Epidemiology of severe sepsis occurring in the rst 24 hrs in

intensive care units in England, Wales, and Northern Ireland

Andrew Padkin, MSc, FRCA; Caroline Goldfrad, MSc; Anthony R. Brady, MSc; Duncan Young, DM, CA;
Nick Black, MD; Kathy Rowan, DPhil
L
iterature reviews have reported
a wide variation in the reported
prevalence and incidence of se-
vere sepsis and in its associated
mortality rate (1, 2). This may reect
differences in the populations studied and
the denitions of severe sepsis used. Pa-
tient populations studied have ranged
from those in a single intensive care unit
(ICU)/hospital (36) to large studies in-
cluding 100 centers (7, 8). Some stud-
ies have investigated all hospital admis-
sions (4, 9, 10), whereas others have been
restricted to specic hospital areas (3,
57, 11).
The denitions used for severe sepsis
also have varied. In 1992, the American
College of Chest Physicians/Society of
Critical Care Medicine (ACCP/SCCM)
consensus conference (12) distinguished
between the systemic inammatory re-
sponse syndrome (SIRS), sepsis, and se-
vere sepsis (Appendix 1). Although the
criteria for SIRS were explicitly physio-
logic, organ system dysfunctions were
not dened in terms of physiologic de-
rangement and guidance was provided
neither for how to judge whether physi-
ologic abnormalities were a consequence
of infection nor how the baseline physio-
logic state should be dened (13, 14). The
time frame within which the observed
derangements had to occur also was not
specied. Consequently, epidemiologic
studies have used a variety of denitions
for organ system dysfunctions (3, 4, 6, 7,
15).
The consensus conference denition
of sepsis (and hence severe sepsis) de-
pended on a conrmed infectious pro-
cess being present. Some have inter-
preted this to mean microbiological
conrmation (7, 10), although the fre-
quent lack of microbiological results dur-
ing the acute phase means that the diag-
nosis is only possible retrospectively.
Others have modied the ACCP/SCCM
denitions to make them more clinically
applicable by either including clinically
suspected infection (4, 6, 7) or using
proxies such as the start of antibiotics (5)
or the taking of blood cultures (16).
For all these reasons, the interpreta-
tion of published epidemiologic studies of
severe sepsis presents a major challenge.
As there have been no effective interven-
tions specically for patients with severe
From the Intensive Care National Audit & Research
Centre (KR, AB, CG), London, UK; the Health Services
Research Unit (NB, AP), Department of Public Health &
Policy, London School of Hygiene & Tropical Medicine,
University of London, UK; and the Nufeld Department
of Anaesthetics (DY), University of Oxford, Oxford, UK.
Supported, in part, by Eli Lilly and Company Lim-
ited and by a Medical Research Council Training Fel-
lowship in Health Services Research (AP).
Address requests for reprints to: Kathy Rowan,
DPhil, Intensive Care National Audit & Research Centre,
Tavistock House, Tavistock Square, London WC1H
9HR, UK. E-mail: kathy@icnarc.org
Copyright 2003 by Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000085141.75513.2B
Objective: To investigate the numbers, clinical characteristics,
resource use, and outcomes of admissions who met precise
clinical and physiologic criteria for severe sepsis (as dened in
the PROWESS trial) in the rst 24 hrs in the intensive care unit.
Design: Observational cohort study, with retrospective analysis
of prospectively collected data.
Setting: Ninety-one adult general intensive care units in En-
gland, Wales, and Northern Ireland between 1995 and 2000.
Patients: Patients were 56,673 adult admissions.
Interventions: None.
Measurements and Main Results: We found that 27.1% of adult
intensive care unit admissions met severe sepsis criteria in the
rst 24 hrs in the intensive care unit. Most were nonsurgical
(67%), and the most common organ system dysfunctions were
seen in the cardiovascular (88%) and respiratory (81%) systems.
Modeling the data for England and Wales for 1997 suggested that
51 (95% condence interval, 4658) per 100,000 population per
year were admitted to intensive care units and met severe sepsis
criteria in the rst 24 hrs.
