Research

JAMA | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Incidence and Trends of Sepsis in US Hospitals

Using Clinical vs Claims Data, 2009-2014
Chanu Rhee, MD, MPH; Raymund Dantes, MD, MPH; Lauren Epstein, MD, MS; David J. Murphy, MD, PhD; Christopher W. Seymour, MD, MSc;
Theodore J. Iwashyna, MD, PhD; Sameer S. Kadri, MD, MS; Derek C. Angus, MD, MPH; Robert L. Danner, MD; Anthony E. Fiore, MD, MPH;
John A. Jernigan, MD, MS; Greg S. Martin, MD, MSc; Edward Septimus, MD; David K. Warren, MD, MPH; Anita Karcz, MD, MBA; Christina Chan, MPH;
John T. Menchaca, BA; Rui Wang, PhD; Susan Gruber, PhD; Michael Klompas, MD, MPH; for the CDC Prevention Epicenter Program

Editorial
IMPORTANCE Estimates from claims-based analyses suggest that the incidence of sepsis is Supplemental content
increasing and mortality rates from sepsis are decreasing. However, estimates from claims
data may lack clinical fidelity and can be affected by changing diagnosis and coding practices
over time.

OBJECTIVE To estimate the US national incidence of sepsis and trends using detailed clinical
data from the electronic health record (EHR) systems of diverse hospitals.

DESIGN, SETTING, AND POPULATION Retrospective cohort study of adult patients admitted
to 409 academic, community, and federal hospitals from 2009-2014.

EXPOSURES Sepsis was identified using clinical indicators of presumed infection

and concurrent acute organ dysfunction, adapting Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent
EHR-based surveillance.

MAIN OUTCOMES AND MEASURES Sepsis incidence, outcomes, and trends from 2009-2014
were calculated using regression models and compared with claims-based estimates using
International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe
sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using
medical record reviews.

RESULTS A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%]
women) were identified using clinical criteria among 2 901 019 adults admitted to study
hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731
(6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria
was stable (+0.6% relative change/y [95% CI, −2.3% to 3.5%], P = .67) whereas incidence per
claims increased (+10.3%/y [95% CI, 7.2% to 13.3%], P < .001). In-hospital mortality using
clinical criteria declined (−3.3%/y [95% CI, −5.6% to −1.0%], P = .004), but there was no
significant change in the combined outcome of death or discharge to hospice (−1.3%/y [95%
CI, −3.2% to 0.6%], P = .19). In contrast, mortality using claims declined significantly (−7.0%/y
[95% CI, −8.8% to −5.2%], P < .001), as did death or discharge to hospice (−4.5%/y [95% CI,
−6.1% to −2.8%], P < .001). Clinical criteria were more sensitive in identifying sepsis than
claims (69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], P < .001), with
comparable positive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI,
69.8% to 80.6%], P = .23).

CONCLUSIONS AND RELEVANCE In clinical data from 409 hospitals, sepsis was present in 6%
Author Affiliations: Author
of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of affiliations are listed at the end of this
sepsis nor the combined outcome of death or discharge to hospice changed significantly article.
between 2009-2014. The findings also suggest that EHR-based clinical data provide more Corresponding Author: Chanu
objective estimates than claims-based data for sepsis surveillance. Rhee, MD, MPH, Department
of Population Medicine,
Harvard Medical School
and Harvard Pilgrim Health
Care Institute, 401 Park Dr,
JAMA. doi:10.1001/jama.2017.13836 Ste 401, Boston, MA 02215
Published online September 13, 2017. (crhee@bwh.harvard.edu).

(Reprinted) E1
© 2017 American Medical Association. All rights reserved.
 Research Original Investigation
S
epsis is a major public health problem. It is among the
most expensive conditions treated in US hospitals and
a leading cause of death.1,2 Numerous studies suggest
that the incidence of sepsis is increasing over time, offsetting
declining case-fatality rates.3-6
Despite its importance, reliably measuring sepsis inci-
dence and trends is challenging. Most studies have used claims
data, but increasing clinical awareness, changes in diagnosis
and coding practices, and variable definitions have led to un-
certainty about the accuracy of reported trends as well as
marked heterogeneity in incidence and mortality rates.7-11
Analyses in a limited set of hospitals using clinical data have
also suggested that sepsis incidence and outcomes may be more
stable than previously thought.12-14
The increasing use of electronic health record (EHR) sys-
tems allows for the possibility of widespread sepsis surveil-
lance using consistent clinical criteria for concurrent infec-
tion and organ dysfunction rather than claims data. In this
study, Third International Consensus Definitions for Sepsis and
Septic Shock (Sepsis-3) criteria were adapted for public health
surveillance and optimized for applicability across different
EHR systems. This definition was then applied to EHR data
from a diverse set of hospitals to estimate US sepsis incidence
and trends from 2009-2014 and to compare with trends esti-
mated from claims data.
Methods
Study Design, Data Sources, and Population
This was a retrospective cohort study using EHR and adminis-
trative data from 409 academic, community, and federal acute
care hospitals gathered from 7 independent data sets: Brigham
and Women’s Hospital, Cerner HealthFacts, Emory Health-
care, Hospital Corporation of America, Institute for Health Met-
rics, University of Pittsburgh Medical Center health care sys-
tem, and the Veterans Affairs (VA) hospital system (described
further in eMethods 1 in the Supplement). These data sets
were chosen to include a broad mix of hospitals that resemble
all US acute care hospitals in terms of geographic mix, teach-
ing status, and hospital size (eTable 1 in the Supplement).
The study included adults 20 years or older admitted as
inpatients or under observation status or who died in the
emergency department in calendar years 2009-2014. Fixed
categories of race/ethnicity, as reported by patients in the
EHR systems of each health care system, were included to
characterize the generalizability of the study dataset and
because of previously reported associations between race/
ethnicity and sepsis incidence and outcomes.3 The study was
approved with a waiver of informed consent by the institu-
tional review boards at Harvard Pilgrim Health Care Institute,
Partners HealthCare, University of Pittsburgh, Emory Univer-
sity, and Ann Arbor VA.
Sepsis Clinical Surveillance Definition
As per Sepsis-3 criteria, sepsis was defined as concurrent in-
fection and organ dysfunction.15,16 Suspected infection crite-
ria and the Sequential Organ Failure Assessment (SOFA) score,17
E2 JAMA Published online September 13, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Incidence and Trends of Sepsis in US Hospitals, 2009-2014
Key Points
Question Is the incidence of sepsis in the United States increasing
and mortality decreasing, as suggested by estimates from
claims-based analyses?
Findings In this retrospective cohort study that included detailed
clinical data from 7 801 624 adult hospitalizations, sepsis incidence
did not change significantly between 2009 and 2014 (+0.6%/y).
While in-hospital mortality decreased during the study period,
the combined outcome of death or discharge to hospice did not
change significantly (−1.3%/y).
Meaning Based on clinical data, the incidence of sepsis, and
related mortality or discharge to hospice, has remained stable
between 2009-2014. The findings also suggest that clinical data
provide more objective estimates than claims-based data for
sepsis surveillance.
however, were modified to facilitate widespread retrospec-
tive surveillance using routinely collected EHR data (Box). Pre-
sumed serious infections were defined as a blood culture draw
and sustained administration of new antibiotics. Four or more
antibiotic days, including at least 1 intravenous antibiotic, were
required to identify those most likely to have serious infec-
tions and to eliminate patients treated empirically for 48 to 72
hours before culture results were obtained. Fewer than 4 an-
tibiotic days were allowed if death or discharge to hospice or
another acute care hospital occurred before 4 days elapsed.
Sepsis criteria were met if patients had at least 1 concurrent
acute organ dysfunction, defined by initiation of vasopres-
sors or mechanical ventilation, elevated lactate level, or sig-
nificant changes in baseline creatinine level, bilirubin level, or
platelet count. The first antibiotic day and organ dysfunction
were required to occur within ±2 calendar days of the blood
culture draw.
Organ dysfunction thresholds were selected to generally
yield an increase in SOFA score of 2 or more points, to parallel
Sepsis-3 criteria. The Glasgow Coma Scale score was not in-
cluded because it was not measured in most patients and was
variably assessed across hospitals.18 Vital signs were also
not included because they are not available in all EHRs and are
susceptible to transient perturbations and measurement er-
rors. Although not part of the SOFA score, lactate levels of
2.0 mmol/L or greater were included for the analysis of sepsis
incidence, outcomes, and clinical characteristics in 2014, given
the central role of lactate levels in identifying and risk strati-
fying sepsis.19,20 As discussed below, however, the lactate cri-
terion was excluded from the primary trends analysis be-
cause lactate testing rates are rapidly increasing over time and
may thus introduce ascertainment bias.21
Sepsis was defined as hospital onset (vs present on admis-
sion) if infection and organ dysfunction criteria first occurred
on or after hospital day 3. Baseline laboratory values for cre-
atinine, bilirubin, and platelets were estimated using the best
value during hospitalization for infection present on admis-
sion, or best values within ±2 days of the blood culture for hos-
pital-onset infection. The entire hospitalization was consid-
ered a single case of sepsis if surveillance criteria were met
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Incidence and Trends of Sepsis in US Hospitals, 2009-2014
multiple times. Septic shock was defined as presumed seri-
ous infection concurrent with vasopressors and serum lac-
tate level 2.0 mmol/L or greater.
Blood culture draws were used to anchor the primary defi-
nition because they are an important marker of suspected sep-
sis and are relatively simple to identify in EHRs. However, a
sensitivity analysis was performed using any clinical culture
as a broader definition of presumed infection (eAppendix C
in the Supplement). These definitions were developed through
consensus discussions among the investigative team, in-
formed by prior work using similar approaches.12,14,16,22
Implementation
Case-finding code was created in SAS and SQL and distrib-
uted to partners to execute locally against their EHR data ar-
rayed according to a common data specification (detailed de-
scription provided in eAppendices A-F in the Supplement).
Patient comorbidities were derived from International Classi-
fication of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) codes using the Charlson method.23
Validation Using Medical Record Reviews
Study physicians reviewed full text medical records from 510
randomly selected hospitalizations, stratified into those that
did and did not meet EHR sepsis surveillance criteria. These
hospitalizations were drawn from 3 academic centers and 2
community hospitals in Massachusetts and Georgia. Hospi-
talizations were classified by reviewers as sepsis-positive if
there was definite or possible infection and an increase in SOFA
score by 2 or more points from baseline as a result of infec-
tion, as per Sepsis-3 criteria.15 “Definite infection” required
positive cultures or radiography and a compatible clinical syn-
drome. “Possible infection” required documentation that the
medical team presumed the patient’s illness was due to infec-
tion, treated for infection, and did not find an alternative eti-
ology. Reviewers were blinded to whether cases were flagged
by EHR surveillance criteria and patients’ ICD-9-CM codes
(additional details in eMethods 2 in the Supplement).
Trends
Annual trends in sepsis incidence and in-hospital mortality
from 2009-2014 were calculated in the subset of hospitals with
historical data (at least 84 hospitals per year) (eTable 2 in the
Supplement). In light of rising rates of hospice utilization
nationwide,24 the combined outcome of in-hospital death or
discharge to hospice was also examined to obtain a more com-
plete picture of trends in sepsis outcomes.
An a priori decision was made to exclude the lactate crite-
rion when assessing whether sepsis incidence and outcomes are
changing over time. This was done in light of steady increases
in lactate testing rates, which might create ascertainment bias
and inflate perceived changes in sepsis incidence.21,25 How-
ever, a secondary analysis was performed with the lactate cri-
terion to test this hypothesis.
We also applied 2 claims-based definitions: “explicit” ICD-
9-CM codes for severe sepsis (995.92) and septic shock (785.52)
and an “implicit” method requiring at least 1 infection code
and 1 organ dysfunction code (Angus method) or explicit codes
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© 2017 American Medical Association. All rights reserved.
Original Investigation Research
Box. Sepsis Clinical Surveillance Definition
1. Presumed serious infection:
• Blood culture obtained (regardless of result), AND
• ⱖ4 QADs—starting within ±2 days of blood culture daya
AND
2. Acute organ dysfunction (any 1 of the following criteria within
±2 days of blood culture day):
• Vasopressor initiation (norepinephrine, dopamine, epinephrine,
phenylephrine, or vasopressin)b
• Initiation of mechanical ventilationb
• Doubling in serum creatinine level or decrease by ⱖ50%
of estimated glomerular filtration rate relative to baseline
(excluding patients with ICD-9-CM code for end-stage kidney
disease [585.6])c
• Total bilirubin level ⱖ2.0 mg/dL and doubling from baselinec
• Platelet count <100 cells/μL and ⱖ50% decline from baseline
(baseline must be ⱖ100 cells/μL)c
• Serum lactate ⱖ2.0 mmol/Ld
Sepsis: Presumed serious infection plus ⱖ1 criteria for acute organ dysfunction
Septic shock: Presumed serious infection plus vasopressor plus serum lactate
level ⱖ2.0 mmol/L
Abbreviations: ICD-9-CM, International Classification of Diseases, Ninth
Revision, Clinical Modification; QAD, qualifying antibiotic day.
a
QADs start with the first “new” antibiotic (not given in the prior 2 calendar
days) within the ±2-day period surrounding the day of the blood culture
draw. Subsequent QADs can be different antibiotics as long as the first dose
of each is “new.” Days between administration of the same antibiotic count
as QADs as long as the gap is not more than 1 day. At least 1 of the first 4
QADs must include an intravenous antibiotic. If death or discharge to
another acute care hospital or hospice occurs prior to 4 days, QADs are
required each day until 1 day or less prior to death or discharge.
b
Vasopressors and mechanical ventilation are considered to be “initiated”
during the ±2-day period surrounding the day of the blood culture draw
if there were no vasopressors or mechanical ventilation administered
on the prior calendar day.
c
For presumed infection present on admission (blood culture day or first
QAD occurring on hospital day 1 or 2), baseline laboratory values are
defined as the best values during hospitalization. For hospital-onset
infection (blood culture day and first QAD occurring on hospital day ⱖ3),
baseline laboratory values are defined as the best values during the ±2-day
period surrounding the day of the blood culture draw.
d
Serum lactate criterion was excluded from the primary 2009-2014 trends
analysis because of risk of ascertainment bias from increasing rates of
lactate testing over time.
for severe sepsis or septic shock.26,27 To examine whether rec-
ognition and coding for sepsis is increasing, we calculated the
annual proportion of hospitalizations flagged by the primary
EHR surveillance definition that also received sepsis codes.
Statistical Analyses
To account for different hospitals contributing data in differ-
ent years, 2009-2014 trends were modeled using generalized
estimating equations to fit Poisson regression models, adjust-
ing for hospital characteristics (institution, region, teaching sta-
tus, bed count, and annual admissions) and case mix (median
age of hospitalized patients, sex and race/ethnicity distributions,
and proportion of intensive care unit [ICU] vs total admissions).
Generalized estimating equations were used to account for cor-
relations in the data over time as well as hospital-level clustering.
(Reprinted) JAMA Published online September 13, 2017 E3
 Research Original Investigation Incidence and Trends of Sepsis in US Hospitals, 2009-2014

