A Comparison of Sepsis-2 (Systemic Inflammatory
Response Syndrome Based) to Sepsis-3
(Sequential Organ Failure Assessment Based)
Definitions—A Multicenter Retrospective Study*
Milo Engoren, MD, FCCM1; Troy Seelhammer, MD2; Robert E. Freundlich, MD3;
Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKbH4TTImqenVHKmFUQmZBMKZ7xDjqPIT0Twk3PwDUJ+J2YbWkgMz3nVppTJ8lNAWcg= on 08/23/2020
Michael D. Maile, MD1; Matthew J. G. Sigakis, MD1; Thomas A. Schwann, MD4
Objectives: Recently, the definition of sepsis has changed from
a physiologic derangement (Sepsis-1 and -2) to organ dysfunc-
tion (Sepsis-3) based. We sought to determine the concordance
between the different sepsis phenotypes and how that affected
mortality.
Design: Retrospective, multicenter study.
Setting: Three academic medical centers.
Patients: 29,459 patients who had suspected infection, defined
as obtaining blood cultures and receiving antibiotics: 18,183
(62%) had either Sepsis-2 or Sepsis-3.
Measurements and Main Results: Kappa was used to show agree-
ment between phenotypes. Conditional logistic regression was used
to create models of associations between factors and phenotypes and
between factors and mortality. About 12,981 patients had Sepsis-2;
12,043 had Sepsis-3; and 6,841 patients had both Sepsis-2 and
Sepsis-3. Fifty-three percent of Sepsis-2 patients also had Sepsis-3,
whereas 57% of Sepsis-3 patients also had Sepsis-2. Agreement
between the two phenotypes was poor: kappa = 0.213 ± 0.006.
Mortality was 6% in patients with only Sepsis-2, 10% with only
Sepsis-3, and 18% in patients who had both phenotypes. Com-
bining the variables in Sepsis-2 and Sepsis-3 improved the discrimi-
nation (C-statistic = 0.742 ± 0.005, p < 0.001) of mortality.
Conclusions: We found that Sepsis-2 and Sepsis-3-based sepsis
diagnoses represent separate phenotypes with poor agreement.
Patients who have both phenotypes are at increased risk of mor-
tality compared with having either phenotype alone. Inclusion of
both systemic inflammatory response syndrome and Sequential
*See also p. 1385.
1
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
2
Department of Anesthesiology, Mayo Clinic, Rochester, MN.
3
Department of Anesthesiology, Vanderbilt University, Nashville, TN.
4
Department of Cardiac Surgery, University of Massachusetts, Springfield, MA.
Copyright © 2020 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000004449
1258 www.ccmjournal.org September 2020 • Volume 48 • Number 9
Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Organ Failure Assessment criteria in the same model improves the
discrimination of mortality. (Crit Care Med 2020; 48:1258–1264)
Key Words: mortality; prediction models; sepsis; septic shock;
Systemic Inflammatory Response Syndrome, Sequential Organ
Failure Assessment
D
espite improvements in resuscitation, sepsis remains an
important health problem worldwide with an increasing
incidence (1–3). While many studies, both retrospective
and prospective, have provided valuable insights, gaps remain in
our understanding of this syndrome. Only a minority of patients
show definitive evidence of infection with treatment remaining
limited primarily to antibiotics and supportive therapy (3–5).
For more than 25 years, sepsis remained a syndrome based
on the systemic inflammatory response syndrome (SIRS) de-
fined by its physiologic derangements of vital signs and lab-
oratory values suggestive of infection (Sepsis-1 and Sepsis-2)
(6, 7). Recently, an international collaboration suggested a new
definition based on end-organ dysfunction (Sepsis-3) (8, 9)
(Supplemental Table 1, Supplemental Digital Content 1, http://
links.lww.com/CCM/F589). While Sepsis-3 has similar or
slightly better discrimination to predict mortality than Sepsis-2,
its development raises important questions and concerns about
to what extent the populations identified through the varying
definitions overlap. If, for example, the populations are nearly
identical, historical studies of Sepsis-2 patients are likely gen-
eralizable to Sepsis-3 patients. Additionally, in resource-poor
areas where laboratory values are not easily available, hospitals
may continue to use Sepsis-2. In which case, it is important to
determine how generalizable data based on Sepsis-3 popula-
tions is to Sepsis-2 patients. We hypothesized that the different
sepsis phenotypes would have different mortalities, specifi-
cally for the three groups: 1) Sepsis-2 and Sepsis-3 concordant
sepsis, 2) Sepsis-2 only sepsis, and 3) Sepsis-3 only sepsis. Our
secondary objective is to develop models of mortality based
 Feature Articles

