altered organ function in acutely ill septic patients such that homeostasis is not maintainable without intervention.

In the pediatric population, the definition is modified to a mandatory requirement of abnormal leukocyte count or temperature to establish the diagnosis, as abnormal heart rate and respiratory rates are more common in children. Recent survey data show that most pediatric clinicians define sepsis as infection with life-threatening organ dysfunction, moving away from older pediatric criteria that relied on SIRS and the redundant term "severe sepsis." The SCCM task force now recommends using the Phoenix Sepsis Score, where a score ≥2 in a child with suspected infection indicates sepsis due to dysfunction in respiratory, cardiovascular, coagulation, or neurologic systems. Septic shock is defined by cardiovascular dysfunction, marked by hypotension for age, lactate >5 mmol/L, or need for vasoactive support.

In summary, almost all septic patients exhibit SIRS, but not all patients with SIRS are septic. Kaukonen et al explained exceptions to this theory by suggesting that there are subgroups of hospitalized patients, particularly at extremes of age, who do not meet the criteria for SIRS on presentation but progress to severe infection, multiple organ dysfunction, and death. Establishing laboratory indices to identify such subgroups of patients and the clinical criteria that we currently rely upon has been gaining prominence over recent years.

Several scores exist to assess the severity of damage to individual organ systems. The Acute Physiology and Chronic Health Evaluation (APACHE) score version II and III, multiple organ dysfunction (MOD) score, sequential organ failure assessment (SOFA), and logistic organ dysfunction (LOD) score are to name a few.

Historical Evolution of Systemic Inflammatory Response Syndrome

The emergence of new insights into the pathophysiology and treatment of sepsis in the early 1990s highlighted the growing need to identify a uniform group of potential subjects for clinical trials exploring novel therapeutic strategies. In response to the surge of ongoing research, a consensus has emerged emphasizing the importance of a time-sensitive approach to diagnosis and intervention, aiming to improve patient survival and reduce morbidity. The ability to recognize individuals affected by various conditions across different care settings using standardized, easy-to-apply clinical parameters became essential. To address this, the American College of Chest Physicians and the Society of Critical Care Medicine convened a consensus conference on sepsis definitions in Chicago, Illinois, in August 1991, with the intention of establishing a standard set of clinical criteria for broad application. This effort led to the introduction of the SIRS definition.

A second consensus meeting, held in Washington, DC, in 2001, expanded on this foundation by introducing a conceptual framework for staging sepsis using the PIRO model—predisposition, insult or infection, response, and organ dysfunction. This model aimed to enhance the understanding and clinical categorization of sepsis, offering a more structured approach to guide research and therapeutic decisions.

The goal of the initial definition was to be highly sensitive using easily available parameters across all healthcare settings. An unavoidable corollary of such a definition was, therefore, the lack of specificity. Additional limitations of the SIRS definition include the following:

1. The universal prevalence of the parameters in an ICU setting

2. Lack of ability to distinguish between beneficial host response from pathologic host response that contributes to organ dysfunction

3. Distinguishing between infectious and noninfectious etiology purely based on the definition

4. Lack of weight to each criterion, eg, fever and elevated respiratory rate, has precisely the same significance as leukocytosis or tachycardia by the SIRS definition.

5. Inability to predict organ dysfunction

Kaukonen et al, in their study of over 130,000 septic patients, established that 1 out of 8 patients in their observational study of sepsis did not meet ≥2 SIRS criteria. They also established that each criterion in the SIRS definition does not translate to an equivalent risk of organ dysfunction or death.

Sequential organ failure assessment

In 2016, following this debate, the European Society of Intensive Care Medicine and the Society of Critical Care Medicine (SCCM) established a task force that proposed Sepsis-3, a revised definition for sepsis. The new definition excluded the establishment of SIRS criteria to define sepsis and made it more nonspecific, as any life-threatening organ dysfunction caused by the dysregulated host response to infection. The task force claimed that the sequential organ failure assessment (SOFA) has better predictive validity for sepsis than the SIRS criteria. It has better prognostic accuracy and the ability to predict in-hospital mortality. To reduce the complexity of calculating the SOFA, a simplified version of the SOFA, known as qSOFA, was introduced.

The qSOFA score is a modified version of the SOFA. A score ≥2 is associated with the following poor outcomes due to sepsis:

1. A systolic blood pressure of ≤100 mm Hg indicates a potential problem with the cardiovascular system

2. A respiratory rate of ≥22 breaths/min suggests possible respiratory distress

3. A Glasgow Coma Scale score of <15 indicates a change in the patient's level of consciousness

Although the validity of qSOFA is limited in an ICU setting, it has consistently outperformed SIRS criteria in predicting organ dysfunction in a non-ICU and ER setting. The use of vasopressors, mechanical ventilation, and aggressive therapeutic interventions in the ICU limits the efficacy of qSOFA. Interestingly, Hague et al, in their study of the utility of SIRS criteria in gastrointestinal surgery, also found it a useful criterion for identifying postoperative complications.

A 2023 systematic review comparing qSOFA and SIRS in emergency and critical care settings found that while qSOFA excels in predicting mortality with greater specificity and AUROC values, SIRS criteria are met significantly faster, which may offer practical advantages for early triage. These findings underscore the trade-off between early detection and prognostic accuracy, guiding clinicians in tailoring their approach according to the specific setting and resource availability.