To SIRS With LoveAn Open Letter

Sprung, Charles L. MD, FCCM; Schein, Roland M. H. MD; Balk, Robert A. MD

doi: 10.1097/CCM.0000000000002156
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1The Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

2Section of Critical Care Medicine, Department of Medicine, Veterans Affairs Healthcare System and University of Miami, Miami, FL.

3Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL.

Dr. Sprung’s institution received funding from Data Safety and Monitoring Committee Asahi Kasei Pharma America Corporation (consultant), LeukoDx Ltd. (consultant), and from research study on biomarkers of sepsis, LeukoDx Ltd. (principal investigator). Dr. Sprung disclosed additional funding from International Sepsis Forum (board member) and disclosed: I was a member of the ACCP-SCCM Sepsis Definitions Conference Committee and The 2001 International Sepsis Definitions Conference Committee. Dr. Schein received funding from Josepher and Batteese (expert testimony, individual case medical legal), Peters and Monyak (expert testimony individual case medical legal) and from Florida Society of Critical Care Medicine (travel/accommodations/unrelated meeting expenses). He also disclosed: I was a member of the ACCP-SCCM Sepsis Definitions Conference Committee. His institution received funding from Asahi Kasei Pharma (clinical trial). Dr. Balk’s institution received funding from Ohio Medical (Quality Review Board). He received funding from bioMerieux (advisory board and lectures at CME event), bioMerieux (advisory board), and ThermoFisher Scientific (advisory board). Dr. Balk also disclosed: I was a member of the ACCP-SCCM Sepsis Definitions Conference Committee and The 2001 International Sepsis Definitions Conference Committee.

For information regarding this article, E-mail: charles.sprung@ekmd.huji.ac.il

Article Outline

With the advent of sepsis-3, it is important to consider whether there is still a place for the systemic inflammatory response syndrome (SIRS) (1, 2). In 1991, a conference was convened to develop consensus definitions of sepsis (3). Additionally, the term “SIRS” was coined (3) to recognize the common clinical responses and presumptive common pathophysiology seen in diverse disorders with or without infection (1, 4). SIRS patients with infections were designated as “sepsis” and those without infection as “SIRS” (2). We still need a descriptor to differentiate patients with infection from those with similar characteristics who are not infected and SIRS fulfills this role. SIRS was developed using only elementary, universally available clinical and laboratory data to facilitate early recognition of high-risk patients and to improve outcomes by expeditiously applying standard therapies and developing new innovative strategies (3). Because the SIRS criteria were developed by consensus, they were expected to require validation. Studies using two of the four SIRS criteria produced a sensitive tool for identifying septic patients (5) and validated the use of SIRS, while demonstrating increased mortality with greater sepsis severity in ICU patients (6).

Over the years, the emphasis on inflammation as the primary driver of these conditions has waned, so to keep SIRS we need a new “I” such as “illness” (systemic illness response syndrome). The adult respiratory distress syndrome was also rehabilitated from its superannuated acronym.

Some did not and still do not like SIRS (1, 2, 7). They believe that the SIRS criteria are too sensitive and lack clinical specificity (7). A study of ICU patients with presumed sepsis noted that 12% of the patients with infection, organ failure, and significant mortality did not meet SIRS criteria and thus questioned the sensitivity of the SIRS diagnosis (8). The overwhelming majority of these patients, however, still met SIRS criteria. The sepsis-3 definition is claimed to be more specific and to eliminate confusion regarding sepsis, severe sepsis, and septic shock (2). Rather than using SIRS criteria, the new definition combines infection with a “dysregulated immune response to the infection” that results in organ dysfunction as measured by a two or greater increase in the sequential, sepsis-related, organ failure assessment (SOFA) score (2). There is no reason to expect that “dysregulated immune response” would not suffer from the same obsolescence as “inflammatory” or that organ system dysfunction will be more specific in discriminating between infection and other insults than SIRS criteria. Organ system dysfunctions are not sequelae unique to infection.

The concept of SIRS has been helpful in describing the epidemiology of sepsis and evaluating the success of treatment strategies over the past 25 years (9). The median interval from SIRS to sepsis is inversely correlated with the number of SIRS criteria (6), and there is a stepwise increase in mortality rates from SIRS, sepsis, severe sepsis, and septic shock (6, 10). The prevalence of infection and bacteremia increases with the number of SIRS criteria and with increasing severity of the sepsis syndromes (10). SIRS has prognostic importance in predicting infections, severity of disease, organ failure, and survival (11–20). Patients with three or four SIRS criteria versus two have more infections and noninfected patients with greater than two SIRS criteria are more likely to develop severe sepsis and septic shock (11). Organ system failure and mortality increase with the presence and number of SIRS criteria (11–16, 19, 20).