on both Sepsis-2 and Sepsis-3 criteria. Our tertiary objective
is to determine the ability of Sepsis-2 components to identify
Sepsis-3 and of Sepsis-3 components to identify Sepsis-2.
METHODS
This study was approved by the Institutional Review Board,
which waived informed consent due to the retrospective na-
ture of the study, at each of the three participating sites (Mayo
Clinic, Rochester, MN; Vanderbilt University Medical Center,
Nashville, TN; and University of Michigan Medical Center, Ann
Arbor, MI) (Supplemental Table 2, Supplemental Digital Con-
tent 1, http://links.lww.com/CCM/F589). STROBE guidelines
were followed. The electronic health record (EHR) at each in-
stitution was queried by computer programmers for patients
18 years old or older who had a blood culture obtained and
antibiotics administered within the 24 hours preceding the cul-
ture to 72 hours following the culture. The onset of presumed
infection was defined as the earlier of the culture or the anti-
biotic administration (9). Then, all data to calculate SIRS and
SOFA scores (Table 1) were extracted from the EHR. Data fields
from each institution were established with a common vocab-
ulary and inspected for validity, accuracy, and consistency and
then merged. SIRS scores were calculated as described by Bone
et al (6) and range from 0 to 4. SOFA scores were calculated as
described by Vincent et al (10) and range from 0 to 24. Miss-
ing values were presumed to be normal and contributed zero
points to the scores. To calculate SIRS and SOFA scores, we used
a window from 48 hours before to 24 hours after the onset of
suspected infection (9). Overlap between the populations was
graphically displayed as Venn Diagrams and their agreement
described by kappa. Correlation between point scores was
done with Pearson’s correlation coefficient. As comparisons
between Sepsis-2 and Sepsis-3 patients were not strictly inde-
pendent (some patients had sepsis by both sets of criteria), we
used overlapping t test for continuous variables and the over-
lapping test for proportions (11, 12). To determine if and how
well the four SIRS components could identify Sepsis-3, we used
conditional (on hospital) nonparsimonious logistic regres-
sions. Similarly, to determine if and how well the six SOFA
components could identify Sepsis-2, we used conditional (on

TABLE 1. Demographics for Patients With Sepsis and Septic Shock

Any Sepsis, Sepsis-2, Sepsis-3,
Factor n = 18,183, n (%) n = 12,981, n (%) n = 12,043, n (%) p*

Sex
 Men 9,300 (51) 6,691 (52) 6,118 (51) 0.359
 Women 8,596 (47) 6,046 (47) 5,670 (47) 0.497
 Missing 337 (2) 244 (2) 255 (2) 0.349
Race
 White 14,234 (78) 10,169 (78) 9,375 (78) 0.529
 Black 959 (5) 721 (6) 658 (5) 0.711
 Others/missing 2,990 (16) 2,091 (16) 2,010 (17) 0.355
Mean (sd) Mean (sd) Mean (sd)

Age (yr) 56 (18) 56 (18) 56 (18) 0.654

Septic Shock, Sepsis-2, Sepsis-3,
n = 1,894, n (%) n = 1,758, n (%) n = 676, n (%) p*

Sex
 Men 977 (52) 911 (52) 386 (57) 0.999
 Women 829 (44) 759 (43) 290 (43) 0.142
 Missing 88 (5) 88 (5) 0 (0) 0.003
Race
 White 1,413 (75) 1,314 (75) 519 (77) 0.965
 Black 143 (8) 131 (7) 72 (11) 0.248
 Others/missing 338 (18) 313 (18) 85 (13) 0.599
Mean (sd) Mean (sd) Mean (sd)

Age (yr) 56 (18) 56 (18) 58 (17) 0.046

*p value compares patients meeting Sepsis-2 criteria to patients meeting Sepsis-3 criteria using the overlapping test for proportions and the overlapping t test
for continuous variables.

