multicenter implementation of a severe sepsis and septic shock treatment bundle

Miller et al., Sepsis Bundle and Mortality

1

Multicenter Implementation of a Severe Sepsis and Septic Shock Treatment Bundle

Russell R Miller III1,2

, Li Dong3, Nancy C Nelson

3, Samuel M Brown

1,2, Kathryn G Kuttler

3,4,

Daniel R Probst3, Todd L Allen

3, and Terry P Clemmer

1,2 for the Intermountain Healthcare

Intensive Medicine Clinical Program

1Division of Pulmonary and Critical Care Medicine, Intermountain Healthcare, Murray, Utah,

2Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of

Utah School of Medicine, Salt Lake City, Utah, 3Intermountain Healthcare, Salt Lake City, Utah,

4Homer Warner Center for Informatics Research, Murray, Utah

Corresponding Author:

Russell R Miller III, MD, MPH

Intermountain Medical Center

T4S, Respiratory Intensive Care Unit

5121 South Cottonwood Street

Murray, UT 84107

[email protected]

Funding Source: Supported in part by K23GM094465 (SMB)

Descriptor Number: 4.12

All authors participated in conception and design, analysis and interpretation of data, and

drafting the manuscript or revising it critically for important intellectual content.

Body text: 3443 words

of 42 AJRCCM Articles in Press. Published on 30-April-2013 as 10.1164/rccm.201212-2199OC


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Abbreviations

APS, Acute Physiology Score

CCIS, Charlson Comorbidity Index Score

CI, confidence interval

CVP, central venous pressure

ED, emergency department

ICU, intensive care unit

IQR, interquartile range

OR, odds ratio

ScvO2, central venous oxygen saturation

SD, standard deviation



1

Abstract (250 words)

Rationale: Severe sepsis and septic shock are leading causes of intensive care unit (ICU)

admission, morbidity, and mortality. The effect of compliance with sepsis management

guidelines on outcomes is unclear.

Objectives: To assess the effect on mortality of compliance with a severe sepsis / septic shock

management bundle

Methods: Observational study of a severe sepsis / septic shock bundle as part of a quality

improvement project in eighteen ICUs in eleven hospitals in Utah and Idaho

Measurements and Main Results: Among 4329 adult subjects with severe sepsis or septic

shock admitted to study ICUs from the emergency department between January 2004 and

December 2010, hospital mortality was 12.1%, declining from 21.2% in 2004 to 8.7% in 2010.

All-or-none total bundle compliance increased from 4.9% to 73.4% simultaneously. Mortality

declined from 21.7% in 2004 to 9.7% in 2010 among subjects not compliant with one or more

bundle element. Regression models adjusting for age, severity of illness, and comorbidities

identified an association between mortality and compliance with each of inotropes and/or red cell

transfusions, glucocorticoids, and lung protective ventilation. Compliance with early

resuscitation elements during the first 3 hours following emergency department admission

caused ineligibility, through lower subsequent severity of illness, for these later bundle elements.

Conclusion: Total severe sepsis and septic shock bundle compliances increased substantially and

were associated with a marked reduction in hospital mortality after adjustment for age, severity

of illness, and comorbidities in a multicenter ICU cohort. Early resuscitation bundle element

compliance predicted ineligibility for subsequent bundle elements.

Keywords: mortality, septicemia, outcome studies, quality improvement



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Introduction

Severe sepsis and septic shock (henceforth septic shock) are leading causes of morbidity

and mortality in the intensive care unit (ICU) (1, 2). Published in-hospital mortality due to septic

shock ranges from 25-70% (3-5). Building upon strategies to diminish morbidity and mortality,

including early goal-directed therapy (6), the Surviving Sepsis Campaign in 2004 and 2008 has

promoted bundling appropriate elements of care from the emergency department (ED) and ICU

into two bundles, a resuscitation and a maintenance bundle (7, 8). Bundled care processes

standardize interventions to reduce unintended variation among clinicians as well as within a

single clinician from patient to patient (9-13) by establishing a shared clinical baseline upon

which further care can be built. Additionally, bundled care elements can be measured and

compared against pertinent clinical outcomes. Implementation of Surviving Sepsis Campaign

guidelines has suffered from an unclear relationship among individual bundle elements and

