Review of a Large Clinical Series

Journal of Intensive Care Medicine

28(6) 355-368
The GENESIS Project (GENeralized ª The Author(s) 2012
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Early Sepsis Intervention Strategies): DOI: 10.1177/0885066612453025
jic.sagepub.com
A Multicenter Quality Improvement
Collaborative

Chad M. Cannon, MD1, Christopher V. Holthaus, MD2, Marc T. Zubrow, MD3,

Pat Posa, RN, BSN, MSA4, Satheesh Gunaga, DO5, Vipul Kella, MD5,
Ron Elkin, MD6, Scott Davis, MD7, Bonnie Turman, BSN, RN8,
Jordan Weingarten, MD9, Truman J. Milling, Jr, MD9, Nathan Lidsky, MD10,
Victor Coba, MD11, Arturo Suarez, MD11, James J. Yang, PhD11, and
Emanuel P. Rivers, MD, MPH11

Abstract
Background: Improved outcomes for severe sepsis and septic shock have been consistently observed with implementation of
early best practice intervention strategies or the 6-hour resuscitation bundle (RB) in single-center studies. This multicenter study
examines the in-hospital mortality effect of GENeralized Early Sepsis Intervention Strategies (GENESIS) when utilized in commu-
nity and tertiary care settings. Methods: This study was comprised of 2 strategies to assess treatment. The first was a prospective
before-and-after observational comparison of historical controls to patients receiving the RB after implementation of GENESIS in
4 community and 4 tertiary hospitals. The second was a concurrent examination comparing patients not achieving all components
of the RB to those achieving all components of the RB in 1 community and 2 tertiary care hospitals after implementation of GEN-
ESIS. These 4 subgroups merged to comprise a control (historical controls treated before GENESIS and RB not achieved after
GENESIS) group and treatment (patients treated after GENESIS and RB achieved after GENESIS) group for comparison. Results:
The control group comprised 1554 patients not receiving the RB (952 before GENESIS and 602 RB not achieved after GENESIS).
The treatment group comprised 4801 patients receiving the RB (4109 after GENESIS and 692 RB achieved after GENESIS).
Patients receiving the RB (treatment group) experienced an in-hospital mortality reduction of 14% (42.8%-28.8%, P < .001) and
a 5.1 day decrease in hospital length of stay (20.7 vs 15.6, P < .001) compared to those not receiving the RB (control group). Similar
mortality reductions were seen in the before-and-after (43% vs 29%, P < .001) or concurrent RB not achieved versus achieved
(42.5% vs 27.2%, P < .001) subgroup comparisons. Conclusions: Patients with severe sepsis and septic shock receiving the RB in
community and tertiary hospitals experience similar and significant reductions in mortality and hospital length of stay. These find-
ings remained consistent when examined in both before-and-after and concurrent analyses. Early sepsis intervention strategies
are associated with 1 life being saved for every 7 treated.

1
University of Kansas Hospital, Kansas City, KS, USA
2
Washington University, Barnes-Jewish Hospital, St Louis, MO, USA
3
Christiana Care Health System, Newark, DE, USA
4
St. Joseph Mercy Hospital, Ann Arbor, MI, USA
5
Henry Ford Hospital–Wyandotte, Wyandotte, MI, USA
6
California Pacific Medical Center, San Francisco, CA, USA
7
St Cloud Hospital, St. Cloud, MN, USA
8
Porter Hospital, Valparaiso, IN, USA
9
University Medical Center at Brackenridge, Austin, TX, USA
10
Northwest Community Hospital, Arlington Heights, IL, USA
11
Henry Ford Hospital, Main Campus, Detroit, MI, USA

Corresponding Author:
Christopher V. Holthaus, Division of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 S Euclid Ave, St. Louis, MO 63110, USA.
Email: holthausc@wusm.wustl.edu
356 Journal of Intensive Care Medicine 28(6)

Sepsis Resuscitation Bundle (6 - hour bundle)

1. Suspected infection:
Confirmed or suspected source with  2 systemic inflammatory response syndrome criteria with persistent hypotension (systolic blood
pressure [SBP] < 90 mm Hg or mean arterial pressure [MAP] < 65 mm Hg), lactate  4 mmol/L, vasopressor use, or organ dysfunction.
2. Serum lactate measured
3. Blood cultures obtained before antibiotic administration
4. Broad-spectrum antibiotics, from the time of presentation, administered within 3 hours for ED admissions and 1 hour for non-ED ICU
admissions
5. In the event of hypotension and/or lactate  4 mmol/L (36 mg/dL)
 Deliver an initial minimum of 20 mL/kg of crystalloid (or colloid equivalent)
 Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure > 65 mm Hg
6 In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate  4 mmol/L (36 mg/dL)
 Achieve central venous pressure of  8 mm Hg
 Achieve central venous oxygen saturation (ScvO2) of  70%

Figure 1. Sepsis resuscitation bundle elements.

Keywords
early goal-directed therapy, resuscitation bundle, sepsis, severe sepsis, septic shock, quality improvement, emergency medicine,
critical care, shock