Critical Care Medicine www.ccmjournal.org 1259

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Engoren et al

RESULTS
We had 29,459 patients with suspected infection, de-
fined as obtaining blood cultures and receiving antibiotics:
18,183 (62%) had either Sepsis-2 or Sepsis-3. Patients were
(mean ± sd) 56 ± 18 years old, 9,300 (51%) were men, and
14,234 (78%) were Caucasian (Table 1). Of these septic patients,
12,981 patients (44%) had Sepsis-2, 12,043 (41%) had Sepsis-3,
and 6,841 patients (23%) had both Sepsis-2 and Sepsis-3. Fifty-
three percent of Sepsis-2 patients also had Sepsis-3, whereas
57% of Sepsis-3 patients also had Sepsis-2 (Fig. 1). Agreement
between the two phenotypes was poor: kappa = 0.213, (95%
CI, 0.201–0.225). SIRS and SOFA points correlated poorly
(r = 0.292, p < 0.001). The distribution of SIRS and SOFA points
is shown in the bubble plot (Fig. 2).
Two thousand four hundred twenty-nine (8%) patients
died. Mortality increased as the number of SIRS or SOFA points
Figure 1. Venn diagram for patients with suspected sepsis. Neither increased, Cochran-Armitage p < 0.001 for both (Fig. 3), with
Sepsis-2 nor Sepsis-3 sepsis—335 of 11,276 patients (3%) died. Sepsis-2
sepsis—1,594 of 12,981 patients (12%) died, Sepsis-3 sepsis—1,738
overall mortality being 12% in Sepsis-2 and 14% in Sepsis-3.
patients of 12,043 (14%) died, and both Sepsis-2- and Sepsis-3-sepsis Separately, SIRS and SOFA were independently associated with
1,238 of 6,841 (18%) died. SIRS = systemic inflammatory response hospital mortality. Each additional SIRS point was associated
syndrome, SOFA = Sequential Organ Failure Assessment.
with an increased odds ratio (OR) for mortality (OR, 1.671;
95% CI, 1.605–1.739; p < 0.001; C-statistic = 0.649; 95% CI,
hospital) nonparsimonious logistic regressions. We also used 0.637–0.661), while each additional SOFA point was also associ-
conditional (on hospital) nonparsimonious logistic regres- ated with increased mortality (OR, 1.299; 95% CI, 1.283–1.316;
sions to determine the associations between SIRS, SOFA and C-statistic = 0.725; 95% CI, 0.713–0.737). Combined into one
death. Discriminations of the regression models were measured logistic regression model, both SIRS and SOFA points were in-
with the C-statistic and compared with the Hanley-McNeil test dependently associated with mortality with improved discrimi-
(13). Cochran-Armitage test of trend was used to determine if nation (C-statistic = 0.742; 95% CI, 0.732–0.752). All four SIRS
mortality increased as SIRS or SOFA points increased. A priori components were associated with mortality (Supplemental
subgroup analyses were done on patients who had septic shock, Table 3, Supplemental Digital Content 1, http://links.lww.
defined as sepsis by either of the two scores and receiving vaso- com/CCM/F589), while five of the six SOFA components
pressors (Sepsis-2) or vasopressors and lactic acid >2 mmol/dL (Supplemental Table 4, Supplemental Digital Content 1, http://
(Sepsis-3). p < 0.05 denoted statistical significance. All statistics links.lww.com/CCM/F589) were associated with mortality.
were done with SPSS 25 (IBM, Chicago, IL). The funders had When SIRS and SOFA components were combined into one
no role in the design or analysis of the study. model, all of their individual components, with the exception
No power analysis was done. Sample size was deter- of Glasgow coma scale and WBC count, were independently as-
mined by the number of available records from each sociated with mortality (Supplemental Table 5, Supplemental
institution. Digital Content 1, http://links.lww.com/CCM/F589).
To evaluate the ability of
the Sepsis-3 subset of Sepsis-2
patients to represent all Sepsis-3
patients, we compared Sepsis-3
patients who also had Sepsis-2
to those who did not. Sepsis-3
patients who also had Sepsis-2
had higher overall SOFA scores
(4.8 ± 2.7 vs. 3.7 ± 2.0, p < 0.001)
than Sepsis-3 patients without
Sepsis-2 (Supplemental Table 6,
Supplemental Digital Content
1, http://links.lww.com/CCM/
F589). They also had a near-
doubling of hospital mortality
Figure 2. Bubble plot of systemic inflammatory response syndrome (SIRS) and Sequential Organ Failure (18% vs. 10%, p < 0.001).
Assessment (SOFA) points in patients with suspected sepsis. Bubble area is proportional to the number of Sepsis-2 patients who also had
patients. Largest bubble (0 SOFA and 1 SIRS point) is 4.43 patients. SOFA score 12 is ≥12. Correlation
between SIRS and SOFA points = 0.292, p < 0.001. Sepsis-3 had only slightly higher