outcomes (14). In particular, it is unclear whether compliance with the earliest bundle elements

may lead to a lessening of severity of illness and hence less need for later bundle elements (e.g.,

rapid resolution of shock as a result of prompt, appropriate identification of septic shock and

administration of antibiotics obviates the need for red cell transfusions). We conducted a multi-

hospital quality improvement study to 1) implement a septic shock bundle, 2) evaluate resulting

changes in mortality, and 3) determine the significance of individual bundle elements in

predicting mortality. We hypothesized: 1) compliance with the bundle would be associated with

lower mortality and 2) compliance with early resuscitation bundle elements would cause

ineligibility, through decreased severity of illness, for later bundle elements. Some of these

results have been previously reported in abstract form (15, 16).



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Methods

Study Design

We conducted a quality improvement intervention among patients with severe sepsis and

septic shock admitted directly from the ED to the ICU. Patients were enrolled from eighteen

Intermountain Healthcare ICUs in eleven hospitals in Utah and Idaho between January 1, 2004

and December 31, 2010. Following local adaptation of Surviving Sepsis Campaign bundle

recommendations into a bundle of care processes (Table E1), the study was conducted in three

stages based on ICU admission date: 1) baseline and bundle development stage, January 1, 2004

to December 31, 2004; 2) implementation stage, January 1, 2005 to December 31, 2007; and 3)

tracking stage, January 1, 2008 to December 31, 2010. The first stage represented a period of

identifying bundle elements and eligibility and coordinating a data collection process. The

second stage involved large scale education about elements and intent of the bundle. The last

stage reflected a period when Intermountain Healthcare made compliance with sepsis bundles a

corporate initiative. The Intermountain Healthcare Institutional Review Board granted approval

for waiver of consent for this quality improvement study.

Data Collection and Definitions

All subjects admitted to a participating ICU from the ED, either directly or via the

operating room, were screened. Subjects not admitted to the ICU from the ED directly or from

the ED via the operating room were excluded to diminish potential confounding from care

delivered on the ward or at an outside hospital. The bundle was specifically designed for ED to

ICU resuscitation of subjects with septic shock further necessitating exclusion of other admission



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sources. Subjects <18 years old were excluded, as were those in which initial screening data

were incomplete.

Following identification of subjects (see Supplement), trained study coordinators

reviewed each subject’s medical record and judged the data against standard criteria for sepsis,

which includes a presumed or known source of infection along with at least two systemic

inflammatory response syndrome criteria (17). Subjects were then classified as having either

severe sepsis or septic shock in the first 24 hours. Severe sepsis meant sepsis plus evidence of

end-organ dysfunction (e.g., altered mentation, renal insufficiency) or lactate ≥2 mmol/L (18).

Septic shock included severe sepsis plus either 1) hypotension despite adequate fluid

resuscitation or 2) serum lactate ≥4mmol/L. Subjects identified as either severe sepsis or septic

shock underwent study coordinator review of individual bundle elements using a combination of

paper chart, direct communication with clinicians, and electronic health record review to record

compliance. Demographic data, including age, sex, race/ethnicity, severity of sepsis as either

severe sepsis or septic shock, Acute Physiology Score (APS), Charlson comorbidity index score

(CCIS), and in-hospital mortality were recorded.

We divided the total bundle of 11 individual elements temporally into a 7 element

resuscitation bundle and a 4 element maintenance bundle (Table E1). The first 3 resuscitation

elements, which applied to all subjects regardless of disease severity, were to be completed

within 3 hours of ED admission. The next 4 resuscitation elements were to be completed within

6 hours of ED admission. For hypothesis testing of the role of bundle element ineligibility on

mortality, we evaluated bundle elements 4-11 as “later” bundle elements. Bundle elements 4-11

were deemed later bundle elements because they were invoked only if the subject met a priori

definitions of severity of illness. Compliance with bundle elements 1-3 and 8 (glucose) was



5

classified as “eligible and compliant” or “eligible and non-compliant” because all subjects were

deemed eligible for these criteria. Compliance with bundle elements 4-7 and 9-11 was noted as

“eligible and compliant,” “eligible and noncompliant,” or “ineligible” because not all subjects

were deemed eligible for these treatments. “Ineligible” refers to subjects who are less ill and

therefore did not require advanced therapies. For example, subjects who did not require high

doses of vasopressors were considered ineligible for glucocorticoids. Bundle compliances were

defined as all-or-none at 24 hours from ED admission: non-compliance with any single element

was interpreted as non-compliance with the bundle. Individual bundle element compliance

occurred when the subject was either “eligible and compliant” or “ineligible.”