ing owing to clinical decisions not to order certain tests rather

Table 1. Characteristics and Case Mix of Study Hospitals in 2014
than missing at random. Data completeness was assessed by
Distribution Among Study inspecting each data element required for the EHR sepsis defi-
Hospitals, No. (%)
Hospital Characteristic (N = 409) nition on a hospital-by-hospital–level basis and aggregate rates
Geographic region of organ dysfunction and sepsis incidence and outcomes across
Northeast 56 (13.7) each dataset (eFigures 1 and 2 in the Supplement).
South 205 (50.1) Continuous variables were expressed as means. Non-
Midwest 60 (14.7) normally distributed variables were expressed as medians of
West 88 (21.5) the medians among the 7 datasets. Analyses were conducted
Teaching status using SAS version 9.3 (SAS Institute) and R version 3.3.1
Teaching 152 (37.2) (http://www.r-project.org). For all analyses, P < .05 (2-sided) was
Nonteaching 257 (62.8) considered statistically significant.
AHA hospital size
Small (<200 beds) 220 (53.8)
Medium (200-499 beds) 155 (37.9) Results
Large (≥500 beds) 34 (8.3)
Sepsis Incidence, Clinical Characteristics,
Annual admissionsa
and Outcomes in 2014
0-5000 127 (45.4)
The 2014 study cohort included 2 901 019 adult encounters in
5001-10 000 53 (18.9)
409 hospitals, representing approximately 10% of all US adult
10 001-20 000 76 (27.1)
hospitalizations. Study hospitals’ characteristics are re-
>20 000 24 (8.6)
ported in Table 1. There were 423 758 patients with presumed
Characteristics of hospitalized patients,
median (IQR)b
serious infection (14.6% incidence [95% CI, 14.6% to 14.7%),
Age, y 62 (58-66) of which 32 574 (7.7% [95% CI, 7.6% to 7.8%]) died in the hos-
Women, % 41.3 (37.7-44.9)
pital. There were 173 690 patients with sepsis (overall hospi-
tal incidence, 6.0% [95% CI, 6.0% to 6.0%]). The clinical char-
Race/ethnicity, %
acteristics of patients with sepsis are reported in Table 2. Mean
White 80.5 (62.9-90.8)
age was 66.5 years (SD, 15.5), and 42.4% (95% CI, 42.2% to
Black 6.6 (1.4-14.9)
42.6%) were women. Comorbidities were common, includ-
Hispanic 1.4 (0.1-8.6)
ing diabetes (35.7% [95% CI, 35.5% to 36.0%]), pulmonary dis-
Asian 0.6 (0.3-1.5)
ease (30.9% [95% CI, 30.7% to 31.2%]), renal disease (26.8%
Other 1.7 (0.6-4.3)
[95% CI, 26.7% to 27.0%]), and cancer (19.7% [95% CI, 19.5%
Median proportion of ICU vs total 12.4 (8.0-16.7)
admissions, % to 19.9%]). Most sepsis cases (86.8% [95% CI, 86.7% to 87.0%])
were present on admission. Among hospitals (n = 280) for
Abbreviations: AHA, American Hospital Association; ICU, intensive care unit;
IQR, interquartile range. which culture results were available, 17.2% (95% CI, 17.0% to
a
Data on annual number of admissions were not available for Veterans Affairs 17.4%) of patients with sepsis had positive blood cultures.
(VA) hospitals (n = 129); thus, the denominator for this category includes Of the 173 690 patients with sepsis in study hospitals in
280 hospitals. 2014, 94 956 (54.7%) required ICU care during hospitaliza-
b
The data shown represent the median value of hospital-level medians among tion, 27 502 (15.8%) had septic shock, 26 061 (15.0%) died in
all 409 hospitals, along with the IQRs of these medians. Individual
the hospital, and 10 731 (6.2%) were discharged to hospice
hospital–level data were unavailable for VA hospitals; thus, VA hospitals were
considered a single institution, and median values in the entire VA dataset (Table 2). Median ICU length of stay was 5 days (range, 2-6).
were calculated. Median hospital length of stay was 10 days (range, 8-12).
Hospital mortality was 25.5% among patients with hospital-
Adjusted rates for 2009-2013 were generated by creating binary onset sepsis vs 13.4% for patients with sepsis present on ad-
indicators for each year in the model, with 2014 as the reference mission (difference, 12.1% [95% CI, 11.5% to 12.7%]; P < .001).
year. The overall change from 2009 to 2014 was summarized Sepsis was present during hospitalization in 34.7% of the 75 079
as the exponentiated slope of the line between these 2 years on study patients who died in the hospital in 2014. When adjust-
the log scale. All percentages were presented as relative annual ing for hospital region, size, and teaching status, the esti-
changes. VA hospitals were excluded from trends analyses be- mated national weighted incidence of sepsis was 5.9% (95%
cause only data from 2014 were available. CI, 5.5% to 6.3%), and the in-hospital mortality rate was 15.6%
The national weighted incidence and mortality of sepsis (95% CI, 14.8% to 16.5%) (strata-specific counts reported in
among hospitalized adults in 2014 was estimated by project- eTable 3 in the Supplement). Mortality rates for septic pa-
ing study hospital case counts into stratifications of US hos- tients were higher for older patients, men, teaching hospi-
pitals by region, size, and teaching status (eMethods 3 in the tals, and larger hospitals (eTable 4 in the Supplement).
Supplement). The distribution of organ dysfunctions, and their associ-
Missing laboratory data for organ dysfunction calcula- ated mortality rates, are shown in Figure 1. Approximately
tions were assumed to be normal. Multiple imputation was not 50% of patients with sepsis met at least 2 criteria for acute
performed because missing data were presumed to be miss- organ dysfunction.

E4 JAMA Published online September 13, 2017 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Incidence and Trends of Sepsis in US Hospitals, 2009-2014 Original Investigation Research

Validation Table 2. Demographics and Clinical Characteristics of Patients

On medical record reviews, EHR surveillance criteria had With Sepsis in 2014
69.7% sensitivity (95% CI, 52.9% to 92.0%), 98.1% specificity
Patients With Sepsis, No. (%)
(95% CI, 97.7% to 98.5%), 70.4% positive predictive value Characteristic (N = 173 690)
(PPV) (95% CI, 64.0% to 76.8%), and 98.0% negative predic- Age, y
tive value (95% CI, 95.9% to 99.6%), relative to Sepsis-3 crite- Mean (SD) 66.5 (15.5)
ria. Explicit sepsis codes had lower sensitivity (32.3% [95% CI, 20-39 11 475 (6.6)
24.4% to 43.0%] vs 69.7% [95% CI, 52.9% to 92.0%] for EHR 40-59 40 975 (23.6)
criteria, P < .001) but with comparable PPV (75.2% [95% CI, 60-79 80 857 (46.6)
69.8% to 80.6%] vs 70.4% [95% CI, 64.0% to 76.8%] for EHR ≥80 40 383 (23.3)
criteria, P = .23). The combination of explicit or implicit codes Sex
had comparable sensitivity compared with EHR criteria (66.0% Men 100 030 (57.6)
[95% CI, 51.4% to 80.7%], P = .37) but lower PPV (31.0% [95% Women 73 660 (42.4)
CI, 24.9% to 40.4%], P < .001) (eTable 5 in the Supplement). Race/ethnicitya
Among the 13 Sepsis-3 cases missed by EHR criteria, the White 117 081 (67.4)
most common reason was hypoxemia causing an increase in Black 26 564 (15.3)
SOFA score of 2 or more points without need for mechanical Hispanic 18 417 (10.6)
ventilation (eTable 6 in the Supplement). None of these 13 pa- Asian 3499 (2.0)
tients died. There were 57 false-positives flagged by EHR cri- Other 4497 (2.6)
teria; most were because clinicians initially suspected infec- Comorbidities
tion but medical record reviewers ultimately deemed no Diabetes 62 043 (35.7)
infection was present or because patients’ organ dysfunction Chronic pulmonary disease 53 742 (30.9)
did not increase SOFA score by 2 or more points (typically pa- Renal disease 46 560 (26.8)
tients with elevated lactate levels alone) (eTable 7 in the Supple- Congestive heart failure 44 168 (25.4)
ment). If sepsis was defined as clinically suspected infection Cancer 34 229 (19.7)
with organ dysfunction at the thresholds specified by EHR cri- Dementia or cerebrovascular disease 17 862 (10.3)
teria, PPV was 87.9% (95% CI, 82.7% to 92.0%). Liver disease 17 437 (10.0)
HIV or AIDS 1726 (1.0)
Trends From 2009-2014 Clinical characteristics
The trends analysis included 7 801 624 hospitalizations be- Present-on-admission sepsis 150 801 (86.8)
tween 2009-2014 (Figure 2). The annual incidence of sepsis Hospital-onset sepsis 22 889 (13.2)
(without the lactate criterion) was stable (+0.6% relative Positive blood culturesb 24 949 (17.2)
change/y [95% CI, −2.3% to 3.5%], P = .67). In-hospital mor- No. of organ dysfunction criteria met
tality decreased (−3.3%/y [95% CI, −5.6% to −1.0%], P = .004), Mean (SD) 2.1 (1.4)
but there was no significant change in the combined out- Median (range)c 2 (1-2)
come of death or discharge to hospice (−1.3%/y [95% CI, −3.2% Required ICU admission 94 956 (54.7)
to 0.6%], P = .19). Patients with sepsis were increasingly dis- ICU length of stay
charged to hospice over time (+6.3%/y [95% CI, 1.1% to 11.6%], Mean (SD) 6.4 (8.8)
P = .02). Median (range)c 5 (2-6)

When including lactate as a criterion, sepsis incidence in- Hospital length of stay

creased (+3.5%/y [95% CI, 0.7% to 6.4%], P = .02), mortality Mean (SD) 12.0 (12.1)

decreased (−5.0%/y [95% CI, −7.3% to −2.7%], P < .001), and Median (range) c 10 (8-12)

death or discharge to hospice decreased (−2.0%/y [95% CI, Discharge dispositiona

−3.8% to −0.2%], P = .03). Home 86 301 (49.7)

Sepsis incidence using explicit severe sepsis/septic shock In-hospital death 26 061 (15.0)

codes increased significantly (+10.3%/y [95% CI, 7.2% to 13.3%], Hospice 10 731 (6.2)

P < .001), as did sepsis/septic shock defined using explicit codes Nonacute care facility 42 127 (24.3)

or implicit codes (+7.3%/y [95% CI, 5.0% to 9.5%], P < .001). Transfer to acute care hospital 4216 (2.4)

Mortality declined using explicit codes (−7.0% [95% CI, −8.8%
to −5.2%], P < .001) and explicit or implicit codes combined
(−6.6%/y [95% CI, −8.3% to −4.8%], P < .001). The combined
outcome of death or discharge to hospice also decreased with
explicit codes (−4.5% [95% CI, −6.1% to −2.8%], P < .001) and
with explicit or implicit codes combined (−3.6% [95% CI, −4.9%
to −2.3%], P < .001).
Among patients meeting EHR clinical criteria for sepsis,
the proportion who received explicit sepsis codes increased
from 24.9% in 2009 to 30.5% in 2014 (difference, 5.6% [95%
Abbreviation: ICU, intensive care unit.
a
Data missing for 3499 (2.0%) cases for race/ethnicity and 4254 (2.4%) cases
for discharge disposition.
b
Blood culture results were available in 280 of the 409 hospitals in the
datasets; percentage of positive blood cultures reflects the denominator of
sepsis cases (n = 145 236) in those 280 hospitals. Positive blood cultures
excluded common skin contaminants and were counted if they occurred
anytime during hospitalization, not necessarily during the sepsis episode.
c
Reported median organ dysfunctions, ICU length of stay, and hospital length
of stay represent median of the median values in each of the 7 datasets, along
with range of medians across the datasets.

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© 2017 American Medical Association. All rights reserved.

 Research Original Investigation Incidence and Trends of Sepsis in US Hospitals, 2009-2014

EHR-based vs claims-based trends (eFigure 3 in the Supple-

Figure 1. Organ Dysfunction Distribution and Associated Mortality
in Patients With Sepsis in 2014 and Associated Mortality by Number
ment). When any clinical culture was used to indicate pre-
of Organ Dysfunction Criteria Met sumed infection rather than blood cultures alone, sepsis in-
cidence rates in 2014 were higher (7.1% vs 6.0%; difference,
Proportion of sepsis cases 1.1% [95% CI, 1.0% to 1.1%]; P < .001) and mortality rates lower
A Organ dysfunction or associated mortality with organ dysfunction (14.0% vs 15.0%; difference, 1.0% [95% CI, 0.8% to 1.2%];
Associated mortality
P < .001). Clinical characteristics and trends were similar
Vasopresssor initiation (eTables 8-9 in the Supplement).