1260 www.ccmjournal.org September 2020 • Volume 48 • Number 9

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Feature Articles

Of the 18,183 patients who

had sepsis by either SIRS or
SOFA criteria, 1,894 (10%)
had septic shock by Sepsis-2
(n = 1,758, 93%) or Sepsis-3
criteria (n = 676, 36%), with
540 meeting both criteria
(29%) (Supplemental Fig. 1,
Supplemental Digital Content
2, http://links.lww.com/CCM/
F590; legend, Supplemental
Digital Content 4, http://
links.lww.com/CCM/F592).
Agreement between the diag-
noses was fair (kappa = 0.412;
se = 0.013; p < 0.001), however,
correlation between SIRS points
and SOFA points was poor
(r = 0.091; p < 0.001)
(Supplemental Fig. 2,
Supplemental Digital Content
3, http://links.lww.com/CCM/
F591; legend, Supplemental
Digital Content 4, http://links.
lww.com/CCM/F592). Of the
1,758 Sepsis-2 patients with
shock, 595 (34%) died, while
349 of the 676 (52%) patients
with Sepsis-3 shock died (Fig. 4).
While increasing SIRS and
SOFA points were associ-
ated with increased mortality
(Cochran-Armitage p = 0.040
and < 0.001, respectively) in
the Sepsis-2 patients, neither
was associated with increased
mortality in Sepsis-3 patients
(Cochran-Armitage p = 0.103
and 0.710, respectively).
Figure 3. A, Mortality (black bars) and number of patients (line) by number of systemic inflammatory response SIRS components had poor
syndrome (SIRS) points. B, Mortality (black bars) and number of patients (line) by number of Sequential Organ ability to discriminate mor-
Failure Assessment (SOFA) points.
tality in both Sepsis-2 shock
SIRS points (2.5 ± 0.6 vs. 2.3 ± 0.5, p < 0.001), but much higher (C-statistic = 0.563; 95% CI, 0.534–0.592) and Sepsis-3
mortality (18% vs. 6%, p < 0.001) than Sepsis-2 patients shock patients (C-statistic = 0.560; 95% CI, 0.517–0.603)
without Sepsis 3 (Supplemental Table 7, Supplemental Digital (Supplemental Tables 10 and 11, Supplemental Digital
Content 1, http://links.lww.com/CCM/F589). Using logistic Content 1, http://links.lww.com/CCM/F589). SOFA compo-
regression to determine the SIRS components associated with nents’ discrimination was 0.631; 95% CI, 0.607–0.655 to predict
Sepsis-3, we found that all four factors were significantly as- death in patients with Sepsis-3 shock (Supplemental Table 12,
sociated with SOFA-sepsis; however, the discrimination was Supplemental Digital Content 1, http://links.lww.com/CCM/
only 0.669; 95% CI, 0.657–0.681 (Supplemental Table 8, F589) and Sepsis-2 shock (C-statistic = 0.640; 95% CI, 0.613–
Supplemental Digital Content 1, http://links.lww.com/CCM/ 0.667) (Supplemental Table 13, Supplemental Digital Content
F589). Similarly, we found that five of the six SOFA factors, but 1, http://links.lww.com/CCM/F589). Combining the SIRS and
not bilirubin, were associated with Sepsis-2. The model’s dis- SOFA components into the same models improved the discrim-
crimination was 0.710; 95% CI, 0.698–0.722 (Supplemental ination (C-statistic = 0.651; 95% CI, 0.627–0.675) for Sepsis-3
Table 9, Supplemental Digital Content 1, http://links.lww.com/ shock (Supplemental Table 14, Supplemental Digital Content
CCM/F589). 1, http://links.lww.com/CCM/F589) compared with SIRS only