Statistical Analysis

Descriptive statistics summarized subject characteristics (age, sex, and race) and

compliance with the sepsis bundle over the three study stages: baseline (January 1, 2004-

December 31, 2004), implementation (January 1, 2005-December 31, 2007), and tracking stage

(January 1, 2008-December 31, 2010) (See Table E2 for additional details about study ICUs.)

The mean and standard deviation (SD) or median and interquartile range (IQR) were used to

describe continuous measures, where appropriate. A chi-square test compared mortality over the

study periods. Changes in the median number of compliant elements over time were evaluated

with the Kruskal-Wallis statistic. A statistical process control chart (p-chart) was generated to

illustrate total bundle compliance and mortality over time. Generalized linear mixed model for

conditional logistic regression analysis (GLMM-CLRA) with random intercepts was performed

to examine the association between inpatient mortality and independent variables (age, sex, race,

severity of sepsis, and sepsis bundle elements) while controlling for CCIS and APS. We



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considered study hospital to be the random effect. We assessed for multicollinearity using

tolerance and variance inflation factor statistics. Any variable with a variance inflation factor

>2.5 was removed from the model (19). A stepwise, backward selection method was used for

feature selection for the final model. Interactions between lactate and septic shock, fluid

resuscitation and septic shock, as well as glucocorticoids and septic shock were evaluated for

effect modification based on severity of sepsis. Finally, we created regression models using

compliance with early bundle elements 1, 2, and 3 to predict ineligibility for later elements that

had been identified as associated with mortality in the final, multivariate regression model. Due

to potential bias in the estimated effect of early bundle compliance on later bundle element

ineligibility in this observational study, two propensity score adjustment methods—stratification

and matching—were used to validate the hypothesis that early bundle element compliance

caused later element ineligibility. Study period, severity of sepsis, age, APS, and CCIS were

included in the propensity score model of early bundle element compliance. A random 1:1

matching without replacement selection method was implemented for the propensity score with

matching, and caliper width was 0.2. All statistical analyses were performed using SAS 9.3 (SAS

Institute Inc., Cary, NC). Two-tailed statistical significance level, α, was defined at 0.05.



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Results

Of 4379 subjects who met inclusion criteria over 7 years, 1.1% (n=50) were excluded

(Figure 1). Among the remaining 4329 subjects, baseline demographics, APS, CCIS, and

severity of sepsis are noted in Table 1 by survival and in Table E3 by study period. Central

tendencies of initial ED serum lactate level, initial ED systolic blood pressure, and ED length of

stay were unchanged from 2004 to 2010 (data not shown). Mortality was 12.1% for the overall

cohort, including 17.0% among septic shock subjects and 8.9% among severe sepsis subjects

(Table 1). Concomitant with a 68.5% absolute increase in all-or-none total bundle compliance

from 4.9% at baseline to 73.4% in 2010, relative mortality declined 59.0% from 21.2% at

baseline to 8.7% for 2010 (p<0.0001; Figure 2). Compliances with resuscitation and maintenance

bundles were similarly associated with improved mortality (data not shown).

Mortality among subjects non-compliant with the total bundle decreased 55.3% over the

study period from 21.7% at baseline to 9.7% for 2010 (see Table E5 for results by hospital).

Concomitantly, the median number of non-compliant total bundle elements among non-

compliant subjects fell over time (p<0.0001 for trend) from 4 (interquartile range [IQR] 2-5, max

11) in 2004 to 2 (IQR 1-3, max 10) for 2005-2007 and then 1 (IQR 1-2, max 8) for 2008-2010.