Mechanical ventilation
initiation

Hyperlactatemia
Acute kidney injury
Hepatic injury
Thrombocytopenia
0 10 20 30 40 50
Organ Dysfunction or Mortality, %
B Associated mortality by number of organ dysfunction criteria met
No. of criteria met
≥1
≥2
≥3
≥4
0 20 40 60 80
Organ Dysfunction or Mortality, %
A, Number of sepsis cases with each organ dysfunction and associated
in-hospital deaths were n = 49 400 (16 715 deaths) for vasopressor initiation;
n = 45 088 (14 290 deaths) for initiation of mechanical ventilation; n = 92 779
(18 345 deaths) for hyperlactatemia (serum lactate level ⱖ2.0 mmol/L);
n = 75 553 (9664 deaths) for acute kidney injury (doubling in baseline
creatinine level or decrease in estimated glomerular filtration rate by ⱖ50%);
n = 26 083 (3717 deaths) for hepatic injury (doubling in baseline total bilirubin
level to ⱖ2.0 mg/dL); n = 21 830 (4869 deaths) for thrombocytopenia
(decrease in baseline platelet count by ⱖ50%, with baseline platelets
>100 cells/μL). Further details on organ dysfunction criteria are described
in the Box. Total number of sepsis encounters, 173 690. B, Number of sepsis
cases meeting the specified number of organ dysfunction criteria and
associated in-hospital deaths were n = 173 690 (26 061 deaths) for 1
or more organ dysfunction criteria; n = 88 248 (20 687 deaths) for 2 or
more organ dysfunction criteria; n = 50 466 (16 506 deaths) for 3 or more
organ dysfunction criteria; and n = 29 161 (11 725 deaths) for 4 or more organ
dysfunction criteria. Number of organ dysfunction criteria includes different
organ dysfunctions that may have occurred at separate times during
hospitalization if surveillance criteria were met more than once.
CI, 5.1% to 6.1%]; P = .007); the proportion who received im-
plicit or explicit codes increased from 58.1% to 63.7% (differ-
ence, 5.6% [95% CI, 5.0% to 6.2%]; P = .04).
Sensitivity Analyses
Sensitivity analyses restricted to hospitals that reported
data each year from 2009-2014 yielded similar differences in
Discussion
In this retrospective analysis of more than 2.9 million adults
admitted to 409 US hospitals in 2014, clinical indicators of sep-
sis were present in 6% of hospitalized patients, of whom 21%
died in the hospital or were discharged to hospice. Sepsis was
present in 35% of all hospitalizations that culminated in death.
In contrast to claims-based analyses, sepsis incidence rates
using clinical data were stable from 2009-2014; in-hospital
60 mortality rates declined, but there was no significant change
in the combined outcome of death or discharge to hospice.
Reliable sepsis surveillance is essential given its high bur-
den, the proliferation of treatment and prevention initia-
tives, and new national sepsis quality measures. Identifying
sepsis using consistent clinical criteria through EHR data, rather
than relying on explicit clinical diagnoses or hospital coders,
enhances confidence in sepsis estimates because clinicians un-
derrecognize sepsis and vary widely in their knowledge and
application of sepsis definitions.28-30 Hospitals also vary sig-
nificantly in how they assign codes for infection and organ dys-
function, and the presence of both of these codes at dis-
charge does not guarantee that they occurred concurrently.31-33
EHR-based criteria were more sensitive than explicit sepsis
100
codes on medical record review, with comparable PPV; EHR-
based criteria had similar sensitivity to implicit or explicit codes
combined but higher PPV.
EHR-based clinical surveillance also provides more cred-
ible estimates of sepsis trends compared with claims, which
can be biased by changing diagnosis and coding practices over
time.9,10,13,34 Among patients with sepsis identified using EHR
clinical criteria, there was an increase over time in the propor-
tion assigned explicit and implicit sepsis codes, presumably
reflecting ongoing efforts to improve sepsis awareness, docu-
mentation, and coding. Improving sepsis recognition, includ-
ing less severe cases, likely accounts for the difference in clini-
cal vs claims-based incidence trends as well as the greater
mortality decline seen with claims. The apparent improve-
ment in sepsis-associated mortality was also nullified when
also considering discharge to hospice, underscoring the need
to consider temporal changes in end-of-life care patterns when
assessing trends in clinical outcomes.24
When including elevated lactate levels in the surveillance
definition, mild increases in sepsis incidence and decreases in
mortality or discharge to hospice were observed. This likely re-
flects increasingly aggressive lactate testing over time and iden-
tification of progressively less ill patients with sepsis, parallel-
ing the increase in sepsis awareness and coding.21,25 Thus,
although lactate surveillance can be useful for identifying sepsis

E6 JAMA Published online September 13, 2017 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Incidence and Trends of Sepsis in US Hospitals, 2009-2014 Original Investigation Research

cases at a single point, it risks generating misleading impres-

Figure 2. Sepsis Trends From 2009-2014: Incidence, In-hospital Sepsis
sions of changes in sepsis incidence and outcomes over time. Mortality, and In-hospital Mortality or Discharge to Hospice.
Ongoing improvements in sepsis coding suggest that claims
may eventually reach the accuracy of EHR data. However, the A Adjusted sepsis incidence
variability of claims between hospitals and their susceptibility 12
Implicit or explicit sepsis codes
to shifting policy and reimbursement incentives limits their use
10
to compare hospitals or assess trends—limitations particularly
important in the new era of sepsis quality measures and 8

Incidence, %
regulations.9,35 Surveillance experience from other domains, Clinical criteria
6
such as health care–associated infections, speak to the risk of re-
imbursement policies changing coding practices and hence per- 4
Clinical criteria without lactate level
ceived rates that do not reflect true changes in infection rates.36-38
The national weighted sepsis incidence of 5.9% among hos- 2
Explicit sepsis codes
pitalized patients and in-hospital mortality of 15.6% estimated 0
in this study would translate into approximately 1.7 million US 2009 2010 2011 2012 2013 2014

adult sepsis hospitalizations and 270 000 deaths in 2014. This Year
Annual total
falls within the wide incidence range of 900 000 to 3.1 million hospitalizations, No. 696 807 737 695 747 236 780 193 2 485 637 2 354 056

previously estimated using 4 different claims-based definitions.7 B Adjusted in-hospital sepsis mortality
The observed mortality rate exceeds the 10% mortality re- 40

ported in the Sepsis-3 derivation and validation studies.16 This 35

may reflect the more stringent definition of presumed infec- 30 Explicit sepsis codes
tion (requiring blood cultures and ≥4 days of antibiotics rather

Mortality, %
25
than a single dose) and SOFA score adaptations.
20 Clinical criteria without lactate level

15
Strengths and Limitations Clinical criteria
Strengths of the current study include the use of detailed clini- 10
Implicit or explicit sepsis codes
cal data from a large number of diverse hospitals that to- 5
gether account for approximately 10% of all US acute care hos- 0
pitalizations in 2014. The data sets came from unrelated 2009 2010 2011 2012 2013 2014
Year
hospital networks, limiting the possibility of bias from idio-
syncratic clinical, diagnosis, or coding patterns. A sensitivity C Adjusted in-hospital sepsis mortality or discharge to hospice
45
analysis using a broader definition of presumed infection dem-
40
Death or Discharge to Hospice, %

onstrated relatively little change in sepsis incidence and out- Explicit sepsis codes
comes and no difference in trends, supporting the robust- 35

ness of the primary definition. 30

Clinical criteria without lactate level
This study also has several limitations. First, EHR-based 25

surveillance may be affected by differences in clinical prac- 20 Clinical criteria

tice between clinicians and hospitals as well as changes over 15

time. This may be most evident with rising rates of lactate test-
ing, but earlier initiation of vasopressors for hypotension and
increasing use of noninvasive ventilation and high-flow
nasal cannulas for respiratory failure could also affect esti-
mates. The partial dependence on clinician-initiated interven-
tions to measure organ dysfunction, however, is also a limi-
tation of the SOFA score and thus the Sepsis-3 criteria.
Second, only adults in US acute care hospitals were in-
cluded; future studies should address sepsis in neonates and
children, as well as consider ways to identify sepsis outside hos-
pitals and in countries without widespread EHR systems.
Third, not all hospitals contributed data each year for trends
analyses. However, regression models were used to adjust for
hospital-level differences.
Fourth, the study did not directly ascertain sepsis mortal-
ity that occurs after hospital discharge.
Fifth, medical record reviews were only conducted on
a fraction of the study cohort. Cases were drawn from both
academic and community hospitals, but they still may not be
representative of all hospitals.
Implicit or explicit sepsis codes
10
5
0
2009 2010 2011 2012 2013 2014
Year
Adjusted rates from 2009-2013 calculated relative to observed 2014 rates.
Error bars indicate 95% CIs. “Clinical criteria” indicates blood cultures + antibiotics
+ concurrent organ dysfunction (Box). “Clinical criteria without lactate” excludes
the criterion for lactate level of 2.0 mmol/L or greater. Primary trends assessment
was conducted using clinical criteria without lactate levels. “Explicit sepsis codes”:
discharge diagnoses of severe sepsis (995.92) or septic shock (785.52).
“Implicit sepsis codes”: at least 1 infection diagnosis and 1 organ dysfunction
diagnosis. All trends adjusted for hospital characteristics (institution, region,
teaching status, bed count, annual admissions) and case mix (median age of
hospitalized patients, sex and race/ethnicity distributions, proportion of intensive
care unit vs total admissions). Veterans Affairs hospitals not included in the trends
analysis. Total number of sepsis cases per year was 30 744 (2009), 35 596 (2010),
34 445 (2011), 36 524 (2012), 144 322 (2013), and 145 236 (2014) for clinical
criteria; 28 723 (2009), 32 175 (2010), 30 348 (2011), 32 019 (2012), 120 402
(2013), and 112 355 (2014) for clinical criteria without lactate levels; 50 223 (2009),
61 483 (2010), 65 193 (2011), 76 208 (2012), 275 480 (2013), and 272 679 (2014)
for implicit or explicit codes; and 9062 (2009), 12 688 (2010), 12 571 (2011),
15 309 (2012), 61 285 (2013), and 65 176 (2014) for explicit codes.

jama.com (Reprinted) JAMA Published online September 13, 2017 E7

© 2017 American Medical Association. All rights reserved.

 Research Original Investigation Incidence and Trends of Sepsis in US Hospitals, 2009-2014

Sixth, the study dataset might not be representative of na-
tional data. However, study hospitals had characteristics simi-
lar to those of US hospitals overall and represented a substan-
tial fraction of total admissions nationwide.
Seventh, medical record reviews suggest that EHR-based
surveillance may miss up to 30% of patients with sepsis while
misclassifying another 30%. Quantifying the accuracy of sep-
sis criteria is elusive, however, because there is no true gold
standard for sepsis.30,39,40 Recognizing this problem, the Sep-
sis-3 task force developed and validated criteria based on as-
sociations with adverse outcomes.15,16 The EHR surveillance
definition in this study carried high mortality rates (15%) com-
pared with all encounters with presumed infection (8%), and
mortality increased with increasing numbers of dysfunc-
tional organs. On medical record reviews, the Sepsis-3 cases
missed by EHR surveillance involved mild organ dysfunc-
tion, such as hypoxemia without need for mechanical venti-
lation, and no patients in that group died. False-positives were
most often attributable to reviewers adjudicating the ab-
sence of infection despite patients receiving blood culture
draws and antibiotics, or a noninfectious cause of organ dys-
function. When sepsis was defined as organ dysfunction con-
current with clinically suspected infection (as is common in
practice), PPV of the surveillance definition increased to 88%.
Eighth, neither Sepsis-3 criteria nor EHR-based clinical
surveillance can solve the challenge that clinicians routinely
face in deciding whether their patient is infected and
whether organ dysfunction is due to infection. Instead, EHR
surveillance provides a consistent gauge to estimate sepsis
incidence and outcomes using readily available, objective
clinical data. This method cannot help clinicians identify
sepsis at the bedside since it is retrospective, but it may be
useful for public health surveillance, hospital evaluation,
and assessing the effects of quality improvement efforts.
EHR-based surveillance may further support these objec-
tives by facilitating granular evaluation of the timing of sep-
sis onset and interventions.
Conclusions
In clinical data from 409 hospitals, sepsis was present in 6%
of adult hospitalizations, and in contrast to claims-based analy-
ses, neither the incidence of sepsis nor the combined out-
come of death or discharge to hospice changed significantly
between 2009-2014. The findings also suggest that EHR-
based clinical data provide more objective estimates than
claims-based data for sepsis surveillance.