Critical Care Medicine www.ccmjournal.org 1261

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Engoren et al

patients with and without SIRS

(C-statistic = 0.639; 95% CI,
0.613–0.665) with only oxygen-
ation and cardiovascular SOFA
factors associated with Sepsis-2
septic shock (Supplemental
Table 18, Supplemental Digital
Content 1, http://links.lww.
com/CCM/F589).

DISCUSSION
In this multi-institutional ret-
rospective analysis of patients
with suspected sepsis, we found
similar incidences of Sepsis-2
and Sepsis-3, however, there
was poor agreement between
the Sepsis-2 and Sepsis-3 diag-
noses, kappa = 0.213 ± 0.006.
This finding suggests that they
are, at least in part, different
syndromes or phenotypes,
with patients having both
syndromes having the high-
est mortality (18% vs. 14% for
only Sepsis-3 vs. 12% for only
Sepsis-2). In support of this, we
also found that including both
Sepsis-2- and Sepsis-3-compo-
nents in the same regression
improved the discrimination
of the model over using either
Sepsis-2 or Sepsis-3 compo-
Figure 4. A, Mortality (black bars) and number of patients with septic shock (line) by number of systemic
inflammatory response syndrome (SIRS) points. B, Mortality (black bars) and number of patients with septic nents separately (C-statistic =
shock (line) by number of Sequential Organ Failure Assessment (SOFA) points. 0.757 ± 0.005 vs .730 ± 0.006 for
Sepsis-3 only vs. 0.675 ± 0.006
model, p < 0.001, but not the SOFA only model, p = 0.095. For for Sepsis-2 only components). We found similar agreement
Sepsis-2 shock the combined model (Supplemental Table 15, (kappa = 0.412 ± 0.013 between Sepsis-2 and Sepsis-3 shock
Supplemental Digital Content 1, http://links.lww.com/CCM/ diagnoses, with a higher mortality in Sepsis-3 shock patients
F589) had better discrimination (C-statistic = 0.653; 95% CI, (50%) than Sepsis-2 shock patients (34%). While mortality
0.626–0.680) compared with the SIRS only model, p < 0.001, was higher in Sepsis-3 shock, its incidence was much lower
but not compared with the SOFA only model, p = 0.352. (676 vs. 1,758).
Sepsis-3 shock patients who also had Sepsis-2 shock An important finding of this study is the variation in mor-
had slightly higher SOFA points (7.9  ± 2.8 vs. 7.1  ± 3.0; tality between those patients meeting criteria for concurrent
p < 0.001) than Sepsis-3 shock patients without Sepsis-2 Sepsis-2 and Sepsis-3 diagnosis. While there was no differ-
shock (Supplemental Table 16, Supplemental Digital Content ence in mortality between Sepsis-3 shock with and without
1, http://links.lww.com/CCM/F589). Mortality was slightly also meeting Sepsis-2 criteria, (50% vs. 50%), Sepsis-2 shock
higher in Sepsis-3 shock patients without than with Sepsis-2 patients who did not meet Sepsis-3 shock criteria had a much
shock (60% vs. 50%; p = 0.044). Mortality in Sepsis-2 shock lower mortality rate (27%) compared with those who met
patients also differed by Sepsis-3 shock status—268 of 540, Sepsis-3 criteria (50%). We also found that combining Sepsis-2
50%, if Sepsis-3 shock was present compared with 327 of 1,218, and Sepsis-3 criteria into one mortality model improved pre-
27%, without Sepsis-3 shock. The ability of Sepsis-2 criteria diction and suggest that a combined model might be better. Not
to discriminate between patients with and without Sepsis-3 all SIRS and SOFA components were in the combined model.
septic shock was 0.612; 95% CI, 0.589–0.636 (Supplemental In particular, SIRS-white cell count and SOFA Glasgow score
Table 17, Supplemental Digital Content 1, http://links.lww.com/ were not in the model (Supplemental Table 3, Supplemental
CCM/F589). SOFA points had similar discrimination between Digital Content 1, http://links.lww.com/CCM/F589). While