Age, severity of sepsis, and most bundle elements were associated with mortality after

adjustment for APS and CCIS (Table 2). In the final multivariate model, age, and compliance

with inotropes/red cell transfusions, steroid administration, and use of a lung protective

ventilation strategy were associated with improved mortality after adjustment for APS and CCIS

(Table 2). Of note, there was no interaction between glucocorticoids, lactate, or fluid

resuscitation and presence of septic shock versus severe sepsis (data not shown). A sensitivity

analysis restricted to subjects with septic shock (as opposed to severe sepsis) yielded the same



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results as the overall multivariate model that included both severe sepsis and septic shock

patients. Only 18 subjects were admitted to the ICU from the ED via the operating room, of

which 2 died (p=0.89 for comparison of mortality in this cohort to mortality among subjects

admitted directly to the ICU from the ED).

The percent of subjects ineligible for later bundle elements consistently increased over

time (p<0.01 for each; see Table E6). Subjects were, by definition, always deemed eligible for

element 8, glucose control. After adjustment for age, APS, and CCIS, compliance with early

resuscitation elements—all in the first 3 hours following ED admission—was associated with

increased odds of ineligibility for inotropes/red cell transfusions, glucocorticoids, and use of a

lung protective ventilation strategy in a regression model. Specifically, compliance with lactate

measurement predicted ineligibility for all 3 of these later bundle elements (all p<0.001), as did

compliance with obtaining blood cultures (all p<0.0001) and compliance with antibiotic

administration prior to blood cultures (all p<0.01). Matching 2,084 subjects in propensity score

analysis (1042 who were not compliant with the first 3 elements matched to 1042 who were

compliant with the first 3 elements) yielded the same findings. Compliance with the first 3

elements predicted ineligibility for inotropes/red cell transfusions (OR 1.40, 95% CI 1.10-1.79),

glucocorticoids (OR 1.30, 95% CI 1.06-1.60), and lung protective ventilation (OR 1.48, 95% CI

1.14-1.91). Findings from propensity score analysis using stratification also were the same. For

these 3 later elements, eligible and compliant subjects were as likely to die as eligible and non-

compliant subjects (all p=NS). Subjects ineligible for each of the 3 later elements were

significantly less likely to die than eligible subjects across all study periods (all p<0.0001).



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Discussion

In a multicenter investigation following development and implementation of a septic

shock bundle, absolute compliance with the total bundle increased 68.5% (from 4.9% to 73.4%)

from 2004 to 2010. Total bundle compliance was significantly associated with a 59% relative

reduction in hospital mortality after adjustment for age, severity of illness, and comorbidities.

Compliance with early resuscitation elements—completed within the first 3 hours following ED

admission—also predicted greater ineligibility for inotropes and/or red cell transfusions,

glucocorticoids, and lung protective ventilation. The latter finding is compatible with lower rates

of progression to more severe disease in the first 24 hours when early bundle elements were

performed.

There are several strengths of the current investigation above and beyond previously

published data. First, while the Surviving Sepsis Campaign reported a 6.2% reduction in

unadjusted mortality from 37.0% to 30.8% over 2 years (14), we witnessed a larger 12.5%

absolute reduction, a much larger relative decline (59.0%), and to a much lower mortality over 7

years. These findings may be related to secular changes over the longer period of study (e.g.,

unmeasured changes in clinical practice, adoption of admission order sets for sepsis patients, and

increased early recognition of sepsis). The difference in our results may also reflect unmeasured

differences between the study populations, given the absence of APS or CCIS in Surviving

Sepsis Campaign data. We also achieved a higher rate of total bundle compliance (from 26% to

74% all-or-none total bundle compliance from 2005 to 2010) than Surviving Sepsis Campaign

hospitals (from 11% to 31% over 2 years in the resuscitation bundle and from 18% to 36% over

2 years in the maintenance bundle). Importantly, even the number of individual non-compliant

elements fell significantly over time (from a median of 4 to a median of 1) and with less



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variation. The bundle required significant collaboration between the ED and ICU—both of

which bore responsibility for its completion. Second, we adjusted our multivariate analyses for

severity of illness (APS) and comorbidities (CCIS) using standard scores. Our work confirms the

findings of a much smaller, single-center study from Brazil. In a study of septic shock bundle

implementation in a single hospital ICU, Shiramizo et al. (20) noted that compliance with

glucocorticoids and with lung protective ventilation (plateau pressure <30 cm H2O rather than 6

mL/kg tidal volume) was associated with improved survival.