ARTICLE INFORMATION
Accepted for Publication: August 30, 2017.
Published Online: September 13, 2017.
doi:10.1001/jama.2017.13836
Author Affiliations: Department of Population
Medicine, Harvard Medical School/Harvard Pilgrim
Health Care Institute, Boston, Massachusetts
(Rhee, Chan, Menchaca, Wang, Gruber, Klompas);
Department of Medicine, Brigham and Women’s
Hospital, Boston, Massachusetts (Rhee, Klompas);
Division of Healthcare Quality Promotion, Centers
for Disease Control and Prevention, Atlanta,
Georgia (Dantes, Epstein, Fiore, Jernigan); Division
of Hospital Medicine, Department of Medicine,
Emory University School of Medicine, Atlanta,
Georgia (Dantes); Division of Pulmonary, Allergy,
Critical Care and Sleep Medicine, Department of
Medicine, Emory University School of Medicine,
and Emory Critical Care Center, Atlanta, Georgia
(Murphy, Martin); Clinical Research, Investigation
and Systems Modeling of Acute illness (CRISMA)
Center, Department of Critical Care Medicine,
University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania (Seymour, Angus);
Department of Internal Medicine, University of
Michigan, Ann Arbor (Iwashyna); VA Center for
Clinical Management Research, VA Ann Arbor
Health System, Ann Arbor, Michigan (Iwashyna);
Critical Care Medicine Department, Clinical Center,
National Institutes of Health, Bethesda, Maryland
(Kadri, Danner); Associate Editor, JAMA (Angus);
Hospital Corporation of America, Nashville,
Tennessee (Septimus); Texas A&M Health Science
Center College of Medicine, Houston (Septimus);
Department of Medicine, Washington University
School of Medicine, St Louis, Missouri (Warren);
Institute for Health Metrics, Burlington,
Massachusetts (Karcz).
Author Contributions: Dr Rhee had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Rhee, Dantes, Epstein,
Murphy, Seymour, Iwashyna, Kadri, Angus, Danner,
Fiore, Jernigan, Septimus, Warren, Klompas.
Acquisition, analysis, or interpretation of data:
Rhee, Dantes, Epstein, Murphy, Seymour,
Iwashyna, Kadri, Danner, Martin, Warren, Karcz,
Chan, Menchaca, Wang, Gruber, Klompas.
Drafting of the manuscript: Rhee, Murphy, Martin,
Septimus, Klompas.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Rhee, Murphy, Seymour,
Iwashyna, Chan, Menchaca, Wang, Gruber.
Obtained funding: Rhee, Iwashyna, Fiore, Klompas.
Administrative, technical, or material support:
Murphy, Seymour, Iwashyna, Danner, Fiore,
Jernigan, Martin, Septimus, Karcz.
Supervision: Dantes, Murphy, Seymour, Iwashyna,
Angus, Martin, Klompas.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Seymour reported receiving personal fees from
Beckman Coulter and Edwards Inc. Dr Martin
reported reported receiving grants paid to his
institution from the US Food and Drug
Administration and Bristol-Myers Squibb and
serving on the medical advisory boards of Astute
Medical, Grifols, and Edwards Lifesciences.
Dr Warren reported serving as a consultant for
Centene Corp, Worrell Inc, and BD/Carefusion; and
receiving funds paid to his institution from Pfizer.
No other authors reported disclosures.
Funding/Support: This work was funded by the
Centers for Disease Control and Prevention
(3U54CK000172-05S2) and in part by the Agency
for Healthcare Research and Quality
(1K08HS025008-01A1), National Institutes of
Health (R35GM119519), Department of Veterans
Affairs (HSR&D 11-109), and intramural funding
from the National Institutes of Health Clinical
Center and National Institute of Allergy and
Infectious Diseases.
Role of the Funders/Sponsors: Members of the
Centers for Disease Control and Prevention, who
are coauthors on this study, contributed to the
design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, and approval of the
manuscript; and decision to submit the manuscript
for publication. The other funding sources had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review or
approval of the manuscript; and decision to submit
the manuscript for publication.
Meeting Presentation: This work was presented in
abstract form at the 2017 American Thoracic
Society Conference (poster A5010).
Disclaimer: Dr Angus, JAMA Associate Editor, had
no role in the evaluation of or decision to publish
this article. The findings and conclusions in this
report are those of the authors and do not
necessarily represent the views of the Centers for
Disease Control and Prevention, the National
Institutes of Health, or the Department
of Veterans Affairs.
Additional Contributions: We thank Richard
Platt, MD, MS (Harvard Medical School/Harvard
Pilgrim Health Care Institute), Ravi Chari, MD
(Hospital Corporation of America), and Jonathan B.
Perlin, MD (Hospital Corporation of America),
for their support and review of the manuscript.
They received no compensation for their
contributions. We thank Caren Spencer-Smith, MIS
(Hospital Corporation of America), for her
assistance in obtaining data for this study. She
received no compensation for her time. We thank

E8 JAMA Published online September 13, 2017 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Incidence and Trends of Sepsis in US Hospitals, 2009-2014
the following study team members, who did receive
compensation, for their assistance in obtaining and
analyzing data needed for the study: Brenda
Vincent, MS, Wyndy Wiitala, PhD, Vanessa
Dickerman, PhD, and Jennifer A. Davis, MHSA
(Ann Arbor VA); Jonathan Holton, BS, and Edvin
Music, MBA, MSIS (University of Pittsburgh
Medical Center); Elizabeth Overton, MS (Emory
Healthcare); Richard Schaaf, BS, David Fram, BA,
and Karen Eberhardt, BS (Commonwealth
Informatics); and Robert Jin, MS (Harvard Medical
School/Harvard Pilgrim Health Care Institute).
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E9
 Supplementary Online Content

Rhee C, Dantes R, Epstein L, et al; CDC Prevention Epicenter Program. Incidence and trends
of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA.
doi:10.1001/jama.2017.13836

I. eMethods, eTables, and eFigures

eMethods 1. Health Systems / Datasets Used in Study Page 2

eMethods 2. Validation of EHR Surveillance Definition by Medical Record Reviews Page 3
eMethods 3. National Weighting Methodology for Sepsis Incidence and Mortality Page 4
eTable 1. Characteristics of 2014 Study Hospitals versus American Hospital Page 5
Association (AHA) Acute Care Hospitals
eTable 2. Hospitals Contributing Data for 2009-2014 Trends Analysis Page 6
eTable 3. Sepsis Stratified by Hospital Characteristics in Study vs AHA Hospitals Page 7
eTable 4. Sepsis Mortality Rates per Age Group, Sex, Race, and Hospital Type Page 8
eTable 5. Accuracy of EHR Definition vs Claims Relative to Medical Record Reviews Page 9
eTable 6. EHR Sepsis Definition vs Sepsis-3 by Chart Reviews: False Negatives Page 10
eTable 7. EHR Sepsis Definition vs Sepsis-3 by Chart Reviews: False Positives Page 11
eTable 8. Clinical Characteristics of Sepsis Patients Defined by Clinical Cultures Page 12
eTable 9. Trends for Sepsis Defined by Clinical Cultures Page 13
eFigure 1. Overall Sepsis Rates and Outcomes in Each Study Dataset Page 14
eFigure 2. Organ Dysfunction Rates Among Sepsis Cases in Each Study Dataset Page 15
eFigure 3. Sepsis Trends in Hospitals with Continuous Data from 2009-2014 Page 16
eReferences Page 18

II. eAppendices: Data Specifications for Implementing the EHR Sepsis Surveillance Definition

Introduction/Overview Page 20
eAppendix A. Detailed Description of EHR Sepsis Surveillance Definition Page 21
eAppendix B. Medications Used in Study (Antibiotics and Vasopressors) Page 23
eAppendix C. Definitions of Blood Cultures and Clinical Cultures Page 24
eAppendix D. Input Datasets Page 25
eAppendix E. Overview of SAS Programs Page 32
eAppendix F. Glossary of Terms for Output Tables Page 35

This supplementary material has been provided by the authors to give readers additional information
about their work.

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I. SUPPLEMENTAL METHODS, TABLES, AND FIGURES

eMethods 1. Healthcare Systems / Datasets Used in Study

The institutions involved in our study included a broad array of academic, community, and federal
hospitals with diverse electronic health record (EHR) systems. For this study, acute care hospitals were
included, while psychiatric, rehabilitation, and children’s hospitals were excluded. Each dataset is
described below.

1. Hospital Corporation of America (HCA): HCA is the largest for-profit healthcare system in the U.S.,
with 165 hospitals spread across 20 different states. The hospitals mainly consist of urban and
suburban community medical centers but also include several complex tertiary referral and academic
medical centers. From geographic, demographic, and socioeconomic standpoints, this population is
representative of the U.S. population as a whole.1 HCA hospitals primarily use the Meditech EHR
system. Comprehensive clinical data is stored in a centralized data warehouse and undergoes line-
item validation until >99% accuracy is achieved. This data warehouse has been used in the analysis
2-7
of large cluster randomized trials, quality improvement initiatives, and other retrospective studies.
For this study, HCA provided complete data from 137 acute care hospitals for 2013 and 2014.
2. Veterans Affairs (VA) Hospitals: the VA is the largest integrated health system in the U.S and
includes 130 hospitals, including at least one in every state. The VA has long been a national leader
8
in the adoption of EHRs and has used a homegrown integrated EHR system since 1999. Data from
the VA EHR system has been used in multiple retrospective studies, including in the validation of the
9-12
Sepsis-3 clinical criteria. For this study, the VA provided complete data from 129 hospitals for
2014.
3. University of Pittsburgh Medical Center (UPMC) System: UPMC includes academic and
community hospitals distributed throughout western Pennsylvania that collectively provide care for
over 400,000 patients per year and utilize the Cerner EHR system. This dataset served as the
12
primary dataset for derivation of the Sepsis-3 clinical criteria. For this study, UPMC provided data
from 11 hospitals for 2010-2014. The data did not overlap with the Cerner HealthFacts dataset.
4. Cerner HealthFacts® Dataset: rather than a single integrated healthcare system, HealthFacts is a
de-identified patient database that receives granular clinical data from a subset of hospitals that use
the Cerner EHR system. This dataset was first launched in 2000 and has been utilized in several
retrospective studies spanning a range of different conditions.13-19 For this study, we included 78
hospitals with complete data in 2014. A smaller subset of hospitals (at least 41 hospitals per year)
provided data from 2009-2013.
5. Institute for Health Metrics (IHM): IHM is a non-profit organization that assists more than 100
hospitals across 30 states using the Meditech EHR system to extract and aggregate their electronic
20,21
clinical data to support regulatory, reporting, quality improvement, and research initiatives. The
network primarily includes community hospitals with an average size of 160 beds. For this study, 49
hospitals provided one-half year of data for hospitalizations spanning July-December 2014. A subset
of hospitals (at least 27 hospitals per year) provided data from 2009-2013.
6. Brigham and Women’s Hospital (BWH): this academic medical center in Boston, Massachusetts
provides inpatient care for over 50,000 patients per year. During the years of this study, BWH used a
homegrown EHR system and stored detailed electronic clinical data from 2002 onwards in a clinical
22
data warehouse (the Partners Research Patient Data Repository). Data from this repository has
been used for numerous research studies, including several studies of sepsis epidemiology and
23-26
trends.
7. Emory Healthcare: Emory Healthcare is the largest healthcare system in the state of Georgia and
uses a Cerner EHR system. It has stored data in the Emory Clinical Data Warehouse since 1993 and
27,28
has supported analysis of several quality improvement initiatives. For this study, Emory
Healthcare provided complete data from 4 hospitals for 2010-2014. The data did not overlap with the
Cerner HealthFacts dataset.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eMethods 2. Validation of EHR Surveillance Definition by Medical Record Reviews
In the Emory Healthcare system, one internist (R.D.) and one infectious disease physician (L.E.)
29
reviewed a total of 310 hospitalizations using a standardized data abstraction tool in REDCap. 110
cases were drawn from the surveillance definition-positive cohort, 110 were drawn from the definition-
negative but presumed infection-positive cohort, and 90 were drawn from the definition-negative/infection-
negative cohort. Reviewers were blinded to results of the EHR surveillance definition as well as
discharge diagnosis codes. The initial 10 charts were reviewed together by the two reviewers;
subsequently, 30 charts were reviewed independently and assessed for concordance. Agreement
amongst those cases was good (kappa 0.73). The 4 cases where reviewers disagreed were excluded,
yielding a total of 306 cases for analysis.
At Brigham and Women’s Hospital (BWH), one intensivist (C.R.) reviewed 200 hospitalizations
(100 surveillance definition-positive and 100 definition-negative, regardless of whether or not infection
criteria was met), blinded to results of the surveillance definition and discharge diagnosis codes, using the
same REDCap tool. This intensivist had previously been demonstrated to have good interrater reliability
(kappa 0.80) compared to a second intensivist when adjudicating the presence of sepsis on medical
26
record reviews in this dataset.
Hospitalizations were classified as sepsis if there was either definite (i.e., positive cultures or
radiography and compatible syndrome) or possible infection (i.e., infection presumed and treated by the
medical team and no definitive alternate etiology found), and if organ dysfunction was present (with a rise
LQ6HTXHQWLDO2UJDQ)DLOXUH$VVHVVPHQW6FRUHE\•IURPEDVHOLQH and was felt to be related to
infection. Baseline SOFA scores were determined by the reviewer based on an array of available data in
the medical records, estimating the degree of organ dysfunction prior to infection onset (if infection
occurred during hospitalization) or at baseline health (if infection was present-on-admission).
The EHR surveillance definition was then compared to the results of the medical record
reviews. To calculate sensitivity, specificity, positive predictive value, and negative predictive value, the
proportions were extrapolated back to the entire hospitalized population at the BWH and Emory hospitals.
10,000 bootstrapped samples were then created to calculate percentile-based confidence intervals for
sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using
R version 3.3.1 (r-project.org). An identical method was used to calculate performance of claims-based
definitions (explicit severe sepsis or septic shock codes, and the combination of implicit codes for
30,31
infection and organ dysfunction [Angus method] or explicit severe sepsis / septic shock codes).
Sensitivity for EHR vs claims-based definitions was compared on the pooled number of sepsis-
positive reviewed charts (n=163) using McNemar’s test of paired proportions. The PPV for EHR vs
claims-based definitions was compared by using a multinomial-based Wald statistic to test for
equality. The test statistic in this paired study design was based on a bootstrapped estimate of the
variance-covariance matrix, and accounts for correlations that arise from applying each surveillance
32
definition to the same charts. The results are summarized in eTable 5.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eMethods 3. National Weighting Methodology for Sepsis Incidence and Mortality
In order to obtain a weighted estimate of sepsis incidence and mortality in all U.S. hospitals,
study hospitals and American Hospital Association (AHA) acute care hospitals were stratified by bed size
(large - •EHGVmedium - 200-499 beds, and small - <200 beds), teaching vs nonteaching status (as
defined by the Accreditation Council for Graduate Medical Education), and U.S. region (Northeast, South,
West, and Midwest). Hospitals in the AHA database were excluded if they were rehabilitation, pediatric,
or psychiatric hospitals, or had zero general medical or surgical beds.
To account for the fact that the 49 Institute of Health Metrics (IHM) hospitals only had data from
July-December 2014, sepsis incidence and death rates for January-June 2014 were imputed by
averaging January-June sepsis incidence and mortality rates from IHM hospitals in 2013 and 2015. The
total number of hospital admissions for January-June 2014 were also imputed by averaging the overall
hospital admission rates in January-June vs July-December from calendar years 2013 and 2015.
The weighted sepsis incidence was obtained by a weighted mean of stratum specific sepsis
incidence, estimated from study hospitals, with weights proportional to the number of AHA adult
admissions in the stratum (eTable 3 below). The number of adult admissions in each hospital was not
available in the AHA database; thus, to project the number of adult sepsis cases in each stratum, we
multiplied the ratio of adult to total (adult and pediatric) admissions in our study hospitals against the AHA
estimate for total admissions in each stratum. The weighted mortality rate was calculated similarly.
Confidence intervals were generated based on the variance.
Standard errors and confidence intervals for the estimates were generated based on the binomial
distributions and accounting for both within- and between- hospital variations in sepsis and mortality
rates.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eTable 1. Characteristics of 2014 Study Hospitals versus American Hospital
Association (AHA) Acute Care Hospitals