1262 www.ccmjournal.org September 2020 • Volume 48 • Number 9

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

further study is needed to explain this, it may be related to the
collinearities between these variables and the other SIRS and
SOFA components that remained in the model.
Another salient finding was that utilization of Sepsis-3 patients
as a subset of Sepsis-2 population missed 43% of Sepsis-3 patients.
While this may limit the utility of reanalyzing Sepsis-2 studies for
the subset of patients with Sepsis-3, the missed patients have less
organ dysfunction (SOFA scores 3.7 ± 2.0 vs. 4.8 ± 2.7; p < 0.001)
and much less mortality (10% vs. 18%; p < 0.001). However,
using Sepsis-3 shock patients derived from Sepsis-2 shock popu-
lation misses only 20% of Sepsis-3 shock patients and the missed
patients, whereas having slightly lower SOFA scores, have the
same mortality (50%) as the included patients. This might be
useful in applying information from studies that used Sepsis-2
criteria to patients with Sepsis-3 criteria.
While our study confirms other studies that found that
Sepsis-3 is better than Sepsis-2 at mortality discrimination,
we could find few studies that assessed the overlap between
Sepsis-2 and Sepsis-3 (14–17). In Thailand, Khwannimit et al
(14) found that 95% of Sepsis-2 patients also had Sepsis-3,
whereas we found only 53% also had Sepsis-3. They did not
assess non-Sepsis-2 patients for the presence of Sepsis-3. In
a small study of ICU admissions (n = 186), Cheng et al (15)
found that Sepsis-3 patients (n = 175) were a subset of the
Sepsis-2 patients with high mortality in both groups (31% in
Sepsis-2 and 33% in Sepsis-3). They found no patient who had
Sepsis-3 without also having Sepsis-2. A third study using a
Japanese registry of patients admitted to an ICU with severe
sepsis or septic shock by Sepsis-2 criteria, found that only 43%
of these patients had Sepsis-3 shock (17). However, this study
was limited by using a nonstandard time window (7 days)
for calculating SOFA score, by starting with Sepsis-2 patients,
and did not evaluate Sepsis-3 patients who did not also have
Sepsis-2. Our study differs from these three studies by using
the EHR to include Sepsis-3 patients who did not also have
Sepsis-2. We also differ by including non-ICU patients and
having a lower mortality, 12%, compared with 44% and 33%,
respectively, in the first two studies, but a higher mortality in
septic shock than the third study. Future study is needed to in-
vestigate these international differences. In another small study
(n = 241) of ICU patients with either Sepsis-2 or Sepsis-3,
Fullerton et al (16) found that more patients had Sepsis-3- than
Sepsis-2 and that 28-day hospital mortality was similar between
Sepsis-2 (21%) and Sepsis-3 (20%) sepsis patients. Our study
extends their finding of poor agreement (kappa = 0.12 ± 0.05)
between the two groups by showing how the criteria of each
type of sepsis poorly discriminates the other type of sepsis.
Specifically, our study demonstrates that patients who have both
sepsis phenotypes have increased mortality and the inclusion of
both SIRS and SOFA criteria improves model discrimination of
mortality. Our study is similar to an English study that found
overlap between Sepsis-2 shock and Sepsis-3 shock patients
with higher mortality in the Sepsis-3 patients (18). However,
that study was limited by only including patients who had sepsis
on ICU admission or within 24 hours of admission. Our study
extends the sepsis comparisons to patients who develop sepsis
Critical Care Medicine www.ccmjournal.org 1263
Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Feature Articles
more than 24 hours after ICU admission and to patients treated
in the emergency department or in the wards. We also created
models that identify the components of Sepsis-2 that predict
Sepsis-3 and the components for Sepsis-3 that predict Sepsis-2.
As there is only modest agreement (kappa = 0.213 ± 0.006)
between Sepsis-2 and Sepsis-3 diagnoses (Fig. 1), the differ-
ent phenotypes or syndromes may reflect different responses