SIRS, as initially hoped, has demonstrated utility in diseases other than sepsis. The occurrence of SIRS in patients with subarachnoid hemorrhage is associated with higher mortality and morbidity rates (13). SIRS is a major determinant of multiple organ failure and mortality in alcoholic hepatitis (14) and acute liver failure (15). The presence of SIRS in patients admitted for emergency surgery predicts poorer outcomes including more surgical interventions, longer hospital stay, and more deaths (16). SIRS has also been found to be helpful in patients with spinal cord injury, diabetic foot infections, acute pancreatitis, acute coronary syndrome without congestive heart failure, and acute small bowel obstruction (17–21).

SIRS criteria were used as inclusion criteria in most sepsis trials conducted over the last 20 years (9, 22). The use of SIRS criteria was based on the premise that early identification and intervention would result in improved outcome (1, 3). Because a majority of innovative pharmacologic strategies were designed to counter proinflammatory cascades as soon as feasible, they required entry criteria capable of identifying likely septic subjects. SIRS indicators combined with the clinical suspicion of infection as their source were ideal as culture results, mediator levels, or other sophisticated testing imposed too great a delay. What should the inclusion criteria for future sepsis trials be if SIRS criteria are abandoned? The performance of the Sepsis-3 definitions has not yet been validated. The ability to compare characteristics of study populations over time may be lost to shifting definitions. Although changes to our research paradigm may be necessary (22), failed trials are likely the consequence of ineffective treatments rather than a problem of inclusion criteria.

SIRS has also been widely used for quality improvement initiatives (23, 24). Based on the clinical trial evidence from studies employing the previous consensus criteria, the Surviving Sepsis Campaign has developed recognition and management guidelines that emphasize early recognition and rapid administration of antibiotics and resuscitative measures to improve outcome (24). The SIRS criteria have proven worthy in this arena and there is concern that the new Sepsis-3 criteria will be unable to identify patients as early, thus potentially resulting in worse outcomes (25). The era of the SIRS-based sepsis definition has seen a steady decline in hospital mortality rates, in part, related to the early recognition of patients at risk of mortality and morbidity and treatment based on guidelines/bundles of care (1, 9, 23, 25, 26). We have also been able to evaluate management efforts over time with a relatively constant definition for the past 25 years. Changing the definition of sepsis and septic shock at this juncture will make comparing studies difficult (25, 26).

The United States Center for Medicare and Medicaid Services initiated a severe sepsis/septic shock sepsis management bundle on October 1, 2015, to improve sepsis care (27). This surveillance tool employs SIRS criteria and lactate elevation to identify and manage patients with suspected sepsis. There are as yet no compelling reasons to justify a process whereby sepsis patients are identified with one definition for a quality initiative, another for research enrollment, and possibly a third for third-party/insurance reimbursement purposes (25, 26).

Sepsis is a global concern so the definition should be applicable across the spectrum of healthcare systems. The SIRS criteria have met this requirement. The complexity of the Sepsis-3 definition with the need for SOFA score determination of organ dysfunction/failure may not be readily available in some low- and medium-income countries (26). The advantages of a new definition would have to be substantial to warrant a tiered set of definitions dependent on resources. Furthermore, many physicians are unfamiliar with SOFA scores or do not use them (25).

Regardless of specific criteria used, the construct of SIRS should remain as a reminder that many pathologic conditions, infectious or otherwise, can produce similar clinical presentations. Not all patients with fevers and leukocytosis or even a two-point increase in SOFA score are infected. Thus, it is important to recognize similarities of host responses to different inciting processes. If and when responses are found to differ substantially, the construct will no longer be valid and should be abandoned. As far as criteria for defining sepsis, that is, SIRS versus a rise in SOFA, the new Sepsis-3 conceptualization may be shown to have greater specificity. But that advantage must be substantial to abandon the familiar, universal, timely, and sensitive SIRS criteria. If the new criteria identify individuals later in their septic course, it will confound comparisons of populations and management strategies and raise questions as to whether the new definition defines a sicker population or is just ineffective at identifying the patient early enough to effect outcome. Dear SIRS, our love may be conditional but until we know these answers or there are paradigm-changing breakthroughs in our understanding of sepsis, we still need you!

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mortality; organ failure; sepsis; SIRS; systemic inflammatory response syndrome

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