Hospital Characteristic Study Hospitals (N=409) AHA Hospitals (N=4,810)

N % of Study N % of AHA
Cohort Cohort
Geographic Region
Northeast 56 13.7% 598 12.4%
South 205 50.1% 2,168 45.1%
Midwest 60 14.7% 1,096 22.8%
West 88 21.5% 948 19.7%
Teaching Status
Teaching 152 37.2% 1,425 29.6%
Nonteaching 257 62.8% 3,385 70.4%
AHA Hospital Size
Small (<200 beds) 220 53.8% 2,606 54.2%
Medium (200-499 beds) 155 37.9% 1,939 40.3%
/DUJH•EHGV 34 8.3% 265 5.5%

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eTable 2. Hospitals Contributing Data Each Year for 2009-2014 Trends Analysis

Year BWH Cerner IHM Emory UPMC HCA VAa Total Total Adult
b
Admissions
2009 1 50 33 0 0 0 0 84 696,807
2010 1 51 34 2 6 0 0 94 737,695
2011 1 48 27 2 9 0 0 87 747,236
2012 1 41 36 3 10 0 0 91 780,193
2013 1 73 53 3 11 137 0 278 2,485,637
2014 1 78 49 4 11 137 0 281 2,354,056

Abbreviations: BWH = Brigham and Women’s Hospital, Cerner = Cerner HealthFacts, IHM = Institute of Health Metrics, Emory =
Emory Healthcare, UPMC = University of Pittsburgh Medical Center, HCA = Hospital Corporation of America, VA = Veterans Affairs
Hospitals
a
Veterans Affairs Hospitals were not included for the trends analysis since they only provided data for 2014 and were unable to
provide granular institution and hospital case mix data.
b
The total number of adult hospitalizations from 2009-2014 was 7,801,624.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
 eTable 3. Sepsis Stratified by Hospital Characteristics in Study vs AHA Hospitals in 2014

Region Size Teaching AHA Study AHA Study Study % of Study Study Projected Projected
Status Hospitals Hospitals Admissions Admissions AHA Adult Adult Sepsis Sepsis
Admissions Sepsis Sepsis Cases Deaths
Cases Deaths
MW S T 42 9 93,330 41,769 44.8% 2,488 385 5,559 860
MW M T 120 7 1,398,302 76,091 5.4% 2,938 482 53,991 8,858
MW L T 36 3 947,093 43,155 4.6% 2,774 406 60,879 8,910
MW S N 728 34 611,166 71,714 11.7% 3,187 398 27,161 3,388
MW M+La N 170 7 1,114,379 60,340 5.4% 3,513 475 64,877 8,779
NE S T 30 8 93,136 35,237 37.8% 1,582 247 4,182 652
NE M T 201 9 2,548,213 99,780 3.9% 4,555 863 116,327 22,040
NE L T 56 5 1,944,739 119,804 6.2% 8,123 1,610 131,858 26,135
NE S N 168 28 300,015 94,859 31.6% 4,973 671 15,729 2,121
NE M N 138 4 989,448 45,689 4.6% 2,241 319 48,525 6,905
NE L N 5 2 166,721 8,771 5.3% 448 69 8,516 1,312
S S T 106 18 234,144 93,512 39.9% 4,714 667 11,802 1,670
S M T 419 53 4,737,772 669,097 14.1% 41,957 5,992 297,092 42,428
S L T 128 19 3,665,933 317,304 8.7% 19,227 3,353 222,141 38,742
S S N 1,036 67 1,214,262 241,005 19.8% 13,886 1,805 69,963 9,092
S M N 470 46 3,600,393 490,080 13.6% 32,682 4,415 240,099 32,436
S L N 9 2 232,093 9,499 4.1% 384 45 9,382 1,100
W S T 55 2 111,861 4,908 4.4% 205 15 4,672 342
W M T 203 16 2,431,704 159,130 6.5% 9,838 1,562 150,341 23,862
W L T 29 3 675,164 38,858 5.8% 3,079 647 53,498 11,242
W S N 441 54 467,995 165,980 35.5% 8,946 1,271 25,225 3,583
W M+La N 220 13 1,764,184 149,071 8.4% 10,037 1,523 118,784 18,023

Abbreviations: Regions - NE = northeast, MW = Midwest, S = south, W = west; Size - L = large •EHGVM = medium (200-499 beds), S = Small (<200 beds); Teaching Status – N
= nonteaching, T = teaching hospital. AHA = American Hospital Association.
a
The Midwest Large Nonteaching hospital stratum was combined with the Midwest Medium Non-teaching hospital stratum because there was only 1 AHA hospital in that stratum.
The West Large Nonteaching hospital stratum was combined with the West Medium Non-teaching hospital stratum for the same reason.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eTable 4. Sepsis Mortality Rates per Age Group, Sex, Race, and Hospital Type in
2014

Strata Patients per Sepsis Cases Sepsis Deaths

Strata
N N % of N Strata
Strata Mortality %
Overall 2,901,019 173,690 100% 26,061 15.0%
Age Category
20-39 years 555,722 11,475 2.1% 991 8.6%
40-59 years 731,904 40,975 5.6% 5,228 12.8%
60-79 years 1,123,203 80,857 7.2% 12,568 15.5%
• years 490,190 40,383 8.2% 7,274 18.0%
a
Sex
Male 1,493,335 100,030 6.7% 15,643 15.6%
Female 1,407,617 73,660 5.2% 10,418 14.1%
Race/Ethnicitya
White 1,946,801 117,081 6.0% 17,396 14.9%
Black 464,554 26,564 5.7% 3,862 14.5%
Hispanic 296,055 18,417 6.2% 2,635 14.3%
Asian 54,357 3,632 6.7% 608 16.7%
Other 79,210 4,497 5.7% 832 18.5%
b
Hospital Teaching Status
Teaching 1,660,773 98,516 5.9% 15,708 15.9%
Nonteaching 1,231,776 74,311 6.0% 10,142 13.6%
Hospital Sizeb
Small (<200 beds) 670,070 35,599 5.3% 4,841 13.6%
Medium (200-499 beds) 1,697,047 104,431 6.2% 15,153 14.5%
/DUJH•EHGV 525,432 32,797 6.2% 5,856 17.9%

a
Data was missing for 48 patients for sex and 60,042 patients for race/ethnicity.
b
One hospital in Puerto Rico did not have data on hospital characteristics and was excluded from the analysis.

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eTable 5. Accuracy of EHR Definition vs Claims Relative to Medical Record
Reviews

EHR Clinical Implicit or Explicit Explicit Sepsis

Surveillance Criteria Codes Codes
Sensitivity 69.7% 66.0% 32.3%
[52.9, 92.0%] [51.4, 80.7%] [24.4, 43.0%]
Specificity 98.1% 90.4% 99.3%
[97.7, 98.5%] [89.6, 91.6%] [99.1, 99.5%]
NPV 98.0% 97.6% 95.7%
[95.9, 99.6%] [95.8, 98.8%] [93.7, 97.3%]
PPV 70.4% 31.0% 75.2%
[64.0, 76.8%] [24.9, 40.4%] [69.8, 80.6%]
Abbreviations: NPV = negative predictive value, PPV = positive predictive value. Numbers in brackets refer to the 95% confidence
intervals.

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eTable 6. EHR Sepsis Definition vs Sepsis-3 by Chart Reviews: False Negatives

Reasons for EHR Surveillance False Negatives vs Sepsis-3 Chart Reviews False Negatives
(Total N=13)
5LVHLQ62)$VFRUHE\•SRLQWV but no EHR organ dysfunctiona 10
Hypoxemia without requiring mechanical ventilation 6
Hypotension without requiring vasopressors 2
Abnormal Glasgow Coma Scale 1
SOFA by creatinine but no doubling in baseline creatinine 3
SOFA by bilirubin but not bilirubin >2.0 mg/dL with doubling from baseline 1
SOFA by thrombocytopenia but platelets not <100 cells/μL with >50% decrease 2
from baseline
No blood cultures drawn 2
5LVHLQ62)$VFRUHE\•SRLQWVUHODWHGWRLQIHFWLRQRFFXUUHGRXWVLGHRIWKH-2 day 1
EHR surveillance window around blood culture dayb
a
Five cases hDGPXOWLSOHFRQWULEXWRUVWRDWRWDOULVHLQ62)$VFRUHE\•SRLQWVRQHSDWLHQWKDGK\SR[HPLDQRWUHTXLULQJ
mechanical ventilation (1 SOFA point) + hypotension not requiring vasopressors (1 SOFA point); one patient had hypoxemia not
requiring mechanical ventilation (1 SOFA point) + abnormal Glasgow Coma Scale (1 SOFA point); two patients had abnormal
creatinine and bilirubin contributing 1 SOFA point each; and one patient had abnormal creatinine and thrombocytopenia contributing
1 SOFA point each.
b
The case that occurred outside the ±2 day surveillance window developed a rise in creatinine and hypoxemic respiratory failure
OHDGLQJWRDULVHLQ62)$VFRUHE\•SRLQWV

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eTable 7. EHR Sepsis Definition vs Sepsis-3 by Chart Reviews: False Positives

Reasons for EHR Surveillance False Positives vs Sepsis-3 Chart Reviews False Positives
(Total N=57)
No infection present in retrospect despite blood culture order and antibiotics 25
Infection present, but EHR organ dysfunction not caused by infection:a 20
Vasopressor initiation 12
Mechanical ventilation initiation 3
Doubling in baseline serum creatinine RUGHFUHDVHLQH*)5E\• 4
7RWDOELOLUXELQ• mg/dL and doubling from baseline 1
Platelet count <100 cells/μL and decrease by •50% from baseline 2
EHR organ dysfunction criteria did not cause rise in SOFA by • 2 pointsb 12
LactDWH•2.0 mmol/L but no rise in SOFA by 2 11
7RWDOELOLUXELQ•DQGGoubling from baseline 1
Doubling in serum creatinine RUGHFUHDVHLQH*)5E\• 1

a
The various reasons why EHR organ dysfunction criteria were not caused by infection add up to more than the total N=20 in that
category because 2 cases had multiple non-sepsis related organ dysfunctions. These included a patient who had a doubling in
serum creatinine and mechanical ventilation unrelated to infection; and a patient with doubling in serum creatinine and decline in
platelet count by >50% to <100 unrelated to infection.
b
One patient had both lactate •DQGGRXEOLQJLQVHUXPFUHDWLQLQHZLWKRXWDFRUUHVSRQGLQJULVHLQ62)$VFRUHE\•SRLQWV

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eTable 8. Demographics and Clinical Characteristics for Sepsis Patients in 2014
Defined by Clinical Cultures

This table represents the patients who met EHR sepsis criteria when presumed infection was defined by
any clinical culture test rather than blood cultures alone. The list of clinical cultures used for this definition
is described in eAppendix C later in this Supplement.

Characteristic Patients with Sepsis

by Clinical Cultures
(n=204,663)
Age
Mean (SD), years 66.5 (15.5)
20-39 years (No., %) 13,622 (6.7)
40-59 years (No., %) 48,022 (23.5)
60-79 years (No., %) 95,251 (46.5)
•years (No., %) 47,768 (23.3)
Sex
Male (No., %) 116,188 (56.8)
Female (No., %) 88,474 (43.2)
Race/Ethnicitya
White (No., %) 138,385 (67.6)
Black (No., %) 30,991 (15.1)
Hispanic (No., %) 21,716 (10.6)
Asian (No., %) 4,159 (2.0)
Other (No., %) 5,249 (2.6)
Comorbidities
Diabetes (No., %) 72,356 (35.4)
Chronic Pulmonary Disease (No., %) 62,552 (30.6)
Congestive Heart Failure (No., %) 51,299 (25.1)
Renal Disease (No., %) 54,475 (26.6)
Cancer (No., %) 39,850 (19.5)
Dementia or Cerebrovascular Disease 20,994 (10.3)
Liver Disease (No., %) 20,416 (10.0)
HIV or AIDS (No., %) 1,940 (0.9)
Clinical Characteristics
Positive Blood Culturesb (No., %) 26,385 (18.2)
Required ICU Admission (No., %) 108,673 (53.1)
Median ICU LOS (Range)c 5 (1-6)
Median Hospital LOS (Range) c 10 (8-11)
Discharge Dispositiona
Home (No., %) 103,503 (50.6)
In-Hospital Death (No., %) 28,675 (14.0)
Hospice (No., %) 12,032 (5.9)
Non-Acute Care Facility (No., %) 50,213 (24.5)
Transfer to Acute Care Hospital (No., %) 4,879 (2.4)
Abbreviations: HIV=human immunodeficiency virus, AIDS = acquired immune deficiency syndrome, ICU = intensive care unit, LOS
= length of stay
a
Data was missing in 1 case for sex, 4,163 (2.0%) of cases for race/ethnicity and 5,361 (2.6%) of cases for discharge disposition.
b
Blood culture results were available in 280 of the 409 hospitals in our datasets; the percentage of positive blood cultures reflects
the denominator of sepsis cases in those 280 hospitals (n=170,735). Positive blood cultures excluded common skin contaminants
and were counted if they occurred anytime during hospitalization. The number of patients with positive blood cultures is higher than
that reported for the primary sepsis definition in Table 2 in the main manuscript because some patients met EHR clinical criteria for
sepsis based on concurrent clinical cultures + antibiotics + organ dysfunction and had positive blood cultures at another point during
hospitalization outside of the +/-2 day window where all criteria were required to occur.