to different organisms. Further study is needed to determine
if particular organisms are more likely to cause one syndrome
or the other. Larger multicenter studies would be required to
obtain sufficient power. Alternatively, the different phenotypes
may be caused by different genes or different gene expression.
Determining the genes associated with the different pheno-
types may permit development of medicines that are effica-
cious in one or the other phenotype.
The 2016 edition of the Surviving Sepsis Campaign uses
Sepsis-3 to define sepsis, but explicitly states that “Sepsis-3
clinical criteria (i.e., qSOFA) were not used in studies that in-
formed the recommendations in this revision;” hence their rec-
ommendations are based on clinical studies that used Sepsis-1
and Sepsis-2 (SIRS) criteria to define sepsis and septic shock
(19). Our study provides the first evidence of how sepsis and
septic shock studied using Sepsis-1 and Sepsis-2 criteria may
relate to the newer Sepsis-3 criteria.
Given the voluminous research on conducted on patients
with Sepsis-1 and Sepsis-2, our study provides some evidence
of how this may pertain to patients with Sepsis-3. It suggests
that reanalysis of these Sepsis-1 and Sepsis-2 studies to focus on
those who also had SOFA-sepsis would select a population of
SOFA-sepsis patients with more organ dysfunction and greater
mortality (18% vs. 10%; p < 0.001) than Sepsis-3 patients
without Sepsis-2 and hence not included in those study.
In patients with septic shock, we found that only a few patients
(31%) with Sepsis-2 shock also have Sepsis-3 shock. However,
most (80%) of Sepsis-3 shock patients also had Sepsis-2.
Dissimilar to the sepsis patients, the Sepsis-3 shock patients
without Sepsis-2 had similar mortality (50%) as Sepsis-3 shock
patients who also had Sepsis-2. These results suggest that reana-
lyzing Sepsis-2 shock to find Sepsis-3 shock patients would miss
only a small minority of patients with the same mortality.
The main limitation of our study is that we included only
three tertiary care American academic medical centers; thus,
our data may be less generalizable to community or foreign
hospitals. However, by including patients in the emergency de-
partment and the general wards, similar to the Sepsis-3 study
(9), as well as ICU patients, our results may still be applicable to
less referral-based hospitals. Further study needs to be done in
other hospital settings. Another relevant limitation is that both
SIRS and SOFA criteria depend on the recording of vital signs
and obtaining laboratory values. In the absence of measured
values, both criteria assume the value is normal and assign zero
points for that item. Institutions that have different frequencies
of obtaining these values may have different relationships be-
tween Sepsis-2 and Sepsis-3 sepsis than what we found. Finally,
as patients were diagnosed and treated over several years,
changes in clinical care may have affected our results.
Engoren et al
The main strength of this study was that we leveraged the
extensive informatics expertise at three hospitals to obtain
the necessary vital sign, laboratory value, and outcomes data
needed to calculate SOFA and SIRS scores in patients with sus-
pected sepsis, based on blood cultures and antibiotics, and bet-
ter characterize their respective outcomes.
CONCLUSIONS
We found that Sepsis-2 and Sepsis-3-based sepsis diagnoses
represent separate phenotypes with poor agreement. Patients
who have both phenotypes are at increased risk of mortality
compared with having either phenotype alone. Inclusion of
both SIRS and SOFA criteria in the same model improves the
discrimination of mortality.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
ccmjournal).
Dr. Freundlich was supported by NIH NCATS-KL2-TR002245-01. Dr. Seel-
hammer was supported by Mayo Clinic CTSA grant UL1TR002377 from
the National Center for Advancing Translational Sciences (NCATS).
Dr. Engoren received funding from Aerogen. Dr. Freundlich’s institution
received funding from Medtronic. The remaining authors have disclosed
that they do not have any potential conflicts of interest.