Third, we identified three elements of the bundle associated with improved survival:

inotropes and/or red cell transfusions, glucocorticoids, and lung protective ventilation. The

findings may be taken as supportive of Levy et al.’s original “sepsis change bundle” (21) focused

on avoiding refractory hypotension (here, reflected by glucocorticoids), hypoperfusion

(inotropes/red cell transfusions), and organ dysfunction (lung protective ventilation). Inotropes

and/or red cell transfusions for septic shock date back over 40 years (22) and are part of early

goal-directed therapy (6). Although improving oxygen delivery in the first 6 hours appeared to

improve mortality in early-goal directed therapy with a special catheter in the ED environment

(6), optimizing oxygen delivery during the first 24 hours of established septic shock has not held

up in randomized clinical trials (23, 24). Lung protective ventilation improves survival in acute

respiratory distress syndrome (25). Septic patients frequently have concomitant lung injury,

though specific evaluation of lung protective ventilation in a cohort of septic subjects does not

exist. Glucocorticoids, on the other hand, represent an intriguing finding in our investigation.

Significant debate over the safety and benefits of glucocorticoids for sepsis persists (26, 27). In a

recent review of the literature, Patel and Balk poignantly concluded that “bedside clinical

judgement with expert opinion” guide use of glucocorticoids in septic shock (28).



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Fourth, we investigated why bundle elements beyond the first 3 hours of care were

associated with mortality in the multivariate model. Prior investigators (14, 20) have not

described the implication of ineligibility for later bundle elements in their analyses. Later bundle

elements— inotropes/red cell transfusions, glucocorticoids, and lung protective ventilation—may

be associated with mortality because the overall severity of illness of our cohort decreased over

time or because compliance with early resuscitation bundle elements is beneficial in decreasing

the number of subjects progressing to septic shock with worsening organ failure over the first 24

hours. The former is not supported by our data. The latter is supported by two observations: 1)

the magnitude of decrease in eligible and compliant subjects over time is mostly reflected by an

increase in ineligible subjects, and 2) ineligible subjects had higher survival at all times than

eligible subjects. Early resuscitation bundle compliance in the cohort predicts ineligibility of

(less severity of illness in) subjects at 24 hours following ED admission. We believe the

association of glucocorticoids with mortality, for example, likely reflects a statistical finding in

the setting of fewer eligible subjects as a result of increasing early resuscitation compliance.

Even if the specific physiological interventions may not be beneficial in isolation, they appear to

improve mortality as markers of an integrated bundle of all-or-none interventions (21, 29, 30).

Prospective study is necessary to determine whether early identification of an elevated lactate,

for example, might alert the ED physician to the appropriate diagnosis sooner, prompt more

aggressive fluid resuscitation, increase the likelihood of ICU admission, or heighten clinical

suspicion for severe disease, thereby enhancing quality of care and driving improved mortality.

Our study suffers from important limitations. First, as a largely retrospective cohort, the

study may suffer from unintended selection or measurement biases. Of note, the number of cases

increased markedly between the second and third study periods. We acknowledge three possible



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contributors to this increase issues: 1) up to a 160% increase in severe sepsis (31) during this

time nationally; 2) an increased local emphasis identifying subjects with sepsis (i.e., increased

ascertainment); and 3) the opening of a new, large trauma and tertiary care hospital in October

2007, which markedly increased the catchment area and also increased ICU bed capacity. The

number of available ICU beds increased 41% from 2004 to 2010, after the opening of a new

quaternary care medical center and the addition of three hospitals with electronic records. Also,

although data coordinators confirmed that all 4329 subjects met criteria for severe sepsis or

septic shock, the use of an administrative database and data coordinator review to identify

subjects for screening may have introduced selection bias. Another possible source of

measurement bias was higher missingness for severity of sepsis in the first phase compared with

later phases (25% versus 2.2%, respectively). If the percentage of all subjects in 2004 with septic

shock were truly 76%, as found among those with non-missing severity of sepsis, the fall in

percentage of septic shock subjects could contribute to the fall in mortality observed.

Importantly, severity of sepsis was not included in the regression models due to high collinearity

with other variables (e.g., APS).