Introduction Study Setting

There are more than 500,000 cases of severe sepsis and septic
shock annually in the United States, with a mortality of 20%
and 45%, respectively.1 In the last decade, hospital costs have
increased 183%, faster than any cause for hospitalization with
an annual cost of over $54 billion.2 The majority of patients
with sepsis are identified in the emergency department (ED)
with the remainder coming from other inpatient settings.3
Improved survival rates with diseases of similar volume
such as stroke, acute myocardial infarction, and trauma have
been achieved through early intervention strategies comprising
early detection, risk stratification, and rapid therapeutic inter-
ventions. In 2001, a similar strategy for severe sepsis and shock
termed early goal-directed therapy (EGDT) resulted in an in-
hospital absolute mortality reduction of 16% when compared
to controls receiving standard care.4 Combining EGDT with
other early evidence-based strategies has resulted in the creation
of the sepsis resuscitation bundle ([RB] Figure 1).5 Over the last
decade, numerous studies using a before-and-after implementa-
tion of the RB have shown similar reductions in mortality, organ
failure, and health care resource consumption.6
The purpose of this multicenter collaborative was to exam-
ine the impact of real-time quality initiatives in the form of
GENeralized Early Sepsis Intervention Strategies (GENESIS)
on in-hospital mortality, morbidity, and health care resource
consumption in community and tertiary care hospitals in the
United States.
Methods
Institutional Review Board Approval
The GENESIS was approved by the institutional review board
at each participating center (Appendix A).
The GENESIS was a continuous quality improvement (CQI)
initiative implemented at 5 community and 6 tertiary US
hospitals. The GENESIS is comprised of a comprehensive
strategy which includes (1) an institutional assessment of the
sepsis prevalence and mortality, (2) identification of high-
risk patients or a sepsis alert,7 (3) mobilization of resources,
(4) timely intervention of the 6-hour sepsis bundle via a sepsis
team or sepsis order sets, (5) quality indicators to assess com-
pliance, (6) quantification of health care resource consumption,
(7) assessment of outcomes, and (8) a CQI program which
includes feedback and continuing education.8
Study Design
Evaluation of GENESIS consisted of 2 assessment strategies.
The first was a before-and-after RB implementation strategy
conducted in 8 hospitals, analyzing outcomes between histori-
cal controls and patients after RB implementation. The second
was to assess the impact of complete versus incomplete bundle
compliance through examining a concurrent RB implementa-
tion strategy in 3 hospitals (Figure 2). These 4 groups gave rise
to the control and treatment groups for comparison. The control
group comprised patients not receiving the RB before imple-
mentation or group I (historical controls-IA and concurrent
RB not achieved-IB). The treatment group comprised
patients receiving the RB or group II (after implementation-
IIA and concurrent RB achieved-IIB; Figure 2).
Participants
Patients were routinely screened in the ED, general floor
(general practice unit [GPU]), operating room, and intensive
Cannon et al 357

GENESIS
Implemented in 11 Hospitals

Patients assessed for eligibility

N=6624

Excluded from analysis

(mortality missing)
N=269 (4.1%)

Before and After Implementation Concurrent Implementation

8 Hospitals 3 Hospitals
N=5061 Control N=1294
Group-I A&B
N=1554
Group-IA Mortality 42.8%
Group-IB
Before implementation
RB not achieved
RB not received
N=602
N=952
Mortality 42.5%
Mortality 43%

Treatment
Group-II A&B
N=4801
Mortality 28.8%
Group-IIA Group-IIB
After implementation RB achieved
RB received N=692
N=4109 Mortality 27.2%
Mortality 29%

Figure 2. The GENeralized Early Sepsis Intervention Strategies (GENESIS) flow diagram.
Abbreviations: RB, Resuscitation Bundle.

care units (ICUs) based on regional practices. Historical
controls were found via chart reviews using International
Classification of Diseases, Ninth Revision codes for severe
sepsis (995.92) or septic shock (785.52). Inclusion criteria were
a sepsis diagnosis with a lactate 4 mmol/L, vasopressor
use, or organ dysfunction (Figure 1). Exclusion criteria were
age <18 years, shock suspected secondary to cause/causes other
than sepsis, or advanced directives which compromised the
intended care.
biostatisticians from Washington University, Henry Ford
Hospital, and the University of Kansas Medical Center.
Results
The size of the community hospital beds ranged from 301 to
431 beds, with 33,000 to 95,000 annual ED visits. Tertiary
hospital size ranged from 440 to 1200 beds with 46,000 to
160,000 annual ED visits.