Of the intensive care unit admissions who met severe sepsis
criteria in the rst 24 hrs, 35% died before intensive care unit
discharge and 47% died during their hospital stay. Hospital mor-
tality rate ranged from 17% in the 1619 age group to 64% in
those >85 yrs. In England and Wales in 1997, an estimated 24
(95% condence interval, 2128) per 100,000 population per year
died after intensive care unit admissions with severe sepsis in the
rst 24 hrs.
For intensive care unit admissions who met severe sepsis
criteria in the rst 24 hrs, median intensive care unit length of
stay was 3.56 days (interquartile range, 1.509.32) and median
hospital length of stay was 18 days (interquartile range, 836
days). These admissions used 45% of the intensive care unit and
33% of the hospital bed days used by all intensive care unit
admissions.
Conclusions: Severe sepsis is common and presents a major
challenge for clinicians, managers, and healthcare policymakers.
Intensive care unit admissions meeting severe sepsis criteria
have a high mortality rate and high resource use. (Crit Care Med
2003; 31:23322338)
KEY WORDS: severe sepsis; organ dysfunction; critical care;
clinical database; prevalence; mortality.
2332 Crit Care Med 2003 Vol. 31, No. 9
sepsis until recently, this lack of rigorous
data has had few clinical consequences.
However, the PROWESS trial (17) sug-
gests that recombinant human activated
protein C is effective in reducing all-
cause 28-day mortality rate for patients
with severe sepsis. One of the strengths of
the trial was that it used precise physio-
logic denitions for both SIRS and organ
system dysfunction. An understanding of
the numbers, clinical characteristics, re-
source use, and outcomes of patients sat-
isfying the denition for severe sepsis
used in that trial is now, therefore, of
practical importance to all ICU clinicians
and policymakers.
The primary objective of this study
was to investigate the numbers, clinical
characteristics, resource use, and out-
comes of adult ICU admissions who met
precise clinical and physiologic criteria
for severe sepsis in the rst 24 hrs follow-
ing admission to an ICU in England,
Wales, and Northern Ireland. These de-
nitions were matched as closely as possi-
ble to those used in the PROWESS trial
(17).
METHODS
Database. The Case Mix Programme is a
comparative audit of ICUs in England, Wales,
and Northern Ireland coordinated by the In-
tensive Care National Audit and Research Cen-
tre. Adult general intensive care units in these
countries contribute data on all admissions for
the rst 24 hrs of ICU, including details of
sociodemographics, diagnostic and physio-
logic characteristics, and ICU and hospital
outcome (survival/nonsurvival). Precise rules
and denitions are available for each variable
collected, and data are checked for complete-
ness and accuracy before inclusion in the da-
tabase (18). Training is available for data col-
lectors.
Patient Selection. This study used vali-
dated data from all units that had submitted
6 months of data for admissions between
1995 and 2000. The criteria used for severe
sepsis, based on those used in the PROWESS
study (17), were evidence of infection plus at
least three SIRS criteria plus at least one or-
gan system dysfunction criterion (Appendix
2). The denitions used in the PROWESS trial
could not be used precisely as we were gov-
erned by the data available in the Intensive
Care National Audit and Research Centre Case
Mix Programme Database. Cases were dened
as surgical if admission to ICU was directly
from an operating theater/recovery. If physi-
ology data were missing, they were assumed to
have been normal and a normal value was
included. In applying the denition of severe
sepsis, we were impaired by the absence of
data on weight and on the use of other inter-
ventions (e.g., a uid challenge). We assigned
a weight of 70 kg to all patients to calculate
the average hourly urine output per kilogram
body weight for the rst 24 hrs in ICU.
Analyses. The percentage of admissions
with severe sepsis in the rst 24 hrs in ICU was
dened as the number of rst ICU admissions
in a hospital stay who met the severe sepsis
criteria in the rst 24 hrs in ICU expressed as
a percentage of the total number of rst ICU
admissions. Readmissions of patients to ICU
during the same hospital stay were excluded
from all except the sensitivity analysis. The
percentage of adult ICU admissions with se-
vere sepsis in the rst 24 hrs was determined,
as were the ultimate ICU mortality rate, ulti-
mate hospital mortality rate, and 28-day mor-
tality rate. Ultimate ICU/hospital mortality
refers to a patients status on discharge from
the nal ICU/hospital at which the patient was
an inpatient during a continuous ICU/hospital
stay, which thus accounts for transfers be-
tween ICUs/hospitals. The 28-day mortality
rate refers to death on or by the 28th day
following admission to ICU. Twenty-eight-day
Kaplan-Meier survival curves were produced.