Second, we cannot exclude a change over time either in unmeasured confounders or in

subjects’ severity of illness. We used initial ED systolic blood pressure, initial serum lactate

level, and CCIS to confirm that there was not an important shift in ED admission severity of

illness over time. Instead, APS, which is measured using worst physiologic values across the first

24 hours of admission, increased from 2005-2007 to 2008-2010 simultaneous with declining

mortality. We suspect increasing compliance with early resuscitation elements near the time of

admission may have led to a decrease in a subject’s subsequent illness severity.



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Third, the lower absolute mortality in our study compared to others (14, 20) may reflect

that we had a less severely ill population. Four possible reasons for a less severely ill study

population include: 1) we excluded subjects transferred from outside, non-Intermountain

Healthcare hospitals, 2) our ICU cohort had fewer or less severe baseline comorbidities than

prior studies, 3) we excluded subjects who became septic while in the hospital or ICU, and 4)

only included 18 subjects who went to the OR prior to arrival in the ICU. Further study of only

septic shock subjects may be useful in clarifying whether our low mortality reflects local

admission factors or effects of the treatment bundle. Fourth, racial homogeneity may limit the

external validity of these findings (32). Fifth, the decline in mortality among non-compliant

subjects mirrors the decline among compliant subjects, suggesting that total bundle compliance,

alone, may not have been the primary driver of decreased mortality. Subjects who did not meet

criteria for total bundle compliance nevertheless had fewer non-compliant elements over time, an

effect that likely contributed to the overall decrease in mortality. In addition to a decrease in the

median number of non-compliant elements, variance also decreased, suggesting decreased

variation in practice over time.

In a large cohort of critically ill patients with septic shock admitted from the ED to an

ICU, compliance with bundle elements was associated with increased survival. Compliance with

therapy to increase oxygen delivery, glucocorticoids, and lung protective ventilation was

associated with lower mortality. Compliance with early resuscitation bundle elements (first 3

hours) was associated with a lower probability of being eligible for later resuscitation and

maintenance bundle elements. Bundling care processes for severe sepsis and septic shock

patients appears beneficial in this multicenter cohort.



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Acknowledgements

We gratefully acknowledge the efforts of Cempaka Martial, MStat, John Holmen, PhD, Justin

Dickerson, PhD, and the emergency department and critical care physicians, nurses, and

additional personnel from the eleven participating facilities within the Intermountain Healthcare

Intensive Medicine Clinical Program for their efforts, without which this project would not have

been possible.



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References

1. 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;29:1303-1310.

2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the united

states from 1979 through 2000. N Engl J Med 2003;348:1546-1554.

3. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A,

Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Jr., group RhpCWEiSSs. Efficacy

and safety of recombinant human activated protein c for severe sepsis. N Engl J Med

2001;344:699-709.

4. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, Network CU-R. Current

epidemiology of septic shock: The cub-rea network. Am J Respir Crit Care Med 2003;168:165-

172.

5. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization

and mortality rates for severe sepsis in the united states: A trend analysis from 1993 to 2003. Crit

Care Med 2007;35:1244-1250.

6. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E,

Tomlanovich M, Early Goal-Directed Therapy Collaborative G. Early goal-directed therapy in

the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.

7. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus

DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ,

Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS,

Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines C, American



16

Association of Critical-Care N, American College of Chest P, American College of Emergency

P, Canadian Critical Care S, European Society of Clinical M, Infectious D, European Society of

Intensive Care M, European Respiratory S, International Sepsis F, Japanese Association for

Acute M, Japanese Society of Intensive Care M, Society of Critical Care M, Society of Hospital

M, Surgical Infection S, World Federation of Societies of I, Critical Care M. Surviving sepsis

campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit

Care Med 2008;36:296-327.

8. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J,

Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving

Sepsis Campaign Management Guidelines C. Surviving sepsis campaign guidelines for

management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873.

9. Wennberg JE. Unwarranted variations in healthcare delivery: Implications for academic

medical centres. BMJ 2002;325:961-964.

10. Wennberg DE, Wennberg JE. Addressing variations: Is there hope for the future? Health

Aff (Millwood) 2003;Suppl Web Exclusives:W3-614-617.

11. Wennberg JE, Bunker JP, Barnes B. The need for assessing the outcome of common

medical practices. Annu Rev Public Health 1980;1:277-295.