Statistical Analysis Patient Groups

Data are presented as the mean + standard deviation.
Continuous and categorical variables were analyzed with a 2-
tailed Student t test, Mann-Whitney U test, Kruskal-Wallis,
or Chi-square test as appropriate. Multivariate logistic regres-
sion with risk-adjusted odds ratios (ORs) and 95% confidence
intervals was conducted to eliminate confounding between
variables and multiple test performance. A P value <.05 was
statistically significant. Statistical analysis was performed by
There were 6,624 patients assessed for eligibility. Due to missing
mortality data, 59 (3.7%) and 210 (4.3%) patients were excluded
from group I and group II, respectively. Group I, the control group
(n ¼ 1,554) consisted of patients before RB implementation or
group IA (n ¼ 952) and concurrent RB not achieved or group
IB (n ¼ 602). Group II, the treatment group (n ¼ 4,801), consisted
of patients after RB implementation or group IIA (n ¼ 4,109) and
concurrent RB achieved or group IIB (n ¼ 692; Figure 2).
358
Presentation Characteristics
Group II patients were significantly older (2.8 years) and had
more females (3%) and less Caucasians (5.2%) when compared
to group I (all P < .03). Group II had a significantly higher
percentage of patients originating from the ED (15.8%) and a
lower percentage from the GPU (8.3%) and ICUs (7.5%; all
P < .006). Group II also had a significantly higher temperature
(0.15 C, P < .001). In both groups, the lung was the most
common source of infection followed by urinary, gastrointest-
inal, blood, catheter, and other sources (Table 1).
Baseline Resuscitation Parameters and Organ Function
In group II patients, the baseline serum bicarbonate was
0.5 mEq/L higher (P ¼ .047), central venous oxygen saturation
[ScvO2] was 2.6% higher (P ¼ .01), and lactate was
0.42 mmol/L lower (P ¼ .006). There were no significant dif-
ferences in the percentage of patients presenting with baseline
hypotension (systolic blood pressure [SBP] <90 mm Hg or
mean arterial pressure (MAP) <65 mm Hg) or baseline lactate
4 mmol/L between groups (Table 1). Group II baseline organ
dysfunction or Acute Physiology and Chronic Health Evalua-
tion (APACHE)-II scores were 11.2% higher (P < .001) and
baseline Sequential Organ Failure Assessment (SOFA) scores
were 12.9% higher (P ¼ .002) than group I (Table 2).
Resuscitation Parameters at 6 and 24 Hours
At 6 hours, group II had a significantly higher SBP (2.7 mm
Hg, P ¼ .047), ScvO2 (4.4%, P < .001), lower lactate
(0.67 mmol/L, P ¼ .002), greater urine output (10.6 mL/h,
P ¼ .023), and greater lactate clearance (19%, P ¼ .044;
Table 1). No significant differences existed for MAP or central
venous pressure (CVP) between groups (Table 1). At 24 hours,
group II had a significantly lower heart rate (11.7 beats/min,
P < .001), 8 mm Hg higher MAP (P < .001), 0.10 units lower
shock index (P ¼ .002), 0.7 mEq/L higher bicarbonate level
(P ¼ .044), 0.75 mmol/L lower lactate (P < .001), and 26%
greater lactate clearance (P ¼ .003; Table 1).
Organ Function Over the First 24 Hours
Group II APACHE-II scores significantly decreased by 15.7%
compared to an 11.7% increase in group I over 24 hours
(P < .001). Similarly, the SOFA scores significantly decreased
by 15.4% in group II compared to an 18.6% increase in group I
over 24 hours (P < .001; Table 2). The absolute improvement in
organ dysfunction at 24 hours in group II compared to group I
was 27.4% (APACHE-II) and 34% (SOFA).
Mortality Overall
There was a significant 14.0% absolute and a 32.7% relative
risk reduction for in-hospital mortality (42.8% vs 28.8%,
P < .001) between groups I and II. Similar and significant in-
hospital mortality reductions were seen between groups IA and
Journal of Intensive Care Medicine 28(6)
IIA (14%) and between groups IB and IIB (15.3%), both
P < .001 (Figure 2 and Table 2). A cumulative examination
of mortality showed a consistent decrease in mortality from
2003 to 2009 (Figure 3). Multivariate regression was used to
control for baseline differences in age, sex, race, origin at pre-
sentation, temperature, bicarbonate, lactate—0 hour, ScvO2—0
hour, APACHE-II score—0 hour, and SOFA score—0 hour. Of
these variables, the SOFA score—0 hour remained signifi-
cantly associated with in-hospital mortality with an adjusted
OR of 1.14 (1.03-1.27, P ¼ .01). Overall, the treatment group
(group II) had a significantly greater likelihood of death at
baseline compared to those not receiving the RB (group I).
Mortality by Hemodynamic Subgroups
Group II consistently showed statistically significant lower mor-
talities across all hemodynamic subgroup strata of lactate levels
and/or hypotension (SBP <90 mm Hg or MAP <65). Group II
absolute in-hospital mortality reductions for the following sub-
group strata are as follows (all P < .02): lactate 4 mmol/L,
18.4%; hypotensive, 17.7%; lactate 4 mmol/L or hypotensive,
15.7%; lactate 4 mmol/L and hypotensive, 22.2%; lactate
4 mmol/L and no hypotension, 17.9%; and lactate 2 mmol/
L and hypotension, 5.7% (Table 2).
Mortality by Hospital Location and Type
The absolute in-hospital mortality reduction in group II versus
group I for patients diagnosed in the following locations was
12.1% for the ED (P < .001), 15.4% for the GPU (P ¼ .006),
and 13.9% for the ICU (P < .001; Table 2). Participating cen-
ters experienced an overall absolute in-hospital mortality
reduction ranging from 8.1% to 25.7% and a relative risk
reduction from 21.3% to 48.9% (Table 3).
Duration of Mechanical Ventilation, Length of Hospital
Stay, and Hospital Charges
Group II had significantly less mechanical ventilation (5.0%)
from 0 to 6 hours (P ¼ .02) and 6.2% less from 6 to 72 hours
(P ¼ .02). There was a 1.3-day trend toward a shorter duration
of mechanical ventilation in group II (P ¼ .06). There was no
significant difference in mean ED length of stay. Mean hospital
length of stay was significantly shorter (5.1 days) and hospital
charges were $47,923 less in group II (both P < .001; Table 2).
Time to Completion of Therapeutic Interventions
Time to completion of interventions and reaching hemody-
namic targets in group II versus group I comparisons were sig-
nificantly reduced (hours) for a fluid challenge (1.18),
obtaining a lactate (3.07), antibiotic administration (1.21),
reaching the CVP target (2.98), and reaching the ScvO2 target
(1.95; all P  .002). There was a trend in decreasing the time
(0.77 hours) to achieving the MAP target (P ¼ .05; Table 1).
Cannon et al 359

Table 1. Patient Demographic and Resuscitation Characteristics Group I and Group II.