Those discharged alive from hospital before 28
days were assumed to have survived to 28 days.
A limited predened list of factors, affecting
both occurrence of severe sepsis and ultimate
hospital mortality rate in patients with severe
sepsis, were investigated using logistic regres-
sion. These included gender, source of admis-
sion, organ dysfunction, and hospital type.
The length of stay (LOS) in the admitting ICU
and total continuous hospital LOS were cal-
culated and compared for hospital survivors
and nonsurvivors.
Population Incidence. The numbers of ad-
missions to each ICU in 1997 in England and
Wales with severe sepsis and their hospital
mortality rates were estimated by gender and
age group. Complete data for 1997 were un-
available for 25 ICUs. In such instances, the
closest available full years data were used. For
units with less than a full years data, admis-
sions during the missing months were as-
sumed to be similar to those during the avail-
able months. Results were extrapolated to the
235 ICUs (or combined ICU/high-dependency
units) found by the Audit Commission to be
present in England and Wales (19), and con-
dence intervals were estimated through
bootstrapping (20). The age- and gender-
specic incidence of severe sepsis, dened as
the number of rst ICU admissions within a
hospital stay that met the criteria per 100,000
population per year, then was estimated for
England and Wales using baseline population
data (21). A sensitivity analysis was performed
to investigate the effect of including ICU re-
admissions.
RESULTS
Data were available for 56,673 adult
admissions (aged 16 yrs) to 91 adult
general ICUs in England, Wales, and
Northern Ireland between December
1995 and February 2000 after excluding
2,841 readmissions within the same hos-
pital stay.
Admissions With Severe Sepsis. In to-
tal, 15,362 (27.1%; 95% condence inter-
val [CI], 26.727.5%) ICU admissions had
severe sepsis in the rst 24 hrs (Table 1).
The median age was 65 yrs (interquartile
range [IQR], 5173 yrs). Severe sepsis
was more common in female admissions
(30.1%) than male admissions (25.0%)
and was slightly less likely to occur in the
younger age groups (Table 1, Fig. 1). The
risk of severe sepsis was cyclic, varying
from a low of 24.8% in June to a high of
33.4% in January and shared an increas-
ing trend over time (Table 1). A lower
percentage was observed in university
hospitals than other types, although con-
siderable variation existed between indi-
vidual units (Fig. 2).
Most admissions with severe sepsis in
the rst 24 hrs were nonsurgical, and the
most common organ system dysfunctions
were seen in the cardiovascular and re-
spiratory systems (Table 1). Most patients
(65.2%) had two or three organ system
dysfunctions (Table 2). The most com-
mon combinations were cardiovascular/
respiratory and cardiovascular/respira-
tory/metabolic, which each occurred in
approximately one fourth of admissions.
Of patients with severe sepsis, 6,983
(45.5%) would not have been eligible for
entry into the PROWESS trial due to ex-
clusion criteria.
When we modeled the data for En-
gland and Wales for 1997, the total num-
ber of admissions to the 235 ICUs was
estimated to be 78,047 (95% CI, 70,060
86,625) with 21,191 (95% CI, 18,800
23,740) estimated to have severe sepsis in
the rst 24 hrs. This equates to an inci-
dence of 51 per 100,000 population per
year (95% CI, 4658 per 100,000). Inci-
dence ranged from 14 in the 2024 age
group to 158 per 100,000 per year in the
7579 age group, with a higher rate in
males than females (Fig. 3).