The work was done at University of Michigan, Mayo Clinic, Vanderbilt Uni-
versity, and University of Massachusetts.
For information regarding this article, E-mail: engorenm@med.umich.edu
REFERENCES
1. Kaukonen KM, Bailey M, Suzuki S, et al: Mortality related to severe
sepsis and septic shock among critically ill patients in Australia and
New Zealand, 2000-2012. JAMA 2014; 311:1308–1316
2. Kadri SS, Rhee C, Strich JR, et al: Estimating ten-year trends in septic
shock incidence and mortality in United States academic medical
centers using clinical data. Chest 2017; 151:278–285
3. Rhee C, Dantes R, Epstein L, et al; CDC Prevention Epicenter Pro-
gram: Incidence and trends of sepsis in US hospitals using clinical vs
claims data, 2009-2014. JAMA 2017; 318:1241–1249
4. Sigakis MJG, Jewell E, Maile MD, et al: Culture-negative and culture-
positive sepsis: A comparison of characteristics and outcomes.
Anesth Analg 2019; 129:1300–1309
5. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign:
International guidelines for management of sepsis and septic shock:
2016. Crit Care Med 2017; 45:486–552
1264 www.ccmjournal.org September 2020 • Volume 48 • Number 9
Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
6. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis. The
ACCP/SCCM Consensus Conference Committee. American Col-
lege of Chest Physicians/Society of Critical Care Medicine. Chest
1992; 101:1644–1655
7. Levy MM, Fink MP, Marshall JC, et al; SCCM/ESICM/ACCP/ATS/
SIS: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Defi-
nitions Conference. Crit Care Med 2003; 31:1250–1256
8. Singer M, Deutschman CS, Seymour CW, et al: The third Interna-
tional Consensus definitions for Sepsis and Septic Shock (Sepsis-3).
JAMA 2016; 315:801–810
9. Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of clinical cri-
teria for sepsis: For the third International Consensus definitions for
Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:762–774
10. Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ
Failure Assessment) score to describe organ dysfunction/failure. On
behalf of the Working Group on Sepsis-Related Problems of the Euro-
pean Society of Intensive Care Medicine. Intensive Care Med 1996;
22:707–710
11. Derrick B, Toher D, White P: How to compare the means of two sam-
ples that include paired observations and independent observations.
Quant Meth Psych 2017; 13:120–126
12. Bland JM, Butland BK: Comparing Proportions in Overlapping Sam-
ples. Available at: https://www-users.york.ac.uk/~mb55/overlap.pdf.
Accessed March, 19, 2020
13. Hanley JA, McNeil BJ: A method of comparing the areas under re-
ceiver operating characteristic curves derived from the same cases.
Radiology 1983; 148:839–843
14. Khwannimit B, Bhurayanontachai R, Vattanavanit V: Comparison of
the performance of SOFA, qSOFA and SIRS for predicting mor-
tality and organ failure among sepsis patients admitted to the in-
tensive care unit in a middle-income country. J Crit Care 2018;
44:156–160
15. Cheng B, Li Z, Wang J, et al: Comparison of the performance be-
tween Sepsis-1 and Sepsis-3 in ICUs in China: A retrospective multi-
center study. Shock 2017; 48:301–306
16. Fullerton JN, Thompson K, Shetty A, et al; The Australian and New
Zealand Intensive Care Society Clinical Trials Group; The George In-
stitute for Global Health: New sepsis definition changes incidence of
sepsis in the intensive care unit. Crit Care Resusc 2017; 19:9–13
17. Takauji S, Hayakawa M, Fujita S. A nationwide comparison between
Sepsis-2 and Sepsis-3 definition in Japan. J Intensive Care Med
2019 Jan 13. [online ahead of print]
18. Shankar-Hari M, Harrison DA, Rubenfeld GD, et al: Epidemiology of
sepsis and septic shock in critical care units: comparison between
Sepsis-2 and Sepsis-3 populations using a national critical care data-
base. Br J Anaesth 2017; 119:626–636
19. Overview of the Surviving Sepsis Campaign: The International
Guidelines for Management of Sepsis and Septic Shock 2017:
Available at: https://fdocuments.net/download/overview-of-the-sur-
viving-sepsis-campaign-the-surviving-sepsis-campaign. Accessed
June 9, 2020