Group I Group II

Characteristic N Value (+SD) N Value (+SD) P Value

Demographics
Total number of patients 1554 4801
Age, y 1524 64 (17) 4776 62 (17) <.001
Sex, % female 746 48 2164 45 <.001
Body weight, kg 838 82 (28) 2061 81 (27) NS
Race, % White/Other 1554 75.1 4801 80.3 .003
Origin at presentation, %
Emergency department 558 50.1 1987 65.9 <.001
General practice unit 139 15.4 168 7.1 .006
Intensive care unit 331 34.5 697 27.0 <.001
SIRS characteristics
Temperature,  C 1070 37.1 (1.6) 2207 37.3 (1.6) .008
Heart rate, beats/min 1034 107.5 (24.7) 1916 109.1 (26.1) NS
Respiratory rate, breaths/min 1096 24.1 (8.4) 2290 23.6 (8.2) NS
White blood cell count 1081 16.5 (14.1) 2228 15.9 (12.6) NS
Source of infection and culture results, %
Lung 208 42.5 492 38.7 NS
Urinary 111 22.7 281 22.1 NS
Gastrointestinal 67 13.7 215 16.9 NS
Blood 43 8.8 98 7.7 NS
Catheter 16 3.3 33 2.6 NS
Other sourcesa 44 9.0 153 12.0 NS
Positive cultures that were sent, % 336 50.4 656 53.2 NS
Positive blood cultures that were sent, % 224 37.7 430 38.4 NS
Laboratories—baseline, 0 hour
Hemoglobin, g/dL 235 10.9 (2.5) 830 11.3 (2.7) NS
Platelet count, 1000 per cubic mL 1042 230.6 (138.7) 1784 230.5 (137.0) NS
BUN/creatinine 806 19.6 (11.6) 1846 19.1 (12.2) NS
Total bilirubin, mg/dL 748 2.1 (3.5) 1281 1.8 (3.1) NS
Albumin, g/dL 629 2.50 (0.77) 1289 2.51 (0.76) NS
Arterial pH 814 7.32 (0.15) 1125 7.31 (0.15) NS
Bicarbonate, mEq/L 690 20.5 (6.5) 1291 21.0 (6.0) .047
Baseline hemodynamic variables
Lactate, mmol/L 907 4.8 (4.1) 2608 4.4 (3.6) .006
Systolic BP, mm Hg 896 97.8 (27.71) 2287 99.6 (29.0) NS
MAP, mm Hg 1055 68.7 (19.9) 2054 69.7 (20.6) NS
CVP, mm Hg 355 10.5 (6.9) 1096 10.8 (6.6) NS
ScvO2, % 318 66.9 (17.0) 985 69.5 (13.8) .02
Heart rate, beats/min 1034 107.5 (24.7) 1916 109.1 (26.1) NS
Shock index (heart rate/systolic BP) 813 1.17 (0.41) 1902 1.16 (0.43) NS
% with systolic BP <90 or MAP <65 (%) 351 56.16 775 51.91 NS
% with lactate 4-0 hour (%) 421 46.42 1122 43.02 NS
6 hours hemodynamic variables
Lactate, mmol/L 414 3.84 (3.58) 893 3.17 (3.28) .002
Systolic BP, mm Hg 446 109.1 (23.2) 1014 111.7 (23.7) .05
MAP, mm Hg 771 72.5 (15.3) 1975 73.4 (16.4) NS
CVP, mm Hg 311 12.2 (5.8) 850 11.7 (5.1) NS
ScvO2, % 242 69.3 (12.5) 740 73.8 (10.4) <.001
Urine output, ml/hour (0-6 hours) 401 65.73 (78.0) 989 76.3 (80.6) .03
Lactate clearance (0-6 hours) 404 0.02 (1.83) 857 0.21 (0.87) .04
24 hour hemodynamic variables
Lactate, mmol/L 257 3.16 (3.01) 414 2.41 (2.55) <.001
Systolic BP, mm Hg 130 113.2 (21.3) 343 117.9 (21.0) .03
MAP, mm Hg 409 64.8 (19.5) 419 72.8 (17.1) <.001
Heart rate, beats/min 413 113.4 (26.9) 462 101.7 (23.9) <.001
Shock index (heart rate/systolic BP) 130 0.99 (0.31) 182 0.89 (0.28) .001
pH 286 7.31 (0.15) 612 7.32 (0.13) NS
(continued)
360 Journal of Intensive Care Medicine 28(6)

Table 1. (continued)

Group I Group II

Characteristic N Value (+SD) N Value (+SD) P Value

Bicarbonate, mEq/L 328 20.5 (5.7) 660 21.1 (5.6) .04

BUN/creatinine 548 20.1 (12.5) 1101 19.0 (11.5) .08
Lactate clearance (0-24 hours) 216 0.11 (1.12) 234 0.39 (0.50) <.001
Time from diagnosis to intervention, h
Lactate obtained 494 7.09 (11.38) 1148 4.02 (8.37) <.001
Blood cultures 632 7.7 (12.1) 1706 6.1 (10.4) .002
Antibiotics 436 2.87 (5.11) 863 1.66 (3.28) <.001
Fluid challenge, 20-40 mL/kg 373 3.51 (5.48) 1141 2.33 (4.35) <.001
MAP >65 mm Hg 564 6.04 (7.9) 1182 5.27 (6.80) .05
CVP >8 mm Hg 302 8.27 (10.96) 912 5.29 (7.27) <.001
ScvO2 >70% 219 8.61 (8.52) 808 6.66 (7.22) <.002
Antibiotic and cultures
Correctness of antibiotics, % 386 93.2 799 88.1 .004
Duration of antibiotics, days 499 9.73 (10.37) 793 11.86 (11.04) .001
Fluid administration, L
0-6 hours 854 2.5 (1.8) 2029 2.7 (1.7) <.001
7-72 hours 667 7.6 (5.1) 1415 8.4 (5.6) <.001
0-72 hour total fluid volume 642 10.1 (5.6) 1393 11.2 (6.2) <.001
Vasopressor use
Administered 0-6 hours, % patients 410 47.5 825 44.2 NS
Administered 0-72 hours, % patients 663 88.1 1178 72.4 <.001
Inotropic therapy, % of patients
Administered 0-6 hours 64 9.9 192 11.6 NS
Administered 6-72 hours 85 13.5 179 12.1 NS
PRBC transfusion
Total used 0-72 hours, units 254 1.3 (2.1) 524 1.3 (1.9) NS
Glucose levels, mg/dL
Baseline 908 158.1 (116.9) 1806 167.6 (132.7) NS
24 hour 582 133.3 (65.7) 1388 130.3 (60.8) NS
Cortisol level, mg/dL 413 37.3 (37.1) 640 39.6 (34.9) NS
Abbreviations: BP, blood pressure; BUN, blood urea nitrogen; CVP, central venous pressure; MAP, mean arterial pressure; NS, not significant; ScvO2, central
venous oxygen saturation; SD, standard deviation.
a
Musculoskeletal, central nervous system, endocarditis, ear nose and throat, obstetrics and gynecology, and wound sources of infection.

Antibiotic Administration and Culture Rates Analysis of Interventions on Mortality

Group II had 5.2% less antibiotic appropriateness (93.2% vs
88.1%, P ¼ .004) with a 2.13-day longer duration of antibio-
tics, P < .001. There were no differences in the overall culture
and primary blood culture positivity rates between groups
(Table 1).
The overall individual RB bundle element compliance was
67.5% in the concurrent group (groups IB and IIB). Obtaining
a lactate (OR ¼ 2.18, P < .001), achieving a MAP 65 mm Hg
(OR ¼ 0.59, P < .001), and achieving a ScvO2 70%
(OR ¼ 0.75, P ¼ .048) were significantly associated with in-
hospital mortality (Table 4).

