To SIRS With Love—An Open Letter
Charles L. Sprung, MD, FCCM1; Roland M. H. Schein, MD2; Robert A. Balk, MD3
W
ith the advent of sepsis-3, it is important to con-
sider 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 dis-
orders 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 differen-
tiate patients with infection from those with similar charac-
teristics 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
Key Words: mortality; organ failure; sepsis; SIRS; systemic inflammatory
response syndrome
1
The Department of Anesthesiology and Critical Care Medicine, Hadassah
Hebrew University Medical Center, Jerusalem, Israel.
2
Section of Critical Care Medicine, Department of Medicine, Veterans
Affairs Healthcare System and University of Miami, Miami, FL.
3
Division of Pulmonary and Critical Care Medicine, Rush University Medi-
cal Center, Chicago, IL.
Dr. Sprung’s institution received funding from Data Safety and Monitoring
Committee Asahi Kasei Pharma America Corporation (consultant), Leu-
koDx Ltd. (consultant), and from research study on biomarkers of sepsis,
LeukoDx Ltd. (principal investigator). Dr. Sprung disclosed additional fund-
ing from International Sepsis Forum (board member) and disclosed: I was
a member of the ACCP-SCCM Sepsis Definitions Conference Commit-
tee 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 individ-
ual 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 Com-
mittee. 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
Copyright © 2016 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000002156
Critical Care Medicine www.ccmjournal.org 1
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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 pri-
mary 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 over-
whelming 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, sep-
sis-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 “inflamma-
tory” 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 treat-
ment 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 crite-
ria 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
Sprung et al
mortality increase with the presence and number of SIRS cri-
teria (11–16, 19, 20).
SIRS, as initially hoped, has demonstrated utility in dis-
eases 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 deter-
minant 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 pharma-
cologic strategies were designed to counter proinflamma-
tory cascades as soon as feasible, they required entry criteria
capable of identifying likely septic subjects. SIRS indica-
tors 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 improve-
ment 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 recogni-
tion and rapid administration of antibiotics and resuscita-
tive 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 mor-
bidity and treatment based on guidelines/bundles of care
(1, 9, 23, 25, 26). We have also been able to evaluate manage-
ment 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 manage-
ment bundle on October 1, 2015, to improve sepsis care (27).
2 www.ccmjournal.org XXX 2016 • Volume XX • Number XXX
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
This surveillance tool employs SIRS criteria and lactate ele-
vation 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 appli-
cable 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 determina-
tion of organ dysfunction/failure may not be readily avail-
able 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 presen-
tations. 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 differ-
ent 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 break-
throughs in our understanding of sepsis, we still need you!
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