12. Morris AH. Developing and implementing computerized protocols for standardization of

clinical decisions. Ann Intern Med 2000;132:373-383.

13. Morris AH. Iatrogenic illness: A call for decision support tools to reduce unnecessary

variation. Qual Saf Health Care 2004;13:80-81.

14. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr

C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M,



17

Regan S, Angus DC, Campaign SS. The surviving sepsis campaign: Results of an international

guideline-based performance improvement program targeting severe sepsis. Crit Care Med

2010;38:367-374.

15. Allen TL, Martial CS, Nelson NC, Clemmer TP. Compliance with a sepsis bundle

improves mortality in patients with severe sepsis and septic shock across an integrated regional

healthcare system: A multi-hospital study. Acad Emerg Med 2010;17:S130.

16. Miller RR, Dong L, Nelson NC, Probst DR, Kuttler KG, Allen TL, Clemmer TP.

Multicenter implementation of sepsis bundle and decreased mortality in severe sepsis and septic

shock patients Am J Respir Crit Care Med 2012;185:A1142.

17. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM,

Vincent JL, Ramsay G. 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference.

Crit Care Med 2003;31:1250-1256.

18. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL,

Christie JD. Serum lactate is associated with mortality in severe sepsis independent of organ

failure and shock. Crit Care Med 2009;37:1670-1677.

19. Allison PD. Multiple regression: A primer. Thousand Oaks, CA: Pine Forge Press; 1999.

20. Shiramizo SC, Marra AR, Durao MS, Paes AT, Edmond MB, Pavao dos Santos OF.

Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle

in a hospital setting. PLoS One 2011;6:e26790.

21. Levy MM, Pronovost PJ, Dellinger RP, Townsend S, Resar RK, Clemmer TP, Ramsay

G. Sepsis change bundles: Converting guidelines into meaningful change in behavior and clinical

outcome. Crit Care Med 2004;32:S595-597.



18

22. Siegel JH, Fabian M. Therapeutic advantages of an inotropic vasodilator in endotoxin

shock. JAMA 1967;200:696-704.

23. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of

systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-

1722.

24. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R. A trial of

goal-oriented hemodynamic therapy in critically ill patients. Svo2 collaborative group. N Engl J

Med 1995;333:1025-1032.

25. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute

lung injury and the acute respiratory distress syndrome. The acute respiratory distress syndrome

network. N Engl J Med 2000;342:1301-1308.

26. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G,

Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low

doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA

2002;288:862-871.

27. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG,

Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J,

Group CS. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-

124.

28. Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock. Am J Respir Crit

Care Med 2012;185:133-139.



19

29. Resar R, Pronovost P, Haraden C, Simmonds T, Rainey T, Nolan T. Using a bundle

approach to improve ventilator care processes and reduce ventilator-associated pneumonia. Jt

Comm J Qual Patient Saf 2005;31:243-248.

30. Nolan T, Berwick DM. All-or-none measurement raises the bar on performance. JAMA

2006;295:1168-1170.

31. Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, Jimenez E, Mohan A,

Khan RA, Whittle J, Jacobs E, Nanchal R, Milwaukee Initiative in Critical Care Outcomes

Research Group of I. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest

2011;140:1223-1231.

32. Moss M. Epidemiology of sepsis: Race, sex, and chronic alcohol abuse. Clin Infect Dis

2005;41 Suppl 7:S490-497.


1

Figure 1. Flow Diagram of Subjects by Study Period


2

Screened (n=15,019)

2004 (n=1314)

2005-2007 (n=4115)

2008-2010 (n=9590)

Not Severe Sepsis/ Septic

Shock (n=10,640)

2004 (n=986)

2005-2007 (n=2742)

2008-2010 (n=6912)

Excluded* (n=50)

Incomplete screening (n=15)

Age less than 18 or missing (n=36) * not mutually exclusive

Study Cohort (n=4329)

2004 (n=325)

2005-2007 (n=1348)

2008-2010 (n=2656)

Severe Sepsis / Septic

Shock (n=4379)

2004 (n=328)

2005-2007 (n=1373)

2008-2010 (n=2678)