Fluid therapy, Vasopressors, Inotropes, and Red Blood Discussion

Cell Transfusions
Group II received 0.2, 0.8, and 1.1 L more fluid during the 0 to
6, 7 to 72, and 0 to 72 time periods, respectively (all P < .001).
There was no significant difference in vasopressor use during
the 0- to 6-hour time period; however, there was a 15.7%
absolute reduction in vasopressor use in group II over the 0-
to 72-hour time period (P < .001). There was no significant
difference in the use of inotropes or red blood cell transfu-
sions between groups (Table 1).
The GENESIS is associated with significantly decreased in-
hospital mortality. The impact on in-hospital mortality was
equally observed in a before-and-after and concurrent obser-
vational analysis based on completing the RB. These results
are similar and consistent with the previous studies.9-14
These ‘‘real-life’’ salutary effects are seen even after inclu-
sion of comorbidities (ie, cancer, end-stage renal, and liver
disease) which could potentially diminish the treatment
effect.
Cannon et al 361

Table 2. Mortality, Organ Dysfunction and Health Care Resource Consumption.

Group I Group II
Relative Risk
Na Value (%) Na Value (%) (95% CI) P Value

In-hospital mortality
Group I vs group II 665 42.8 1383 28.8 0.67 (0.63-0.72) <.001
Group IA vs IIA (before vs after implementation of RB) 409 43.0 1192 29.0 0.68 (0.62-0.74) <.001
Group IB vs IIB (concurrent RB not achieved vs achieved) 256 42.5 188 27.2 0.64 (0.55-0.74) <.001
Mortality by sepsis inclusion category (at baseline)
Lactate 4 mmol/L 229 54.4 404 36.0 0.66 (0.59-0.74) <.001
SBP <90 mm Hg or MAP <65 243 47.3 357 29.6 0.63 (0.55-0.71) <.001
SBP <90 or MAP <65 mm Hg or lactate 4 mmol/L 362 47.2 596 31.5 0.67 (0.60-0.74) <.001
SBP <90 or MAP <65 mm Hg and lactate 4 mmol/L 222 48.0 343 30.4 0.63 (0.56-0.72) <.001
SBP >90 or MAP >65 mm Hg and lactate 4 mmol/L 203 42.8 312 24.9 0.58 (0.50-0.67) <.001
SBP <90 or MAP <65 mm Hg and lactate <2 mmol/L 286 52.2 662 46.5 0.89 (0.81-0.99) .02
Mortality by hospital location
ED 208 35.9 486 23.8 0.66 (0.58-0.75) <.001
GPU 69 48.9 55 33.5 0.66 (0.50-0.87) .006
ICU 150 45.2 218 31.3 0.69 (0.59-0.81) <.001
Mortality by centers, %
Tertiary care 522 43.2 1006 29.0 0.66 (0.61-0.72) <.001
Community 143 41.2 375 29.3 0.71 (0.61-0.83) <.001
Organ dysfunction (SD)
Baseline APACHE score 483 20.6 (7.6) 806 22.9 (8.0) – <.001
24-Hour APACHE score 482 23.0 (8.5) 409 19.3 (7.3) – <.001
Baseline SOFA score 406 7.0 (3.8) 299 7.9 (4.0) – .002
24-Hour SOFA score 407 8.3 (4.2) 296 6.5 (3.3) – <.001
Baseline PaO2/FiO2 577 264.6 (158.6) 820 262.9 (158.9) – NS
24-Hour PaO2/FiO2 348 240.7 (135.5) 630 298.9 (158.2) – <.001
Duration of mechanical ventilation –
0-6 hours, % of patients 281 38.5 549 33.5 – .02
6-72 hours, % of patients 326 50.9 433 44.7 – .02
Duration, days (SD) 391 9.7 (12.5) 933 8.4 (9.8) – .06
Length of stay (SD) –
ED, hours 414 5.7 (4.5) 1584 5.4 (4.3) – NS
Hospital length of stay, days 1554 20.7 (30.7) 4809 15.6 (20.0) – <.001
Financial costs (SD)
Hospital charges, $ 723 143,949 (188 295) 1182 96,026 (141 139) – <.001
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation study; CI, confidence interval; ED, emergency department; FiO2, fraction of inspired
oxygen; GPU, general practice unit; ICU, intensive care unit; MAP, mean arterial pressure; PaO2, partial pressure of arterial oxygen; RB, resuscitation bundle; SBP,
systolic blood pressure; SD, standard deviation; SOFA, Sequential Organ Failure Assessment.
a
For mortality N equals the number of deaths.

As with comparable diseases such as acute myocardial

Figure 3. Cumulative mortality over the study duration.
infarction, stroke, and trauma, a standard operating procedure
that includes early detection, risk stratification, and early inter-
vention decreases morbidity and in-hospital mortality. The
15.8% increase (from 50.1% to 65.9%) in the patients identified
in the ED resulted in a significant decrease in patients diagnosed
in the GPU and ICU. These patients (ICU and GPU) usually face
a 3 times higher mortality risk if they develop septic shock.15
This earlier identification was accompanied by a significant
GPU absolute in-hospital mortality reduction (48.9%-33.5%)
followed by the ICU (45.2%-31.3%) and the ED (35.9%-
23.8%, all P  .006; Table 2).
The GENESIS resulted in a significant decrease in time-
to-fluid challenge, lactate measurement, antibiotic therapy,
and hemodynamic target attainment. Although the total
362 Journal of Intensive Care Medicine 28(6)

Table 3. Individual Study Center Settings and Mortalities.a

Group I Group II Group I Group II Absolute Mortality Relative Mortality

Center Hospital Locations Period Period Mortality Mortality Reduction Reduction

A ED/GMF/OR/ICU 2003-2005 2006-2007 43.0 33.6 9.5 22.0

B ED/ICU 2006 2007-2009 36.7 28.6 8.1 22.1
C ED/ICU 2004 2005-2007 35.3 27.8 7.5 21.3
D ED/ICU 2005 2006-2008 41.3 25.3 16.0 38.7
E ICU 2004-2005 2006-2007 41.6 31.8 9.8 23.6
F ED/GMF/OR/ICU 2003-2005 2006-2009 38.8 30.7 8.1 20.8
G ED/ICU 2004-2004 2005-2008 36.8 18.8 18.0 48.9
H ED/GMF/ICU 2003-2004 2005-2008 55.9 30.2 25.7 46.0
Ib ED/GMF/ICU 2005-2008 56.3 40.0 16.3 28.9
Jb ED/GMF/OR/ICU 2005-2008 36.5 21.4 15.1 41.5
Kb ED/GMF/OR/ICU 2006-2009 43.0 23.2 19.8 46.0
Abbreviations: ED, emergency department; GMF, general medical floor; OR, operating room; ICU, intensive care unit.
a
The identity of the hospitals are blinded.
b
Concurrent centers.