Mortality of ICU Admissions With Se-
vere Sepsis in the First 24 Hrs. Data on
unit and hospital mortality rate were
missing for 105 (0.7%) and 313 (2.0%)
admissions with severe sepsis, respec-
tively. We found that 5,334 (35.0%; 95%
CI, 34.235.7%) admissions with severe
sepsis in the rst 24 hrs died before ICU
discharge, and 7,119 (47.3%; 95% CI,
46.548.1%) died during their hospital
stay. The 28-day mortality rate was 41.5%
(assuming that those discharged alive
2333 Crit Care Med 2003 Vol. 31, No. 9
from hospital before day 28 survived to
day 28). The 28-day Kaplan-Meier sur-
vival curve is shown in Figure 4.
Hospital mortality rate was slightly
lower for females with severe sepsis than
males (Table 1) and ranged from 17.4%
(13.322%) in the 16- to 19-yr-olds to
64.4% (59.968.7%) in those 85 yrs.
Medical and emergency surgical admis-
sions with severe sepsis had considerably
higher hospital mortality rate compared
with elective surgical admissions (Table
1). Although there was no signicant dif-
ference in hospital mortality rate between
university and nonuniversity hospitals af-
ter adjustment for case mix, university-
afliated hospitals had a signicantly
higher mortality rate (Table 1). There was
a slight decrease in hospital mortality
rate over the 4 yrs studied, from 50.2% in
1996 to 47.0% in 1999 (Table 1).
Grouping admissions by the number
Table 1: Number, relative frequency, and hospital mortality rate of admissions to an intensive care unit (ICU) diagnosed with severe sepsis in the rst 24
hrs
Factor
ICU
Admissions
Severe Sepsis
in the First
24 Hrs (%)
Adjusted
Odds Ratio
(95% Condence
Interval)
a
Hospital
Mortality of
Admissions
With Severe
Sepsis (%)
b
Adjusted
Odds Ratio
(95% Condence
Interval)
c
Overall 56,673 15,362 (27.1) 7,119 (47.3)
Gender
Male 33,336 8,336 (25.0) 1.0
d
3,917 (48.0) 1.0
d
Female 23,334 7,026 (30.1) 1.31 (1.251.36) 3,202 (46.5) 0.94 (0.871.01)
Source of admission
Nonsurgical 29,143 10,283 (35.3) 5.61 (5.256.00) 5,139 (51.2) 2.17 (1.873.17)
Emergency surgical 11,235 3,878 (34.5) 5.15 (4.785.54) 1,629 (42.7) 1.57 (1.341.85)
Elective surgical 16,263 1,195 (7.4) 1.0
d
348 (29.4) 1.0
d
Organ dysfunction
e
Cardiovascular 41,309 13,567 (32.8) 2.54 (2.402.69) 6,677 (50.2) 1.03 (0.871.22)
Respiratory 32,571 12,369 (38.0) 3.01 (2.863.15) 6,127 (50.6) 0.80 (0.690.93)
Metabolic 20,920 8,117 (38.8) 1.42 (1.361.48) 4,616 (57.8) 0.81 (0.700.93)
Renal 7,209 2,717 (37.7) 1.09 (1.031.16) 2,113 (78.4) 1.31 (1.111.54)
Hematological 6,304 2,382 (37.8) 1.07 (1.011.14) 1,497 (63.7) 1.0
d
Year of admission
f
1996 10,927 2,832 (25.9) 1,398 (50.2)
1997 17,780 4,557 (25.6) 1.05 per year (1.021.07) 2,134 (47.9) 0.93 per year (0.900.97)
1998 18,144 5,040 (27.8) 2,235 (45.3)
1999 9,675 2,871 (29.7) 1,320 (47.0)
Hospital type
University 8,253 2,090 (25.3) 1.0
d
1,019 (49.3) 1.0
d
University-afliated 12,323 3,412 (27.7) 1.19 (1.111.27) 1,728 (51.9) 1.20 (1.051.36)
Nonuniversity 36,097 9,860 (27.3) 1.22 (1.151.30) 4,372 (45.3) 0.90 (0.811.01)
APACHE II score
(quintiles)
010 10,785 1,060 (9.8) 118 (11.4)
1114 11,673 2,341 (20.1) 1.50 per 10 points 547 (24.0) 2.24 per 10 points
1517 8,523 2,500 (29.3) (1.451.56) 816 (33.6) (2.092.39)
1822 10,307 3,990 (38.7) 1,853 (47.4)
2355 10,134 4,795 (47.3) 3,254 (68.7)
APACHE, Acute Physiology and Chronic Health Evaluation.
a
Adjusted for factors in the table and age (n 51,398);
b
hospital mortality missing for 313 patients;
c
adjusted for factors in table, age, and number of
organ dysfunctions (n 14,384);
d
reference-group;
e
categories not mutually exclusive;
f
data for 1995 and 2000 (n 147) not shown.