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
c
The reported median ICU and hospital LOS represent the median of the median LOS values in each of the 7 datasets, along with
the range of medians across the datasets.
eTable 9. Trends for Sepsis Defined by Clinical Cultures
This table represents the adjusted trends in incidence, in-hospital mortality, and the combined outcome of
in-hospital death or discharge to hospice, for patients who met EHR sepsis criteria when presumed
infection was defined by any clinical culture test rather than blood cultures alone. “Sepsis With Lactate”
refers to the surveillance definition that included elevate lactate as a criterion for organ dysfunction, while
“Sepsis Without Lactate” excluded the lactate criterion. As with the trend analyses for the blood culture-
based EHR surveillance definitions, VA hospitals were excluded.

Sepsis With Lactate Sepsis Without Lactate

(by Clinical Cultures) (by Clinical Cultures)
Incidence Mortality Death or Incidence Mortality Death or
Hospice Hospice
Discharge Discharge
Adjusted 6.1% 17.8% 23.2% 5.5% 18.9% 24.4%
2009 vs [5.0-7.2%] [15.8-19.8%] [21.0-25.4%] [4.4-6.6%] [16.7-21.2%] [21.9-26.9%]
2014 rate vs vs vs vs vs vs
7.3% 14.1% 21.1% 5.8% 15.9% 22.6%
[7.2-7.3%] [13.9-14.2%] [20.9-21.3%] [5.8-5.8%] [15.6-16.1%] [22.3-22.8%]
Annual
Relative +3.6% -4.9% -1.9% +1.1% -3.6% -1.6%
Change [-0.1,+7.3%] [-7.2,-2.5%] [-3.8,+0.0%] [-2.8,+5.1%] [-6.1,-1.2%] [-3.7,+0.5%]
[95% CI]
p-value 0.06 <0.001 0.052 0.58 0.003 0.14
for trend

ΞϮϬϭϳŵĞƌŝĐĂŶDĞĚŝĐĂůƐƐŽĐŝĂƚŝŽŶ͘ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘
eFigure 1. Overall Sepsis Rates and Outcomes in Each Study Dataset in 2014

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Each data point represents the mean rate of the specified variable in one of the 7 study datasets. The “presumed infection cases
with sepsis” refers to the proportion of patients meeting presumed infection criteria (blood culture + 4 qualifying antibiotic days) that
KDG• concurrent organ dysfunction criteria. Bars represent the 95% confidence intervals. The datasets are presented in no
specific order.

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eFigure 2. Organ Dysfunction Rates Among Sepsis Cases in Each Study Dataset
in 2014

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order.

Thresholds for laboratory-based organ dysfunction criteria are as follows (as described in Box 1 in the main manuscript):
hyperlactatemia - VHUXPODFWDWH•PPRO/DFXWHNLGQH\LQMXU\- doubling in baseline creatinine or decrease in estimated
glomerular filtration rate by •WKURPERF\WRSHQLD- decrease LQEDVHOLQHSODWHOHWVE\•ZLWKEDVHOLQHSODWHOHWV!100 cells/μL;
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eFigure 3. Sepsis Trends in Hospitals with Continuous Data from 2009-2014:
A) Incidence, B) In-Hospital Mortality
In this sensitivity analysis, there were 556,029 patients included at 6 hospitals that reported data each
year from 2009-2014. Bars represent the 95% confidence intervals. Numbers adjacent to each line
represent the mean relative change per year, with p-value indicative of significance of the trend.

“Clinical Criteria” refer to blood cultures + antibiotics and at least one concurrent organ dysfunction (refer
to Box 1 in the main manuscript). “Clinical Criteria Without Lactate” is the same except without the
criterion for lactate •PPRO/

“Explicit Sepsis Codes” refers to hospitalizations with diagnoses of severe sepsis (995.92) or septic shock
(785.52) on discharge. “Implicit Sepsis Codes” refers to hospitalizations with at least one infection
diagnosis and one organ dysfunction diagnosis.

For panel B, the total number of sepsis cases per year for each definition was: Clinical Criteria – 4,154
(2009), 4,648 (2010), 4,565 (2011), 4,455 (2012), 4,270 (2013), 4,232 (2014); Clinical Criteria Without
Lactate – 3,901 (2009), 4,261 (2010), 4,090 (2011), 3,934 (2012), 3,664 (2013), 3,531 (2014); Implicit or
Explicit Codes – 6,779 (2009), 7,533 (2010), 7,908 (2011), 8,346 (2012), 9,526 (2013), 10,056 (2014);
Explicit Codes – 1,342 (2009), 1,687 (2010), 1,622 (2011), 1,652 (2012), 1,672 (2013), 1,725 (2014).

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eReferences
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of Universal Decolonization in Adult Intensive Care Units Reduces Central Line-associated
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2. Schweizer ML, Chiang HY, Septimus E, et al. Association of a bundled intervention with surgical
site infections among patients undergoing cardiac, hip, or knee surgery. JAMA.
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3. Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent
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Methicillin-Resistant Staphylococcus aureus Isolates in the REDUCE-MRSA Trial. J Clin
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5. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of
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6. Septimus EJ, Hayden MK, Kleinman K, et al. Does chlorhexidine bathing in adult intensive care
units reduce blood culture contamination? A pragmatic cluster-randomized trial. Infect Control
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7. Huang SS, Septimus E, Hayden MK, et al. Effect of body surface decolonisation on bacteriuria
and candiduria in intensive care units: an analysis of a cluster-randomised trial. Lancet Infect Dis.
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Health Record on productivity in the Veterans Health Administration. Health Econ Policy Law.
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9. Prescott HC, Kepreos KM, Wiitala WL, Iwashyna TJ. Temporal Changes in the Influence of
Hospitals and Regional Healthcare Networks on Severe Sepsis Mortality. Crit Care Med.
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10. Render ML, Deddens J, Freyberg R, et al. Veterans Affairs intensive care unit risk adjustment
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11. Cooke CR, Kennedy EH, Wiitala WL, Almenoff PL, Sales AE, Iwashyna TJ. Despite variation in
volume, Veterans Affairs hospitals show consistent outcomes among patients with non-
postoperative mechanical ventilation. Crit Care Med. 2012;40(9):2569-2575.
12. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third
International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA.
2016;315(8):762-774.
13. Choudhry SA, Li J, Davis D, Erdmann C, Sikka R, Sutariya B. A public-private partnership
develops and externally validates a 30-day hospital readmission risk prediction model. Online J
Public Health Inform. 2013;5(2):219.
14. Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial
infarction. JAMA. 2012;307(2):157-164.
15. Grodzinsky A, Goyal A, Gosch K, et al. Prevalence and Prognosis of Hyperkalemia in Patients
with Acute Myocardial Infarction. Am J Med. 2016;129(8):858-865.
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Models for Hospitalized Patients With Acute Decompensated Heart Failure. Circ Heart Fail.
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17. Chan WW, Waltman Johnson K, Friedman HS, Navaratnam P. Association between cardiac,
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18. Andes D, Azie N, Yang H, et al. Drug-Drug Interaction Associated with Mold-Active Triazoles
among Hospitalized Patients. Antimicrob Agents Chemother. 2016;60(6):3398-3406.
19. Petrick JL, Nguyen T, Cook MB. Temporal trends of esophageal disorders by age in the Cerner
Health Facts database. Ann Epidemiol. 2016;26(2):151-154 e151-154.

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20. Klompas M, Kleinman KP, Karcz A. Variability in mean duration of mechanical ventilation among
community hospitals. Infect Control Hosp Epidemiol. 2012;33(6):635-637.
21. Howard DH, Karcz A, Roback JD. The accuracy of claims data for measuring transfusion rates.
Transfus Med. 2016.
22. Murphy SN, Chueh HC. A security architecture for query tools used to access large biomedical
databases. Proc AMIA Symp. 2002:552-556.
23. Rhee C, Murphy MV, Li L, et al. Comparison of Trends in Sepsis Incidence and Coding Using
Administrative Claims Versus Objective Clinical Data. Clin Infect Dis. 2015;60(1):88-95.
24. Rhee C, Murphy MV, Li L, et al. Improving documentation and coding for acute organ dysfunction
biases estimates of changing sepsis severity and burden: a retrospective study. Crit Care.
2015;19:338.
25. Rhee C, Murphy MV, Li L, et al. Lactate Testing in Suspected Sepsis: Trends and Predictors of
Failure to Measure Levels. Crit Care Med. 2015;43(8):1669-1676.
26. Rhee C, Kadri S, Huang SS, et al. Objective Sepsis Surveillance Using Electronic Clinical Data.
Infect Control Hosp Epidemiol. 2016;37(2):163-171.
27. Lyu PF, Hockenberry JM, Gaydos LM, Howard DH, Buchman TG, Murphy DJ. Impact of a
Sequential Intervention on Albumin Utilization in Critical Care. Crit Care Med. 2016;44(7):1307-
1313.
28. Murphy DJ, Lyu PF, Gregg SR, et al. Using Incentives to Improve Resource Utilization: A Quasi-
Experimental Evaluation of an ICU Quality Improvement Program. Crit Care Med.
2016;44(1):162-170.
29. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data
capture (REDCap)--a metadata-driven methodology and workflow process for providing
translational research informatics support. J Biomed Inform. 2009;42(2):377-381.
30. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of
severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.
Crit Care Med. 2001;29(7):1303-1310.
31. Iwashyna TJ, Odden A, Rohde J, et al. Identifying patients with severe sepsis using
administrative claims: patient-level validation of the angus implementation of the international
consensus conference definition of severe sepsis. Med Care. 2014;52(6):e39-43.
32. Kosinski AS. A weighted generalized score statistic for comparison of predictive values of
diagnostic tests. Stat Med. 2013;32(6):964-977.

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II. DATA SPECIFICATIONS FOR IMPLEMENTING THE EHR SEPSIS DEFINITION

Introduction / Overview

The remainder of this document details the data elements and structure of input EHR datasets used to
implement the case-finding sepsis surveillance definition and the analyses performed in the study.
Essentially, after 9 input datasets were created, a series of SAS codes were run to produce a set of
output data tables. The actual SAS code can be provided as a separate set of files by request to
crhee@bwh.harvard.edu.

The project code anticipates the following files structure when running the analysis:
x Project Folder (e.g. "CDC National Sepsis Surveillance Project", specific name not necessary)
x Sub-Folder Name: "Raw Datasets" - includes all of the input datasets specified below
x Sub-Folder Name: "Working Datasets” - includes working datasets for SAS code
x Sub-Folder Name: "Output Tables" - includes results tables for final reporting
x Sub-Folder Name: "SAS Code" - includes all scripts unzipped

Step-by-step instructions are detailed below:

1. Ensure that all 9 input datasets are structured correctly for the analysis. These are detailed in
eAppendix D, and are summarized briefly below:
i. “Basic” – demographics and basic clinical characteristics (e.g. admit/discharge date, ICU
admit/discharge date, discharge disposition)
ii. “Diagnosis” – discharge diagnosis codes
iii. “Procedure” – procedure codes (daily)
iv. “Medication” – medication prescribing or dispensing information (on a daily basis),
specifically antimicrobials and vasopressors*
v. “Laboratory” – laboratory data (dates and results) for lactate, creatinine ± estimated GFR,
total bilirubin, platelet count
vi. “Blood_Culture” – date of blood culture draws (regardless of result)
vii. “Pos_Blood_Culture” – date of positive blood cultures
viii. “Clinical_Culture” – date of clinical culture draws (regardless of result)
ix. “Hospital” – information on hospitals, if multiple hospitals in a dataset

*The scripts assume that standardized medication names are included the Medication dataset before
running the code. Please refer to eAppendix B below for information on the antimicrobials and
vasopressors that were included. Cultures should be separated into three input datasets before
running the code. These three datasets are Blood_Culture (blood cultures only), Pos_Blood_Culture
(blood cultures with positive results), and Clinical_Culture (all clinical cultures) (described in
eAppendix C).

2. Once the input datasets are prepared to match the documentation in the Data Spec, place the input
datasets in an empty folder “Input Datasets”.

3. Examine the table “Overview of SAS Programs” (eAppendix E) for a thorough explanation of each
SAS program. This table includes the sequence, purpose, inputs, and outputs of each SAS program.
A glossary of terms that are used in the output tables is provided in eAppendix F.

4. Begin running the SAS programs (provided separately). Start by running the file “0.0-
user_inputs_v2.sas” to add the necessary information for the remaining SAS programs to run
properly. This includes the full project path (ex: C:\Users\jdoe\Documents\…\CDC National Sepsis
Surveillance Project) and the names of each input dataset placed into the “Input Datasets” folder. No
additional changes beyond what is in this program should be needed to run the analysis. Then run
the SAS programs in the order described in “Overview of SAS Programs”, beginning with “0.0-
user_inputs_v2.sas”. As the programs run, they will fill the folder “Working Datasets” with interim
datasets. The final six programs will fill the folder “Output Tables” with the results.

