Why We Need A New Definition of Sepsis: Sarah J. Beesley, Michael J. Lanspa

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Why we need a new definition of sepsis


Sarah J. Beesley1, Michael J. Lanspa2
1
Pulmonary and Critical Care, University of Utah School of Medicine, Salt Lake City, UT, USA; 2Pulmonary and Critical Care, Intermountain
Medical Center, Salt Lake City, UT, USA
Correspondence to: Sarah J. Beesley, MD. University of Utah School of Medicine, 50 N Medical Drive, #5A224 Salt Lake City, Utah 84132, USA.
Email: sarah.beesley@hsc.utah.edu.

Abstract: On April 23, 2015, Kaukonen and colleagues published an article in the New England Journal of
Medicine entitled “Systemic inflammatory response syndrome criteria in defining severe sepsis”, which investigated
the sensitivity and validity of using SIRS criteria to define intensive care unit (ICU) patients with severe sepsis. This
study used admission data of over 100,000 patients in order to investigate patients with severe sepsis who either met
or didn’t meet SIRS criteria. The investigators found that in-hospital mortality increased linearly with the number
of SIRS criteria met; raising concern that SIRS criterion is not sensitive enough. This study of SIRS criteria raises
important questions about the recognition and diagnosis of severe sepsis.

Keywords: Sepsis; systemic inflammatory response syndrome (SIRS)

Submitted Oct 28, 2015. Accepted for publication Oct 30, 2015.
doi: 10.3978/j.issn.2305-5839.2015.11.02
View this article at: http://dx.doi.org/10.3978/j.issn.2305-5839.2015.11.02

The systemic inflammatory response syndrome (SIRS) When SIRS criteria were initially defined more than
was described by the American College of Chest Physician 20 years ago, the goal was to provide a “practical framework”
and Society of Critical Care Medicine in a consensus for use in clinical practice as well as in research settings (3).
statement from 1991 as part of a larger effort to uniformly Prior to these definitions, there was limited uniformity to
define sepsis (1). The aim of this recently published study sepsis definitions used across research teams, leading to
by Kaukonen and colleagues, “Systemic inflammatory difficulty with generalizing findings (4). Criteria for SIRS
response syndrome criteria in defining severe sepsis”, was to included specific changes in body temperature, heart rate,
assess the sensitivity and validity of using SIRS criteria for tachypnea or hyperventilation and white blood cell count,
this purpose. This study evaluated patients whose clinical with two or more of these being necessary to label the
presentation suggested severe sepsis, comparing those who patients with SIRS. Sepsis was defined as a subcategory of
met SIRS criteria to those who did not meet SIRS criteria. SIRS patients who had a documented or suspected source of
The study was a remarkable effort involving review of over infection. Severe sepsis narrowed this category to patients
1 million patients cared for in Australian and New Zealand with organ dysfunction, and septic shock was a subcategory
intensive care units (ICUs) from 2000 to 2013, accounting of severely septic patients with hypotension. These criteria
for approximately 90% of all ICU admissions in this area and thresholds were chosen by expert consensus, with
during this time (2). The primary outcome was in-hospital the goal to have some standardization across medical
mortality, with a secondary outcome being place of discharge centers and research groups. Data at the time showed
(home, rehab or other hospital). The hypothesis was that higher risk of mortality for patients meeting these criteria
there would be a linear increase in the risk of death, not a on ICU admission (1). These definitions of SIRS, sepsis
defined transition point after two criteria (the definition and septic shock has been used clinically and throughout
of meeting SIRS criteria). In studying over 100,000 septic research studies for the past few decades, but have evoked
patients, the investigators found no real transitional increase considerable controversy (4-9). SIRS criteria was a clinical
at two criteria, which raises questions on the sensitivity and syndrome description, and as such may combine several
validity of using SIRS to define severe sepsis. distinct pathophysiological pathways (5,9). Septic patients

© Annals of Translational Medicine. All rights reserved. www.atmjournal.org Ann Transl Med 2015;3(19):296
Page 2 of 4 Beesley and Lanspa. New definition of sepsis