Figure 1. Number and percentage of intensive care unit (ICU) admissions satisfying the criteria for
severe sepsis in the rst 24 hrs in ICU by age/gender. Note offset scale on left axis.
2334 Crit Care Med 2003 Vol. 31, No. 9
of dysfunctional organ systems showed a
wide variation in hospital mortality rate
within each group (Table 2), depending
on the actual combination of organ sys-
tems that were dysfunctional. Renal dys-
function was associated with a particu-
larly poor prognosis after adjustment for
the number of dysfunctional organs,
whereas respiratory and metabolic organ
dysfunction were associated with rela-
tively better outcome (Table 1).
It was estimated that in 1997 in En-
gland and Wales, 10,038 (95% CI, 8837
11,672) hospital deaths occurred in ICU
admissions with severe sepsis in the rst
24 hrs, representing 24 deaths per
100,000 population per year (95% CI,
2128 per 100,000).
Resource Use. ICU admissions with se-
vere sepsis in the rst 24 hrs had a me-
dian ICU LOS of 3.59 days (IQR, 1.50
9.33) on the admitting unit and median
total hospital LOS of 18 days (IQR, 836).
They accounted for 46.4% of all ICU bed
days and 33.3% of all hospital bed days
consumed by patients admitted to ICU.
Those discharged alive from hospital
had a median ICU LOS of 3.93 days (IQR,
1.7410.27) and median hospital LOS of
25 days (IQR, 1446), whereas those who
died during their hospital stay had a me-
dian ICU LOS of 3.49 days (IQR, 1.25
9.23) and median hospital LOS of 11 days
(IQR, 423). Survivors at hospital dis-
charge used 56.7% of all ICU bed days
and 68.4% of all hospital bed days con-
sumed by ICU admissions that satised
the severe sepsis criteria in the rst 24
hrs.
Sensitivity Analysis. When readmis-
sions were included in the analysis,
28.1% (27.828.5%) of all ICU admis-
sions met the severe sepsis criteria in the
rst 24 hrs. The median ICU LOS (includ-
ing readmissions in the total ICU LOS)
was 3.76 days (IQR, 1.569.84).
DISCUSSION
Principal Findings
This study conrms that severe sepsis is
a major challenge for clinicians, managers,
and healthcare policymakers. Of all ICU ad-
missions, 27.1% had severe sepsis in the
rst 24 hrs. This is considerably higher
than that recently reported (22). Translat-
ing these data into population incidence, it
is estimated that during 1997 (in England
and Wales), 51 adults per 100,000 popula-
tion were admitted to ICU and had severe
sepsis in the rst 24 hrs. This is much
lower than the incidence reported in a re-
cent large U.S. study, which estimated 300
per 100,000 (8). This difference is only
partly explained by our exclusion of pa-
tients in non-ICU settings. In the U.S.
study, only 51% (153 per 100,000 popula-
tion per year) received intensive care. The
remaining difference may be explained by
our study not including patients who met
severe sepsis criteria after the rst 24 hrs
on ICU or by differences in the denitions
used for severe sepsis.