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eAppendix A. Detailed Description of EHR Sepsis Surveillance Definition

PRESUMED SERIOUS INFECTION

1. Blood Culture obtained
x The blood culture day is the center of a +/-2 day surveillance window period. Sensitivity analyses
were also performed using a broader set of clinical cultures (see eAppendix C).
x Multiple windows during a hospitalization are possible. The surveillance schedule utilizes a “sliding
window” that allows for overlap if multiple blood cultures are drawn in short period of time.
2. •³4XDOLI\LQJ$QWLELRWLF'D\V´4$'– starting within +/-2 days of BC Day:
x First QAD = first day in +/-2 day window period that patient receives a “new antibiotic” (“new” = not
given in the prior 2 calendar days. “New” treats PO and IV formulations of an antibiotic the same
way, EXCEPT for vancomycin). IV and IM antibiotics are treated as equivalents. See eAppendix B
for list of antibiotics that count as potential QADs.
x Subsequent QADs can be the same antibiotic, or different antibiotics as long as first dose of each
antibiotic in the sequence is “new” (i.e., not given in prior 2 calendar days).
x A gap of a single calendar day between administrations of the same antibiotic (PO or IV) count as
QADs as long as the gap is not >1 day. (For example: IV Levofloxacin on Day 1, then PO
Levofloxacin on Days 3, 5, and 7 = 7 QADs).
x There must be at least one new parenteral (IV/IM) antibiotic within the +/-2 day window period.
x For an inpatient, if death, discharge to another hospital, or discharge to hospice occurs before 4
QADs have elapsed, then the patient the patient can qualify for presumed infection with <4 QADs
so long as they have consecutive QADs until day of, or 1 day prior to, death or discharge . For a
patient only seen in the ED or ED observation unit, a QAD is required each day until day of, or 1
day prior to, death.
ACUTE ORGAN DYSFUNCTION
3. Any one of the following, within +/- 2 days of Blood Culture:
x Initiation of a new vasopressor (any dose for any duration): norepinephrine, dopamine, epinephrine,
phenylephrine, vasopressin. To count as a new vasopressor, that specific vasopressor cannot
have been administered in the prior calendar day.
x Initiation of invasive mechanical ventilation. To count as “initiation”, there must be >1 calendar day
between mechanical ventilation episodes. Invasive mechanical ventilation can be identified by
ICD-9 codes (96.7, 96.71, 96.72) or CPT codes (94002, 94003, 94004, 94656, 94657), or directly
from EHR clinical data if available.
x Doubling of serum creatinine RUGHFUHDVHE\•RIH*)5UHODWLYHWREDVHOLQH* - excluding
patients with ICD-9 code for end-stage renal disease (585.6)
x 7RWDOELOLUXELQ•PJG/DQGdoubling from baseline*
x 3ODWHOHWFRXQWFHOOV—/DQG•GHFOLQHIURPEDVHOLQH* - EDVHOLQHPXVWEH•FHOOV—/
x 6HUXP/DFWDWH•PPRO/1RWHIRUthe primary analysis of sepsis trends over time, we excluded
this criterion.)
Sepsis = Presumed Infection •$FXWH2UJDQ'\VIXQFWLRQZLWKLQ-2 days of blood culture day
6HSWLF6KRFN 3UHVXPHG,QIHFWLRQ9DVRSUHVVRU/DFWDWH•PPRO/ZLWKLQ“GD\VRIEORRGFXOWXUH
day

*To determine the “baseline” laboratory values for Creatinine, eGFR, Total Bilirubin, and Platelets:

Determine if the patient had hospital-onset infection vs infection present-on-admission.

x “Hospital-Onset Infection” (vs “Present-on-Admission” Infection) – requires that the Blood
Culture Day and First QAD occur on or after day 3 of admission (where day 1 = day of
admission). In this case, baseline creatinine or bilirubin = lowest value during +/-2 day window
period (around the Blood Culture Day), and baseline eGFR and platelet count = highest value
during +/-2 day window period.
x “Present-on-Admission Infection” – requires that the Blood Culture Day OR First QAD occur
on day 1 or 2. In this case, baseline creatinine or bilirubin = lowest value during hospitalization,
and baseline eGFR and platelet count = highest during hospitalization.

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“Hospital Onset Sepsis” (vs Sepsis “Present-On-Admission”) – requires all 3 of the following occur
on calendar day 3 or later of hospitalization (where day 1 = admission day):
x Blood Culture, First QAD, and all Organ Dysfunction Criteria. In other words, the “Sepsis Onset
Day” is the earliest day in the window period where the blood culture, first QAD, or organ
dysfunction criteria is met. Hospital-onset sepsis requires sepsis onset day to be day 3 or
greater.
x A sepsis case should be defined as Present-on-Admission Sepsis if any one of (Blood Culture
Day, First QAD, or any Organ Dysfunction criteria) occurs on days 1 or 2.

When using blood culture, antibiotic, laboratory, or vasopressor / mechanical vent data to calculate sepsis
cases, data from day -1 and day 0 (i.e. 2 days prior to admission) should be allowed to qualify for sepsis.
(This is to account for data that might result from care in the emergency department prior to admission.)

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eAppendix B. Medications Used in Study (Antibiotics and Vasopressors)

For purposes of case-finding criteria, the antibiotics were divided into parenteral (IV) and oral (PO)
antibiotics. “Antibiotics” include antibacterial, antifungal, and antiviral agents. All PO and IV antibiotics
were considered identical for purposes of determining whether an antibiotic is “new” or not (meaning that
a switch from IV to PO or vice versa does not count as a “new antibiotic.”) The one exception is IV vs PO
Vancomycin (meaning that a switch from IV to PO vancomycin, or initiation of PO vancomycin while still
on IV vancomycin, and vice versa, all count as “new” antibiotics). Intramuscular (IM) antibiotics were
treated equivalently as IV antibiotics. The generic names of the antimicrobials included are listed below.

ANTIBIOTICS
IV Antibacterials
amikacin, ampicillin, ampicillin/sulbactam, azithromycin, aztreonam, cefamandole, cefazolin, cefepime,
cefmetazole, cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftaroline, ceftazidime,
ceftazidime/avibactam, ceftizoxime, ceftolozane/tazobactam, ceftriaxone, cefuroxime, cephalothin,
cephapirin, chloramphenicol, ciprofloxacin, clindamycin, cloxacillin, colistin, dalbavancin, daptomycin,
doripenem, doxycycline, ertapenem, gatifloxacin, gentamicin, imipenem, kanamycin, levofloxacin,
lincomycin, linezolid, meropenem, methicillin, metronidazole, mezlocillin, minocycline, moxifloxacin, nafcillin,
oritavancin, oxacillin, penicillin, piperacillin, pileracillin/tazobactam, polymyxin B, quinupristin/dalfopristin,
streptomycin, tedizolid, telavancin, ticarcillin, ticarcillin/clavulanate, tigecycline, tobramycin,
trimethoprim/sulfamethoxazole, vancomycin
PO Antibacterials
amoxicillin/clavulanate, amoxicillin, ampicillin, azithromycin, cefaclor, cefadroxil, cefdinir, cefditoren,
cefixime, cefpodoxime, cefprozil, ceftibuten, cefuroxime, cephalexin, cephradine, chloramphenicol,
cinoxacin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, dicloxacillin, doxycycline, fidaxomicin,
fosfomycin, gatifloxacin, levofloxacin, lincomycin, linezolid, metronidazole, minocycline, moxifloxacin,
nitrofurantoin, norfloxacin, ofloxacin, penicillin, pivampicillin, rifampin, sulfadiazine, sulfadiazine-trimethoprim,
sulfamethoxazole, sulfisoxazole, tedizolid, telithromycin, tetracycline, trimethoprim, trimethoprim-
sulfamethoxazole, vancomycin
IV Antifungals
amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole,
voriconazole
PO Antifungals
fluconazole, itraconazole, posaconazole, voriconazole
IV Antivirals
acyclovir, ganciclovir, cidofovir, foscarnet, peramivir
PO Antivirals
Oseltamivir

The five vasopressors of interest were Norepinephrine, Epinephrine, Dopamine, Vasopressin, and
Phenylephrine. We only included intravenous administrations of vasopressors, and excluded
vasopressors that were clearly single bolus injections rather than continuous infusions.

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eAppendix C. Definitions of Blood Cultures and Clinical Cultures

For the primary EHR surveillance definition, blood cultures were used as the center of the surveillance
window (regardless of blood culture results). We included bacterial (aerobic and/or anaerobic), acid-fast
bacilli (AFB), and fungal blood cultures. Blood cultures for specific viruses (e.g., cytomegalovirus) were
excluded.

For a sensitivity analysis, a broader range of clinical cultures were used to define suspected infection,
detailed below.

TESTS INCLUDED AS “CLINICAL CULTURES”

Bacterial, fungal, or acid-fast bacilli cultures from the following sites: blood, urine, respiratory,
cerebrospinal fluid, pleural, peritoneal, joint/synovial, abscess, wound, sinus, drain, catheter tip, medical
devices, stool
Respiratory viral tests (rapid antigen, direct fluorescent antibody, polymerase chain reaction): influenza,
parainfluenza, respiratory syncytial virus, adenovirus, metapneumovirus
Clostridium difficile toxin assays (ELISA or polymerase chain reaction)
Specific organism antigens from serum, urine, or cerebrospinal fluid, such as: Cryptococcus,
Histoplasma, Haemophilus influenza, Streptococcus pneumoniae, Legionella pneumophila
Specific organism cultures or smears, such as: Pneumocystis, Nocardia, Legionella, Malaria
Notable microbiology tests that were not included: Surveillance cultures (e.g., MRSA, VRE), tests for
sexually transmitted diseases, HIV tests, parasite tests, H. pylori, Hepatitis, Fungal markers
(galactomannan, beta-D-glucan), serological tests (IgM, IgG), Gram stains alone without a culture, non-
respiratory viral cultures or PCRs (e.g., CMV)

Growth of any organism from a blood culture was considered to be positive, with the exception of the
following common skin contaminants:

x Coagulase negative Staphylococci

x Bacillus species not anthracis
x Corynebacterium species
x Aerococcus species
x Micrococcus species
x Propionibacterium species

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eAppendix D. Input Datasets Required to Run Sepsis Algorithm

1. Dataset Name: “Basic”

Variable Name Description SAS Variable Type Values
"000001",
A unique ID for each patient, consistent Numeric or
patient_id "000002",…
across different hospitalizations Character
1, 2, 3...
A unique identifier for every unique
000001,
hospitalization. One patient with multiple Numeric or
admission_id "000002",…
admissions will have a unique Character
1, 2, 3…
admission_id for each admission.
000001,
Numeric or
hospital_id Unique Hospital Identifier "000002",…
Character
1, 2, 3…
age_yrs Age in years at admission Numeric Integer Values
1-M
gender Patient Gender Numeric
2-F
1 - white
Patient Race-ethnicity 2 - black
Note: Hispanic is often listed as a race. 3 - asian
race If listed separately as Ethnicity, this Numeric 4 - hispanic
takes precedence; . i.e. White Race + 5 - other
Hispanic Ethnicity = Hispanic . - not identified /
missing
Day of hospital discharge relative to
discharge_date Numeric Integer Values
admission day
1 - Home
2 - Transfer to
another acute
care hospital
discharge_dispo Discharge disposition of patient Numeric
3 - Subacute
facility
4 - Death
5 - Hospice
Calendar year of hospitalization (based
year Numeric 4-digit year
on date of admission)
Day of first admission to ICU (relative to
icu_admitdate Numeric Integer Values
admit date)

Total number of calendar days in the

icu_los Numeric Integer Values
ICU

2. Dataset Name: “Diagnosis”

Description: This table should include one row for each unique diagnosis_code/day combination. If
a patient receives the same diagnosis code multiple times in a day, only a single row is needed.
Repeated diagnosis codes in a single encounter but on different days receive separate rows.
Variable Name Description SAS Variable Type Values
A unique ID for each patient, consistent "000001",
patient_id Numeric or Character
across different hospitalizations "000002",…

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 1, 2, 3...

A unique identifier for every unique

000001,
hospitalization. One patient with multiple
admission_id Numeric or Character "000002",…
admissions will have a unique
1, 2, 3…
admission_id for each admission.

Diagnosis code – either ICD-9 or CPT. No

diagnosiscode Character ex: "99591"
decimal points.
"ICD9" - ICD-9
Used to distinguish between ICD and CPT codes
codetype Character
codes "CPT4" - CPT
codes
1 - primary
Sequence of codes at discharge (for ICD-9
sequenceno Numeric 2 - non-
codes).
primary

Present on admission flag (for ICD-9 1 - yes

POA Numeric
codes) 0 - no

Primary (or Principal) Diagnosis at

primary_dx Character ex: "99591"
discharge.

admit_dx Admitting Diagnosis (if available) Character ex: "99591"

3. Dataset Name: “Procedure”

Description: This table should include one row for each unique procedure_code/day combination.
If a patient receives the same diagnosis code multiple times in a day, only a single row is needed.
Repeated procedure codes in a single encounter but on different days receive separate rows.
Variable Name Description SAS Variable Type Values
A unique ID for each patient,
"000001", "000002",…
patient_id consistent across different Numeric or Character
1, 2, 3...
hospitalizations
A unique identifier for every
unique hospitalization. One
000001, "000002",…
admission_id patient with multiple admissions Numeric or Character
1, 2, 3…
will have a unique admission_id
for each admission.

Diagnosis code – either ICD-9 or

procedure_code Character ex: "9670"
CPT. No decimal points.

Used to distinguish between ICD "ICD9" - ICD-9 codes

ICD9orCPT Character
and CPT codes "CPT4" - CPT codes
Day on which the procedure
day Numeric Integer Values
occurred

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4. Dataset Name: “Medication”

Description: This table should include one row for each unique medication administration (or
medication prescription if administration is unavailable).

Variable
Description SAS Variable Type Values
Name
"000001",
A unique ID for each patient, consistent Numeric or
patient_id "000002",…
across different hospitalizations Character
1, 2, 3...

A unique identifier for every unique

000001,
hospitalization. One patient with multiple Numeric or
admission_id "000002",…
admissions will have a unique admission_id Character
1, 2, 3…
for each admission.

Day on which the medication was

day Numeric Integer Values
administered

ex:
"Vancomycin",
med Medication name Character "Cefepime"
String case does
not matter.
"IV" -
Intravenous
Route Administration route of medication Character "PO" - Oral
"Other" - Other
Route

1:
Vasopressors*
2: Systemic
Antibiotics
med_type Type of medication provided Numeric 3: Warfarin**
4: Inotropes**
5: Antifungal
6: Antiviral

* Vasopressor medication type includes IV norepinephrine, epinephrine, phenylephrine, dopamine, and

vasopressin. Systemic antibiotics include antibacterials, antifungals, and antivirals.
**Warfarin and inotropes were included in the original data spec but ultimately not used for the analysis.

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5. Dataset Name: “Laboratory”

Description: This table should include one row for each day that a patient received any of the relevant
lab value measurements.