Table 4. Adjusted Predictors of Mortality–Early Therapeutic Interventions.

Therapeutic Interventions Variable in Database Odds Ratio 95% Confidence Interval P Value

6-Hour resuscitation bundle

Serum lactate measured Lactate—0 hours 2.18 1.89-2.52 <.001
Blood cultures before antibiotics Blood culture in <3 hours 1.01 0.84-1.21 .92
Early treatment with antibiotics Antibiotics in <3 hours 1.00 0.85-1.18 .96
Intravenous fluids delivered Fluid challenge in <3 hours 1.26 0.96-1.66 .09
Mean arterial pressure 65 mm Hg achieved MAP 65 mm Hg—6 hours 0.59 0.50-0.70 <.001
Central venous pressure 8 mm Hg achieved CVP  8 mm Hg—6 hours 1.17 0.88-1.57 .28
Central venous oxygen saturation 70% achieved ScvO2 70%—6 hours 0.75 0.56-0.99 .047
Abbreviations: CVP, central venous pressure; MAP, mean arterial pressure; ScvO2, central venous oxygen saturation.

amount of fluid differed by only 1.1 L over 72 hours between
groups I and II, the time to receiving a fluid challenge and meeting
CVP goals was significantly reduced.16 Early and aggressive fluid
administration modulates early inflammation and reduces vaso-
pressor support (associated with decreased mortality) and qualifi-
cation for corticosteroids.17-21,22 Consistent with previous
studies, we found a significant association between ScvO2, MAP,
lactate measured, and mortality reduction.20,23,24
Group I (control group) in-hospital mortality, in all hemody-
namic subgroups, exceeded 42% (Table 2). When compared to
group II (treatment group), there was a significant in-hospital
mortality reduction after receiving the RB. The in-hospital mor-
tality for patients in this study versus the original EGDT study of
the same hemodynamic subgroup (lactate >4 mmol/L or
SBP <90 mm Hg) was 47.2% versus 46.5% in the control and
31.5% versus 30.5% in the treatment groups, respectively.4
In an examination of 15,022 patients over a similar time
frame, Levy et al showed that a SBP <90 mm Hg or
MAP <65 mm Hg and lactate 4 mmol/L was associated with
a 46.1% hospital mortality which corresponds to a 48.0%
observed mortality in the same subgroup in this study.3 Of
particular interest are normotensive patients with an elevated
lactate who are described as ‘‘cryptic shock’’ and who experi-
enced an in-hospital mortality reduction from 42.8% to 24.9%
(P < .001).25 These patients who appear stable by traditional
vital signs have an underappreciated illness severity and often
later suffer cardiopulmonary collapse or multiorgan failure due
to persistently untreated hypoperfusion.26,27
Despite significantly higher baseline organ dysfunction
scores (APACHE-II and SOFA) in group II, there was still a
significantly greater improvement over the first 24 hours indi-
cating improved organ function compared to group I. For
example, while baseline pulmonary function via partial pres-
sure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2)
ratios were equal, group I significantly worsened by 9.0%
while group II improved by 13.7% at 24 hours (both
P < .001). Paralleling these findings were a lower use of
mechanical ventilation in group II. Early detection and treat-
ment of shock on hospital admission are associated with
decreased need for mechanical ventilation.27
Lactate clearance is significantly associated with the
modulation of inflammatory biomarkers, organ failure, and
outcome.28 In this study, the lactate clearance in group I versus
group II significantly improved over the first 6 hours (2% vs
21%, P ¼ .044) and over 24 hours (11% vs 39%, P < .001).
However, the alactemic patients (lactate <2 mmol/L with
hypotension) had a baseline in-hospital mortality of 52.2% and
were less responsive to the in-hospital mortality reduction of
Cannon et al
GENESIS than any other hemodynamic subgroup. This alacte-
mic patient population raises caution with the use of lactate
clearance as an isolated diagnostic and therapeutic end point.29
There was a 24.6% reduction in duration of hospital stay and
a 33.3% reduction in total hospital charges per admission
following GENESIS implementation which are similar to the
previous reports.30-32 Ross et al found that the association
between hospital volume and 30-day mortality is maximized
when the volume threshold for hospitalization exceeds 210
patients per year for pneumonia in particular.33 Applying this
economic model to our study means that 1071 hospital days
could potentially be saved resulting in $10,063,830 in-hospital
charges saved per year.
Limitations
This study was not a prospective randomized trial, thus, it has
the capacity to reveal associations but not causal relationships.
Additional unmeasured procedural changes at institutions, such
as implementation of other quality initiatives, may have led to
unaccounted differences between groups over time. These
include other components of sepsis management in the
subsequent 24 hours such as corticosteroids, protective lung
strategies, glucose control, recombinant activated protein C,
gastrointestinal ulcer, and deep venous prophylaxis.34 These
interventions (some debatable) and the diagnostic coding for
sepsis have seemingly diminished mortality over the last
decade.35-37 In addition, despite the use of consistent criteria
for identifying patients with severe sepsis and septic shock,
variability in diagnosis, and chart abstraction may have led to
heterogeneity in historical controls. The designation of patients
into control and treatment groups was based on assumptions of
care or the treatment effect. The control group patients not
receiving or achieving the RB (Group IA and IB) could have
received partial RB completion. The treatment group or
patients receiving the RB (Group II A) could have received less
than full RB completion. Group IIA in particular was assumed
to have the same intervention as group IIB; however, despite
the lack of quantification of bundle compliance for group IIA,
it is likely they received less than 100% RB compliance, given
363
that the overall concurrent model averaged 67% compliance
between fully achieved and not fully achieved cohorts.
In either scenario regarding the control or treatment groups,
the overall treatment effect of the study and findings of this
study are conservative and understated. Although there is a
4-fold greater number of patients in the before-and-after group
compared to the concurrent group, the findings are comparable.
Baseline illness severity and mortality were similar across all 4
subgroups. The similar mortality reduction seen in both assess-
ment strategies indicate that the treatment effect of the RB is
very robust. Because of incomplete data capture, the post hoc
detail of which bundle element is most important remains
unconfirmed.
Despite these aforementioned issues, this is the first study to
show similar in-hospital mortality reductions in both a before-
and-after and concurrent implementation designs. The concur-
rent findings emphasize the importance of RB compliance and
CQI to realize improved outcomes.38 These findings also sup-
port the notion that implementation trials can be scientifically
acceptable alternatives to randomized controlled trials.39 From
the standpoint of equipoise in following sepsis guidelines, this
study design avoids the ethical issue of randomization to poten-
tially inferior care that is not in accordance with current best
practice recommendations.40
Conclusions
Patients with severe sepsis and septic shock receiving RB
within community and tertiary care settings experience signif-
icant reductions in in-hospital mortality, organ dysfunction,
and health care resource utilization. This results from early
detection of high-risk patients, a reduction in time to delivery
of critical elements of best practice care, and a CQI process.
Future emphasis should be directed to overcoming logistical,
institutional, and professional barriers to the implementation
of RB similar to the approaches for acute myocardial infarc-
tion, stroke, and trauma. In doing so, this may lead to at least
1 life being saved for every 7 patients treated for severe sepsis
and septic shock.
364 Journal of Intensive Care Medicine 28(6)