The estimated population incidence of
severe sepsis in ICU admissions was con-
siderably higher in the elderly than in
younger patients, peaking in the 7579
Table 2. Organ system dysfunctions and hospital mortality rate of all admissions meeting the criteria
for severe sepsis in the rst 24 hrs in an intensive care unit (ICU)
Organ System
Dysfunctions
ICU Admissions With Severe
Sepsis in the First 24 Hrs
(Total 15,362)
(%, 95% condence interval)
Hospital Mortality Rate
(%, 95% condence intervals)
One 2,519 (16.4, 15.817.0) 549 (21.8, 20.223.5)
CVS 1,325 (8.6, 8.29.1) 284 (21.4, 19.223.7)
Resp 950 (6.2, 5.86.6) 217 (22.8, 20.225.6)
Met 154 (1.0, 0.91.2) 28 (18.2, 12.425.2)
REN 100 admissions
Hem 100 admissions
Two
a
5,290 (34.4, 33.735.2) 1,903 (36.0, 34.737.3)
CVS/Resp 3,778 (24.6, 23.925.3) 1,367 (36.2, 34.637.7)
CVS/Met 744 (4.8, 4.55.2) 271 (36.4, 32.940.0)
CVS/Ren 131 (0.9, 0.71.0) 79 (60.3, 51.468.7)
CVS/Hem 122 (0.8, 0.70.9) 38 (31.1, 23.140.2)
Resp/Met 385 (2.5, 2.32.8) 114 (29.6, 25.134.4)
Three
a
4,727 (30.8, 30.031.5) 2,482 (52.5, 51.153.9)
CVS/Resp/Met 3,643 (23.7, 23.024.4) 1,829 (50.2, 48.551.8)
CVS/Resp/Ren 303 (2.0, 1.82.2) 213 (70.3, 64.875.4)
CVS/Resp/Hem 360 (2.3, 2.12.6) 198 (55.0, 49.760.2)
CVS/Met/Ren 164 (1.1, 0.91.2) 129 (78.7, 71.684.7)
CVS/Met/Hem 153 (1.0, 0.81.2) 71 (46.4, 38.354.6)
Four* 2,258 (14.7, 14.115.3) 1,696 (75.1, 73.376.9)
CVS/Resp/Met/Ren 1,273 (8.3, 7.98.7) 1,053 (82.7, 80.584.8)
CVS/Resp/Met/Hem 871 (5.7, 5.36.0) 553 (63.5, 60.266.7)
Five 568 (3.7, 3.44.0) 489 (86.1, 83.088.8)
CVS, cardiovascular; Resp, respiratory; Met, metabolic; Ren, renal; Hem, Hematological.
a
All other possible combinations not analyzed as 100 admissions with those characteristics.
Figure 2. Variation between individual intensive care units (ICUs) in the percentage of admissions with
severe sepsis in the rst 24 hrs in ICU.
2335 Crit Care Med 2003 Vol. 31, No. 9
age group, and up to that age group was
of a similar pattern to that reported in
U.S. hospital patients (8). However, U.S.
hospital incidence continues to increase
in those over the age of 79. If this pattern
were also true for hospital patients in
England, Wales, and Northern Ireland, it
suggests that there may have been many
elderly hospital patients in these coun-
tries who met the severe sepsis criteria
but were not admitted to ICU. Whether
this is due to case mix factors (e.g., other
comorbidities), to patient preference, or
to limitation of intensive care access for
the elderly is unknown.
The incidence was generally higher in
males than in females. This previously
has been reported (8) and has been sug-
gested to be due to differences in the sites
of infection between the sexes (8) or to
genetic factors. The nding that hospital
mortality rate was slightly raised in ad-
missions to university-afliated hospitals
after adjustment for case mix might be
explained by residual confounding due to
unmeasured differences between the
types of patients admitted to different
hospitals.
Hospital mortality rate of patients ad-
mitted to ICU with severe sepsis in the
rst 24 hrs (46.3%) compares unfavor-
ably with that reported from the United
States (34%) (8, 16). This may be due to
differences in case mix (more rigorous
denition of severe sepsis used in this
study), effectiveness of intensive care, ef-
fectiveness of post-ICU care, or hospital
discharge policies. An analysis comparing
outcomes using cases individually
matched for case-mix factors could inves-
tigate the reasons for such differences.
The difference between the ICU mor-
tality rate of 35.0% and the hospital mor-
tality rate of 47.3% is striking: 18% of
those discharged alive from an ICU sub-
sequently died before leaving hospital. Al-
though some of these patients were un-
doubtedly discharged from ICU for
palliative care on the ward, the magni-
tude of this gure raises questions about
whether patients were discharged prema-
turely (23), whether they may have ben-
eted from longer ICU care (24, 25), or
whether post-ICU care could be im-
proved. It is notable that the median
length of ICU stay for patients with severe
sepsis in the United States is 8 days (8)
compared with the 3.56 days found in
this study.