Variable Name Description SAS Variable Type Values

"000001",
A unique ID for each patient, consistent
patient_id Numeric or Character "000002",…
across different hospitalizations
1, 2, 3...
A unique identifier for every unique
000001,
hospitalization. One patient with multiple
admission_id Numeric or Character "000002",…
admissions will have a unique admission_id
1, 2, 3…
for each admission.

Day Day on which the lab values were measured Numeric Integer Values
Maximum estimated glomerular filtration rate
2
for day (mL/min/1.73m ). Note that any Decimal
egfr_max* Numeric
eGFR value >60 should be set as equal to Values
60
Minimum estimated glomerular filtration rate
2
for day (mL/min/1.73m ). Note that any Decimal
egfr_min* Numeric
eGFR value >60 should be set as equal to Values
60
Maximum measured creatinine levels for day Decimal
cr_max Numeric
(mg/dL) Values
Minimum measured creatinine levels for day Decimal
cr_max Numeric
(mg/dL) Values
Maximum measured bilirubin levels for day Decimal
tbili_max Numeric
(mg/dL) Values
Minimum measured bilirubin levels for day Decimal
tbili_min Numeric
(mg/dL) Values
Maximum measured platelet levels for day Decimal
plt_max 9 Numeric
(10 /L) Values
Minimum measured platelet levels for day Decimal
plt_min Numeric
(109/L) Values
Decimal
lactate_max Maximum measured lactate for day (mmol/L) Numeric
Values
Decimal
lactate_min Minimum measured lactate for day (mmol/L) Numeric
Values
* Note that a lab reporting 'creatinine clearance' can be used interchangeably with eGFR

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6. Dataset Name: “Blood_Culture”

Description: This table should include all blood culture orders for encounters in the basic dataset,
where each row is a unique blood culture order.

Variable Name Description SAS Variable Type Values

"000001",
A unique ID for each patient, consistent Numeric or
patient_id "000002",…
across different hospitalizations Character
1, 2, 3...

A unique identifier for every unique

000001,
hospitalization. One patient with multiple Numeric or
admission_id "000002",…
admissions will have a unique admission_id Character
1, 2, 3…
for each admission.

Day on which the blood culture was drawn Integer

bcx_drawn_day Numeric
relative to admission day Values

7. Dataset Name: “Pos_Blood_Culture”

Description: This table should include only positive blood culture orders for encounters in the basic
dataset, where each row is a unique blood culture order. "Positive blood culture" excludes common
skin contaminants (e.g., coagulase negative Staphylococci, Bacillus sp. not anthracis, Corynebacterium,
Aerococcus, Micrococcus, Propionibacterium sp.).
Variable Name Description SAS Variable Type Values
"000001",
A unique ID for each patient, consistent
patient_id Numeric or Character "000002",…
across different hospitalizations
1, 2, 3...

A unique identifier for every unique

000001,
hospitalization. One patient with multiple
admission_id Numeric or Character "000002",…
admissions will have a unique
1, 2, 3…
admission_id for each admission.

Day on which the blood culture was

bcx_drawn_day Numeric Integer Values
drawn relative to admission day

8. Dataset Name: Clinical_Culture

Description: This table should include all blood culture orders and additional clinical cultures
outlined in eAppendix C for encounters in the basic dataset, where each row is a unique culture order.

Variable Name Description SAS Variable Type Values

"000001",
A unique ID for each patient, consistent Numeric or
patient_id "000002",…
across different hospitalizations Character
1, 2, 3...

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 A unique identifier for every unique
000001,
hospitalization. One patient with multiple Numeric or
admission_id "000002",…
admissions will have a unique admission_id Character
1, 2, 3…
for each admission.

Day on which the clinical culture was drawn Integer

bcx_drawn_day Numeric
relative to admission day Values

9. Dataset Name: “Hospital”

Description: This table should include one row for each hospital represented in the dataset.

Variable Name Description SAS Variable Type Values

"000001",
Numeric or
hospital_id Unique Hospital Identifier "000002",…
Character
1, 2, 3...

ex: "MA"
state_code 2-digit state abbreviation Character
ex: "TX"
beds Total number of inpatient beds Numeric Integer Values
1 - Teaching
hospital
teaching To denote if hospital teaching status Numeric
2 - Nonteaching
hospital
Total number of discharges for
annual_discharges Numeric Integer Values
patients aged 20+ per year

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eAppendix E. Overview of SAS Programs

Order SAS code Purpose Input Dataset(s) Output Dataset(s)

0 - User Inputs
Define project
folder path and
1 0.0-user_inputs_v#
input dataset
names
1 - EHR SEPSIS DEFINITION
- Create Datasets
Calculate
mechanical
2 1.0-mechvent_v# ventilator raw.procedure sepsis.mechvent
diagnosis using
procedure data
- Sepsis Algorithm
Calculate infection
cases using blood raw.basic,
3 1.1-ehr_infection_v# culture, raw.blood_culture, sepsis.ehr_infection
medication, and raw.medication
basic dataset
raw.basic,
Create organ raw.blood_culture,
1.2- dysfunction raw.diagnosis,
4 ehr_organ_dysfunction variables used in raw.laboratory, sepsis.ehr_organ_dys
_v# the sepsis raw.medication,
definitions sepsis.mechvent,
sepsis.ehr_infection
raw.basic,
Calculate sepsis
raw.blood_culture,
variables using
5 1.3-ehr_sepsis_def_v# sepsis.ehr_infection, sepsis.ehr_sepsis_def
infection and organ
sepsis.ehr_organ_d
dysfunction criteria
ys
2 - SENSITIVITY ANALYSIS
- Create Datasets
raw.basic,
raw.medication,
2.0- Create bacteremic
6 raw.pos_blood_cultu sepsis.bacteremic_sepsis
bacteremic_sepsis_v# sepsis dataset
re,
sepsis.ehr_infection
- Sepsis Algorithm
Calculate infection
cases using raw.basic,
2.1-
7 clinical culture, raw.medication, sepsis.ehr_infection_cc
ehr_infection_cc_v#
medication, and raw.clinical_culture
basic dataset
raw.basic,
Create organ
raw.diagnosis,
dysfunction
2.2- raw.laboratory,
variables used in
8 ehr_organ_dysfunction raw.medication, sepsis.organ_dys_cc
various sepsis
_cc_v# raw.clinical_culture,
definitions for
sepsis.mechvent,
clinical culture data
sepsis.ehr_infection

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 _cc

raw.basic,
Calculate sepsis
raw.clinical_culture
variables using
2.3- sepsis.ehr_infection
9 infection and organ sepsis.ehr_sepsis_def_cc
ehr_sepsis_def_cc_v# _cc,
dysfunction criteria
sepsis.ehr_organ_d
for clinical cultures
ys_cc
Macro code for
angus
10 2.4-angus_v#
dombrovskiy
definitions
Calculate angus raw.basic,
2.5-
11 and dombrovskiy raw.diagnosis, sepsis.ehr_angus_domb
ehr_angus_domb_v#
diagnosis raw.procedure
2.6- Calculate severe
12 raw.diagnosis sepsis.ehr_severe_sepsis
ehr_severe_sepsis_v# sepsis definition
3- CALCULATE COMORBIDITIES FOR FINAL TABLES
- Charlson Comorbidities
Macro code for
13 3.0-charlson_macro_v# Charlson
Comorbidities
Calculate Charlson
raw.basic,
3.1- Comorbidities
14 raw.diagnosis, sepsis.charlson
sepsis_charlson_v# using
raw.procedure
Charlson_macro
- Elixhauser comorbidities
Create format
library of ICD
15 3.2-comofmt_analy_v# codes and labels
for Elixhauser
Comorbidities
Macro code that
creates
comorbidity
variables based on
the presence of
3.3- secondary
16
elixhauser_macro_v# diagnoses and
redefines
comorbidity group
by eliminating
DRGs directly
related to them.
Calculate
Elixhauser scores
for comorbidities raw.basic,
17 3.4-elixhauser_v# sepsis.elixhauser
[NOTE: does not raw.diagnosis
use DRG to
calculate scores]
4 - TABLES FOR FINAL REPORTING

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 raw.basic,
Table 1.1 Overall
raw.blood_culture,
Incidence and
raw.hospital,
Mortality of Adults
sepsis.bacteremic_s
(>= 20) meeting
4.0- epsis,
infection and all table1_sepsis_mortality1.
18 table1_sepsis_mortality sepsis.ehr_sepsis_d
Sepsis definitions xml
1_v# ef,
(stratified by
sepsis.ehr_angus_d
hospital and
omb,
community onset)
sepsis.ehr_severe_s
criteria
epsis
raw.basic,
Table 1.2-4 Overall raw.blood_culture,
Incidence and raw.hospital
table1_sepsis_mortality2
Mortality of Adults sepsis.bacteremic_s
_agegrp.xml,
4.1- (>= 20) meeting epsis,
table1_sepsis_mortality2
19 table1_sepsis_mortality infection and all sepsis.ehr_sepsis_d
_gender.xml,
2_v# Sepsis definitions ef,
table1_sepsis_mortality2
stratified by sepsis.ehr_angus_d
_race.xml
demographic omb,
criteria sepsis.ehr_severe_s
epsis
Table 2. Organ
Dysfunction
summary of Adult raw.basic,
(>= 20) Patients sepsis.ehr_organ_d
20 4.2-table2_sepsis_v# Meeting Primary ys, table2_sepsis.xml
Sepsis Definition sepsis.ehr_sepsis_d
Stratified by ICU ef
vs. Non-ICU
Patients
Table 3. raw.basic,
Characteristics of raw.hospital,
21 4.3-table3_sepsis_v# table3_sepsis.xml
all Adult (>= 20) raw.pos_blood_cultu
patients re
raw.basic,
raw.hospital, table4_sepsis1.xml,
raw.pos_blood_cultu table4_sepsis2.xml,
re, table4_sepsis3.xml,
sepsis.bacteremic_s table4_sepsis4.xml,
epsis, table4_sepsis5.xml,
Table 4.1
sepsis.ehr_sepsis_d table4_sepsis6.xml,
Characteristics of
ef, table4_sepsis7.xml,
22 4.4-table4_sepsis_v# all Adult (>=20)
sepsis.ehr_sepsis_d table4_sepsis8.xml,
patients for sepsis
ef_cc, table4_sepsis9.xml,
definitions
sepsis.ehr_angus_d table4_sepsis10.xml,
omb, table4_sepsis11.xml,
sepsis.ehr_severe_s table4_sepsis12.xml,
epsis, table4_sepsis13.xml,
sepsis.elixhauser, table4_sepsis14.xml
sepsis.charlson

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 raw.basic,
raw.hospital,
raw.pos_blood_cultu
re,
Table 5.
sepsis.bacteremic_s
Characteristics of
epsis,
all Adult (>=20)
sepsis.ehr_sepsis_d
23 4.5-table5_sepsis_v# patients for Angus, table5_sepsis.xml
ef,
Dombrovskiy,
sepsis.ehr_angus_d
Severe sepsis
omb,
definitions
sepsis.ehr_severe_s
epsis,
sepsis.elixhauser,
sepsis.charlson

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eAppendix F. Glossary of terms for output tables

Term Description
Hospital-RQVHWLHDOOFULWHULDPHWRQGD\•RIKRVSLWDOL]DWLRQZKHUHGD\ 
"Hosp"
day of admission)
Community-onset (i.e., any criteria met on day 1 or 2 of hospitalization)
Note: Hospital-onset and community-onset designations are mutually exclusive.
"Comm"
If a patient meets both community-onset and hospital-onset criteria during a
single encounter, he/she will be classified as community-onset.
Either hospital-onset OR community-onset for the definition of interest. So,
"Hospcomm"
“hospcomm_sepsis” refers to cases meeting criteria for the primary definition.
Qualifying Antibiotic Day
"QAD" Note: Please refer to the formal Data Specification document for more
information about the definition of QAD
Encounters with a blood culture drawn and four consecutive QADs starting within
a ±2 day window of the blood culture order day. Fewer than 4 QADs are also
"Presumed Infection"
allowed if the patient dies or is discharged to hospice or an acute care hospital,
ZLWKFRQVHFXWLYH4$'VXQWLO”GD\SULRUWRGHDWKGLVFKDUJH
Any one of the following, within a ±2 day window of the blood culture order day
• Initiation of a new vasopressor
• Initiation of invasive mechanical ventilation
‡6HUXPODFWDWH•PJG/
‡'RXEOLQJRIVHUXPFUHDWLQLQHRUGHFUHDVHE\•RIH*)5UHODWLYHWR
"Organ Dysfunction"
baseline
‡7RWDOELOLUXELQ•PJG/DQGLQFUHDVHE\IURPEDVHOLQH
• Platelet count <100 cells/μL and •GHFOLQHIURPEDVHOLQH
Note: Please refer to the formal Data Specification document for more
information about these criteria (i.e. definition of baseline).
Sepsis Definitions Description
>= 1 Blood Culture • At least one blood culture anytime during hospitalization
Infection • At least one episode of presumed infection
Primary sepsis definition
Sepsis • Presumed infection
‡•FRQFXUUHQWRUJDQG\VIXQFWLRQ
Sepsis Without Lactate
Sepsis_nolactate • Presumed infection
‡•FRQFXUUHQWRUJDQG\VIXQFWLRQH[FOXGLQJODFWDWHFULWHULD
Septic Shock Definition
• Presumed infection
• Initiation of new vasopressor within ±2-day window of the blood culture order
Shock1_sepsis day
• Lactate •within ±2-day window of the blood culture order day
Note: This is the definition that most closely matches the SCCM/ESICM’s
Sepsis-3 Septic Shock clinical definition.
Angus Claims-Based Sepsis Definition
• Any of the following:
Angus - •LQIHFWLRQFRGHDQG•RUJDQG\VIXQFWLRQFRGH
- Explicit severe sepsis (995.92)
- Septic shock (785.52) code
Simple Code Definition
Severe Sepsis
• Explicit severe sepsis code (995.92) or Septic shock code (785.52)

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