Appendix A

Table A1. GENESIS Participating Members.

Centers Authors and Contributors

Barnes-Jewish Hospital, Division of Emergency Medicine, Washington University School of Medi- Contact: Chris Holthaus, MD
cine, Campus Box 8072, 660 S. Euclid Avenue, St. Louis, MO 63110, USA Office: (314) 747-5994
IRB committee approval: Fax: (314) 362-0419
Washington University in St. Louis Human Research Protection Office (07-1235) Email: holthausc@wusm.wustl.edu
PI:
(1) Chris Holthaus, MD
(2) Brent Ruoff, MD
Sub-PI: NA
Collaborators:
Jennifer Williams, MSN, RN, ACNS-BC
John Stanley
Mac McMasters
Courtney Harrison, RN
Brian Wessman, MD
Craig McCammon, PharmD
Lara Christy, RN
Damon Vincent, MD
Kari Yount, RN
Shelby Rives, RN
Amy Stiefel, RN
Melissa Caldwell, RN
California Pacific Medical Center, 2333 Buchanan St., San Francisco, CA 94115, USA Contact: Ron Elkin, MD
IRB committee approval: Office: (415) 749-5746
California Pacific Medical Center Institutional Review Board (FWA00000921) Email: elkin.ron@gmail.com
PI: Ron Elkin, MD
Sub-PI:
Cathy Camenga, RN
Alice Chang, RN
Gouri Chavan, RN
Minh Nguyen, MD
Bing Tschai, RN
Collaborators:
Christopher Brown, MD
Thomas Knight, MD
Martie Mattson, RN
Thomas Peitz, MD
Michael Rokeach, MD
Christiana Care Health System, 4755 Ogletown-Stanton Rd., Newark, DE 19718, USA Contact: Marc T. Zubrow, MD, FCCP
IRB Committee Approval: Phone: 302-733-1000
Christiana Care Health System Institutional Review Board (CCC#28136) Email: mzubrow@christianacare.org
PI: Marc T. Zubrow, MD
Sub-PI:
Gerard J. Fulda, MD
Collaborators:
Thomas A. Sweeney, MD
Maureen A. Seckel, APN
Alison C. Ellicott, RN
Donna D. Mahoney
Paula M. Fasano-Piectrazak, RN
Megan B. Farraj, PharmD
Henry Ford Hospital-Main Campus, 2799 W. Grand Blvd CFP-2, Detroit, MI 48202, USA Contact: Arturo Suarez, MD
IRB Committee Approval: Email: asuarez1@hfhs.org
Henry Ford Health System Institutional Review Board (#4693) PI: Arturo Suarez, MD
Collaborators:
Victor Coba, MD
Kristine McGregor, RN
(continued)
Cannon et al 365

Table A1. (continued)

Centers Authors and Contributors

Damon J. Goldsmith, BS
Brandon Claxton, BS
Dante Figueroa, MD
Melissa Whitmill, MD
Craig Bailey, MD
Daniel Singer, MD
Anja Kathrin Jaehne, MD
Laura Eichhorn-Wharry, MD
Samantha Brown, BS
Garrett Chapman, BS
Aaron Baugh, BS
Emanuel Rivers, MD, MPH, FCCP
Henry Ford Hospital-Wyandotte (HFWH), Department of Emergency Medicine, 2333 Biddle, Contacts: Satheesh Gunaga, DO
Wyandotte, MI 48192, USA Phone: 734-246-7380
IRB Committee Approval: Email: drgunaga@yahoo.com
Henry Ford Health System Institutional Review Board (#4693) PI:
(1) Satheesh Gunaga, DO
(2) Vipul Kella, MD
Sub-PI: NA
Collaborators:
Jedediah Walker, MS4
Gage Dixon, MS4
Christopher Nedzlek, DO
Jason Fletcher, MS4
Ryan Siwiec, MS4
Asad Mehboob, M4
Ryan Buckley, MS3
Robert McCurren, MD
Mark Pensler, MD, FCCP
Ravinder Gandhi, MD
Kevin Boehm, DO, MSc
Lisa Simpson, RN
Kenda Calhoun, RN
James Machcinski, RN
Lisa Blanchette, RN
Charles Arnold, RN
Lois Vandercook, RN
Travis Esckridge, RN
Northwest Community Hospital, 800 West Central Road, Arlington Heights, IL 60005, USA Contact: Nathan Lidsky, MD
IRB Committee Approval: Email: nlidsky@nch.org
Northwest Community Hospital Institutional Review Board (NCH11-10) PI: Nathan Lidsky, MD
Sub-PI: NA
Collaborators:
Melanie Atkinson, MSN, APRN, BC,
CCRN
Diane Ryzner
Porter Hospital, 814 LaPorte Ave., Valparaiso, IN 46383, USA Contact: Bonnie Turman, MS, RN
IRB Committee Approval: Phone: 219-263-7110
Porter Hospital Institutional Review Board (S-502010) Email:
bonnie.turman@porterhealth.com
PI: Bonnie Turman, MS, RN
Sub-PI:
Douglas Mazurek, MD
Tim Whetsel, MD
Baqhar Mohideen, MD
Collaborators:
Terrie Fontenot, BSN, RN
Lynn Kowert, BSN, RN
(continued)
366 Journal of Intensive Care Medicine 28(6)