All mortality gures should be consid-
ered as associated with rather than attrib-
utable to severe sepsis, as admissions may
have had other comorbidities contribut-
ing to mortality rate.
Although admissions with severe sep-
sis in the rst 24 hrs accounted for 27.1%
of all ICU admissions, they consumed a
disproportionate amount of the resources
used by all ICU admissions: 44.9% of all
ICU bed days and 33.3% of all hospital
bed days.
Strengths and Weaknesses of this
Study. The strengths of this study lie in
its use of high-quality data on consecu-
tive admissions from a large number of
ICUs, allowing a precise clinical and
physiologic denition of severe sepsis to
be used. The external validity of the study
is extremely high due to the large sample
size (91 ICUs).
We do not believe the lack of data on
weight and use of other interventions will
have biased the results, as any misclassi-
cation will have been unrelated to whether
an admission satised other severe sepsis
criteria. Although a uid challenge did not
feature in the ACCP/SCCM denition of se-
vere sepsis, it was required in the PROW-
ESS trial denition of cardiovascular organ
system dysfunction (a patient had to have
Figure 3. Estimated incidence of intensive care unit (ICU) admissions with severe sepsis in the rst 24
hrs in ICUs in England and Wales.
Figure 4. Kaplan-Meier survival curve for intensive care unit (ICU) admissions with severe sepsis in the
rst 24 hrs in ICU; 95% condence band shown.
I
ntensive care unit ad-
missions meeting se-
vere sepsis criteria
have a high mortality rate
and high resource use.
2336 Crit Care Med 2003 Vol. 31, No. 9
an adequate uid challenge of 500 mL
of crystalloid [or 200 mL colloid] over 30
mins, a pulmonary artery occlusion pres-
sure 12 mm Hg, or a central venous pres-
sure 8 mm Hg). It seems likely that most
admissions to ICUs in England, Wales, and
Northern Ireland who otherwise met severe
sepsis criteria will have met at least the rst
of these.
The results of this analysis should not
be interpreted as the number of patients
in ICUs in England, Wales, and Northern
Ireland who would have been eligible for
randomization in the PROWESS trial, as
the trial would have excluded almost half
the patients.
Implications for Future Studies of Se-
vere Sepsis. Previous studies of severe
sepsis have presented the total number of
organ system dysfunctions as a baseline
characteristic for judging the compara-
bility between treatment groups (17), for
stratication or for covariate adjustment.
This study found considerable heteroge-
neity of outcome within each of these
groups, with renal dysfunction associated
with a particularly poor prognosis. This
may have been due in part to our deni-
tion of renal dysfunction (mean hourly
urine output of 0.5 mL/kg in the rst
24 hrs), which is likely to have selected
more severely ill admissions than the
PROWESS trial denition (mean hourly
urine output of 0.5 mL/kg for 1 hr
despite adequate uid replacement). Fu-
ture research might benet from using
information on which, as well as on how
many, organs are dysfunctional.
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Appendix 1: ACCP/SCCM
Consensus Conference
Denitions of the Systemic
Inammatory Response
Syndrome, Sepsis, and Severe
Sepsis
Systemic Inammatory Response
Syndrome (SIRS). This includes, but is not
limited to, more than one of the following:
1. Temperature 38C or 36C
2. Heart rate 90 beats/min
3. Respiratory rate 20 breaths/min
or PaCO
2
32 mm Hg
4. White blood cell count 12,000/
mm
3
or 4,000/mm
3
or 10%
immature neutrophils
These changes should represent an acute
alteration from baseline in the absence of
other known causes for such abnormali-
ties.
Sepsis. Sepsis occurs when the systemic
inammatory response syndrome is the re-
sult of a conrmed infectious process.
Severe Sepsis. Severe sepsis is sepsis
associated with organ dysfunction, hypo-
perfusion, or hypotension. Hypoperfusion
and perfusion abnormalities may include,
but are not limited to, lactic acidosis,
oliguria, or an acute alteration in mental
status.