who do not fulfill SIRS criteria may be excluded from relies on SIRS.
sepsis investigations, and may receive a delay in appropriate Patients labeled as SIRS-positive severe sepsis met two
treatment. Kaukonen and colleagues have made a significant or more SIRS criteria in addition to these criteria for severe
contribution by investigating the clinical outcomes for this sepsis, while SIRS-negative severe sepsis met less than two
group of patients who would otherwise be excluded by the SIRS criteria. Pneumonia, gastrointestinal rupture, and
SIRS definition. biliary infection were common diagnoses (18.2%, 18.5%
This study aimed to evaluate sensitivity, face validity and 10.4%, respectively) among the SIRS-negative patients.
and construct validity of SIRS. Sensitivity is the ability of a Of SIRS-negative patients, 20% (n=2,624) did not meet any
test to recognize true positives, while specificity measures SIRS criteria. This group had a high proportion of patients
number of true negatives correctly identified. In a screening with septic shock (33%, n=866) or mechanical ventilation
test for a potentially life-threatening disease, such as severe (51%, n=1,329). Although these proportions may seem high,
sepsis, high sensitivity would be valued over high specificity they represent a very small percentage of all patients. Only
so that cases are not missed. An important concern raised 0.8% of patients with septic shock and 1.2% of patients
by this study is that one in eight patients with sepsis is with mechanical ventilation had zero SIRS criteria. Taken
missed by the SIRS criteria, indicating an undesirably low together, the data suggest that clinicians are more likely to
sensitivity. Investigators have also criticized SIRS criteria diagnosis a SIRS negative patient with sepsis if they have
for the lack of ability to differentiate between septic and severe organ failure, such as shock or respiratory failure,
non-septic patients (poor specificity) (10). The face validity or if there is evidence of a disease that is highly associated
refers to the transparency or relevance of a test as it appears with infection. Like all studies that rely on clinical registry
to test participants, i.e., that the test looks like it is going surveillance, data were gathered by collectors in the ICU as
to measure what it’s supposed to measure (11). Examining part of a routine process, which is by design susceptible to
the face validity requires some idea of what those using missing information as well as misclassification. However,
the test believe it should show. Construct validity indicates individual validation of whether all 1.2 million patients
the degree to which a test measures what it purports to were appropriately categorized is infeasible. Similarly, in a
measure. Although the study did not explicitly study or study of this magnitude, there is no feasible mechanism by
quantify how much the SIRS criteria contribute to making which one could identify all patients that were incorrectly
a diagnosis of sepsis, it is a reasonable inference that many excluded from the study.
critical care clinicians use SIRS criteria in their diagnosis It is difficult to identify patients with severe sepsis in
of a septic patient. However, SIRS criteria are not required a way that allows classification for both clinical care and
for a diagnosis of sepsis (contrary to the 1991 consensus research purposes. Reliance solely on SIRS criteria may
definition), as some patients were labeled as SIRS-negative be insufficiently sensitive, and is certainly not specific.
and simultaneously identified by clinicians as having sepsis. Therefore, there may be value in using a screening test
SIRS was not designed to measure illness severity or short- for sepsis (highly sensitive) and a confirmatory test (highly
term sepsis mortality but was designed to be exquisitely specific). SIRS has never been very specific (12) and was
sensitive in not missing patients with sepsis, and therefore is not designed to be so. Sepsis and SIRS criteria have been
lacking in construct validity. reevaluated by the Surviving Sepsis Campaign and the
A central limitation of all studies of severe sepsis is that diagnostic criteria for sepsis were significantly expanded
there is no accepted gold standard for a definition of severe to include an extensive list of other indicators of infection,
sepsis. Kaukonen’s study, although excellent, is not immune inflammation, hemodynamic abnormalities or organ
to this limitation. The designation of severe sepsis was dysfunction (13-16). The myriad indicators of sepsis in the
limited to information obtained in the first 24 hours of ICU revised definition may increase sensitivity, but the need
admission and based on coding at that time: severe sepsis for specificity remains unfulfilled. As a response, several
was defined as having APACHE III diagnoses of infection biomarkers have been investigated for use in confirming
plus at least one organ failure or APACHE III diagnoses of the diagnosis of sepsis, including procalcitonin, C-reactive
severe sepsis or septic shock. Therefore, the diagnosis of protein, tumor necrosis factor-α, various interleukins and
sepsis in this study is really a definition based on coding and protein C (7). Procalcitonin may have the most utility for
APACHE III diagnoses, a method which may have inherent identifying an infectious cause of SIRS (7,17) and there
limitations, much like the 1991 consensus definition that have been suggestions for using procalcitonin levels to

© Annals of Translational Medicine. All rights reserved. www.atmjournal.org Ann Transl Med 2015;3(19):296
Annals of Translational Medicine, Vol 3, No 19 November 2015 Page 3 of 4

classify sepsis and grade severity (18). Testing to this point Footnote
indicates that procalcitonin is more sensitive and less
Conflicts of Interest: The authors have no conflicts of interest
specific, depending on cutoff values used (19,20). However,
to declare.
these biomarkers remain investigational, and have yet to be
validated sufficiently for widespread clinical use.
We believe that future directions for improving References
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Cite this article as: Beesley SJ, Lanspa MJ. Why we need a
new definition of sepsis. Ann Transl Med 2015;3(19):296. doi:
10.3978/j.issn.2305-5839.2015.11.02

© Annals of Translational Medicine. All rights reserved. www.atmjournal.org Ann Transl Med 2015;3(19):296

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