Table A1. (continued)

Centers Authors and Contributors

Valerie Johns, RN
Kitty Cavanaugh, BSN, RN
Ellen Rastovski, BS, RN
Jeff Chin, PharmD
Tracy Dabrowiak, PharmD
St. Cloud Hospital, Intensive Care Unit, 1406 Sixth Ave. North, St. Cloud, MN 56303-1901, USA Contact: Scott Davis, MD, FCCP, FCCM
IRB Committee Approval: Work (320)-251-2700
St. Cloud Hospital Institutional Review Board (FWA00001162) Fax (320)-240-7850
Email: Daviss@Centracare.com
PI: Scott Davis, MD
Sub-PI:
John Olsen, MD, FCCP, FACP
Collaborators:
Kirsten Skillings, RN, MA, CCNS
Bonnie Curtis, RN
Gail Jenson, RN
Joe Sauer, RPh
Julianne Heath, BA
St. Joseph Mercy Hospital, 5301 McAuley Drive, Ypsilanti, MI 48197, USA Contact: Pat Posa
IRB Committee Approval: Phone: 248-890-0044
St. Joseph Mercy Health System Institutional Review Board (R-05-670) Email: posap@trinity-health.org
PI: Pat Posa, RN, BSN, MSA
Sub-PI:
Mary-Anne Purtill, MD
Collaborators:
Sheri Brown, RN
Jennifer Cirino, MS1
Christine Curran, MD
Lisa Fetters, RN, MSN
Regina Freeman, RN
Denise Harrison, RN, MSN
Laszlo Hoesel, MD (G3)
Jeong Hyun, MD (G2)
Brian Kurylo, RN
Nicolas Mouawad, MD (G3)
Wendy Nieman, RN
Fran Rocheleau, NP
Lora Silverman, MD (G3)
Cecila Sosonowski, RN
Catherine Stewart, RN
The University of Kansas Hospital, Department of Emergency Medicine, 3901 Rainbow Boulevard, Contact: Chad M. Cannon, MD
Kansas City, KS 66160, USA Office: 913-588-6504
IRB Committee Approval: Fax: 913 588-9104
Kansas University Medical Center Human Subjects Committee (#11157) Email: ccannon@kumc.edu
PI: Chad M. Cannon, MD
Sub-PI:
Scott T. Rawson, MD
Michael Hastings, RN, BSN, CEN, EMT
Jeremy Strom, MD
Carol Cleek, RN, MSN, APRN-BC,
CNAA-BC
Michael Moncure, MD
Steven Q. Simpson, MD, FCCP
Collaborators:
Katherine Mann, RN, BSN
(continued)
Cannon et al 367

Table A1. (continued)

Centers Authors and Contributors

Ira Marsh, MD
Niaman Nazir, MBBS, MPH
Alison Pontious, RN, BSN
Chad Toney, MBA
Nia Thompson, BA
Shannon M. Wimsett, RN, BSN
Rick Blevins, RN, BSN, CEN, EMT-P
Michelle L. Bolen, RN, BSN, CCRN
Amanda Gartner, RN, MSN, CCRN
Akiko Kubo, RN, BSN, CCRN
Doug Peterson, MS, RN
University Medical Center at Brackenridge, ED Administration Offices, 601 E. 15th Street, Austin, Contact: Truman J. Milling Jr, MD
TX 78701, USA Phone: 512-324-7023
IRB Committee Approval: Email: tjmilling@yahoo.com
Brackenridge Hospital Institutional Review Board (#07-BHIRB-353) PI:
(1) Jordan Weingarten, MD, FCCP
(2) Truman J. Milling Jr, MD
Sub-PI:
Patrick Crocker, DO
Collaborators:
Ben King, MPH
Omid Zad, MD
Hassie Cooper
Anna Sicher, RN, MPA

Acknowledgments
The authors would also like to extend tremendous gratitude to the 113
additional participating members (Appendix A) that contributed to
making a study of this magnitude successful, without them this would
have otherwise been impossible. The collaborative is indebted to the
team’s tireless efforts in caring for patients with sepsis and daily dedi-
cation to quality improvement. The authors would like to acknowledge
Kimberly McFarland, PhD, who assisted in the initial preparation of this
manuscript for a total of 15 hours work compensated by the Department
of Emergency Medicine of Henry Ford Hospital.
Authors’ Notes
The authors Cannon, Holthaus, Posa, Gunaga, Turman, Weingarten,
Suarez, and Rivers were involved in the study conception and design,
coordination, data collection, statistical analyses, interpretation of the
data and results, manuscript preparation, approval and overall responsi-
bility for the contents of the manuscript. The authors Zubrow, Kella,
Elkin, Davis, Milling, Lidsky, Coba, and Yang were involved in the study
coordination, data collection, interpretation of the data and results, manu-
script preparation, and approval of the manuscript. This research has been
presented at the (1) Society of Critical Care Medicine Annual Congress
in Nashville, Tennessee and received Annual Scientific Award for Top
Ten Abstracts, 2009. (2) Mediterranean Emergency Medicine Congress
in Valencia, Spain and received the Best Abstract Award, 2009. (3)
American College of Emergency Physicians, Boston, Massachusetts in
2009. (4) International Conference on Emergency Medicine, Singapore
and received the Best Oral Presentation Award, 2010.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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