2337 Crit Care Med 2003 Vol. 31, No. 9
Appendix 2: Denitions of the criteria for systemic inammatory response syndrome (SIRS), infection, and organ dysfunction used in the PROWESS trial
and in this analysis; Severe sepsis was considered to be present if all three were satised
PROWESS Trial CMPD Analysis
SIRS Satisfaction of SIRS criteria required three of the following to
be present within a 24-hr period:
Satisfaction of SIRS criteria required three of the
following to be present within the rst 24 hrs in
ICU:
Temperature Core temperature 38.0C or 36.0C. If only oral or
axillary temperature available, 0.5C added to measured
value. Hypothermia must be conrmed by a rectal or
central temperature.
Core temperature 38.0C or 36.0C. If only
noncentral temperature available, 0.5C added to
measured value. Hypothermia must be conrmed
by a central temperature.
Heart rate 90 beats min. If patients have a medical condition or are
receiving treatment that would prevent tachycardia, patient
only needed to meet two of the remaining SIRS criteria.
90 beats min. If heart block or myxedema is
recorded reason for admission, only two of the
remaining SIRS criteria need be met.
Respiratory rate 20 breaths min or PaCO
2
32 mm Hg or mechanical
ventilation for an acute process.
20 breaths min or PaCO
2
32 mm Hg in a
nonventilated admission or mechanical ventilation
in the rst 24 hrs in an admission not previously
receiving home ventilation.
White cell count 12,000 mm
3
or 4,000 mm
3
or 10% immature
neutrophils on a differential count.
12,000 mm
3
or 4,000 mm
3
.
Infection Known or suspected infection. Diagnosis of infection
a
as primary or secondary
reason for ICU admission or laboratory conrmed
/strongly suspected infection in rst 24 hrs in ICU.
Organ dysfunction Satisfaction of organ dysfunction criteria required at least one
of these to have been induced by sepsis and present for
24 hrs:
Satisfaction of organ dysfunction criteria required at
least one of these to be present during the rst 24
hrs in ICU.
Cardiovascular SBP 90 mm Hg or MAP 70 mm Hg for 1 hr despite
adequate uid resuscitation or use of vasopressors in an
attempt to maintain SBP 90 mm Hg or MAP 70 mm
Hg. Adequate resuscitation dened as an intravenous uid
bolus (e.g., 500 mL crystalloid) over 30 mins or
pulmonary artery occlusion pressure 12 mm Hg or
central venous pressure 8 mm Hg.
SBP 90 mm Hg or MAP 70 mm Hg or the use of
vasoactive drugs for 1 hr in the rst 24 hrs
Renal Urine output 0.5 mL kg body weight for 1 hr, despite
adequate uid resuscitation. If preexisting renal
impairment (creatinine twice upper limit normal) prior
to onset of sepsis, admission needed to meet another organ
dysfunction criteria.
Mean hourly urine output 0.5 mL kg body weight
in the rst 24 hrs in ICU or for the duration of stay
if 24 hrs in ICU. If on chronic renal replacement
therapy, admission needed to meet another organ
dysfunction criteria.
Respiratory PaO
2
/FiO
2
ratio 250 mm Hg. If the lung is the sole organ
meeting an organ dysfunction criterion, in addition to
being the suspected site of infection, the PaO
2
/FiO
2
ratio
must be 200 mm Hg.
PaO
2
/FiO
2
ratio 250 mm Hg. If the lung is the sole
organ meeting an organ dysfunction criterion and
primary/secondary reason for ICU admission
indicated lung infection, PaO
2
/ FiO
2
must be 200
mm Hg.
Hematological Platelet count 80,000 mm
3
or a 50% decrease from the
highest value in the previous 3 days.
Platelet count 80,000 mm
3
.
Metabolic pH 7.30 or base decit 5.0 mmol/L in association with a
plasma lactate 1.5 times the upper limit of normal.
Base decit 5.0 mmol/L
CMPD, Case Mix Programme Database; ICU, intensive care unit; SBP, systolic blood pressure; MAP, mean arterial pressure
a
99 diagnoses were identied that are considered to have an infectious origin: details available from authors.
2338 Crit Care Med 2003 Vol. 31, No. 9