3

Table 1. Comparison of Study Subjects by Survival, 2004-2010

Characteristic

Died

(n=526)

Survived

(n=3803)

Overall

(n=4329)

P value

Mean (±SD) age, y 68.9 (15.2) 61.9 (17.3) 62.7 (17.2) <0.0001

Mean (±SD) Acute Physiology Score 23.5 (10.2) 15.3 (7.6) 16.3 (8.4) <0.0001

Mean (±SD) Charlson Comorbidity Index Score 5.8 (3.6) 4.9 (3.6) 5.0 (3.6) <0.0001

Female, n (%) 264 (50.2) 1901 (50.0) 2165 (50.0) 0.93

Race/Ethnicity, n (%)

White, non-Hispanic

Black, non-Hispanic

Hispanic

Other

474

4

26

22

(90.1)

(0.8)

(4.9)

(4.2)

3364

42

209

188

(88.5)

(1.1)

(5.5)

(4.9)

3838

46

235

207

(88.7)

(1.1)

(5.4)

(4.8)

0.29

Severity of sepsis,*n (%)

Septic shock in first 24h

Severe sepsis in first 24h

242

235

(50.7)

(49.3)

1184

2420

(32.9)

(67.1)

1426

2655

(34.9)

(65.1)

<0.0001

Abbreviations: SD = standard deviation

*There were 49 subjects who died and 199 who survived for which severity of sepsis could not

be determined because of missing data. Percentages listed are for non-missing data only. Among

all septic shock subjects (n=1426), 1184 (83.0%) survived. Among all severe sepsis subjects

(n=2655), 2420 (91.1%) survived.


4

Figure 2. P-Chart of Total Bundle Compliance and Mortality, 2004-2010

(a) Among all subjects mortality (-●-) decreased while all-or-none total bundle compliance (-■-) increased over time. 95% statistical

process controllimits are represented by dashed lines.

(b) Among only septic subjects mortality (-●-) decreased while all-or-none total bundle compliance (-■-) increased over time. 95%

statistical process control limits are represented by dashed lines.


5

0

10

20

30

40

50

60

70

80

0

5

10

15

20

25

30

2004

n=325

2005

n=394

2006

n=331

2007

n=623

2008

n=757

2009

n=934

2010

n=965

Total Bundle Compliance (%)

Mortality (%)

Control

Limits

21.2%

8.7%

4.9%

73.4%


6

0

10

20

30

40

50

60

70

80

0

5

10

15

20

25

30

2004

n=325

2005

n=394

2006

n=331

2007

n=623

2008

n=757

2009

n=934

2010

n=965

Total Bundle Compliance (%)

Mortality (%)

Control

Limits


7

Table 2. Logistic Regression Models of Hospital Mortality

Variable Value

Trivariate Model Final Multivariate Model

OR (95% CI) P value OR (95% CI) P value

Age* Per year 1.03 (1.02, 1.03) <0.0001 1.03 (1.03, 1.04) <0.0001

Acute Physiology Score† Per point 1.11 (1.10, 1.12) <0.0001 1.12 (1.11, 1.14) <0.0001

Charlson Comorbidity Index Score† Per point 1.06 (1.04, 1.09) <0.0001 1.05 (1.02, 1.08) <0.001

Inotropes and/or packed red blood cells*

Compliant‡ referent

Non-compliant‡ 2.31 (1.72, 3.11) <0.0001 1.62 (1.12, 2.33) <0.01

Glucocorticoids*


Non-compliant‡ 2.06 (1.62, 2.62) <0.0001 1.76 (1.32, 2.37) <0.001

Use of low tidal volume ventilation, if

mechanically ventilated*


Non-compliant‡ 2.77 (1.98, 3.87) <0.0001 1.84 (1.24, 2.73) <0.01

Sex

Male referent

Female 1.00 (0.84, 1.21) 0.97

Severity of sepsis*

Severe Sepsis referent

Septic Shock 2.08 (1.71, 2.53) <0.0001


8

Serum lactate measured*


Non-compliant‡ 1.22 (0.92, 1.61) 0.17

Blood cultures before antibiotics*


Non-compliant‡ 1.55 (1.14, 2.11) <0.01

Broad-spectrum antibiotics*


Non-compliant‡ 1.26 (0.97, 1.65) 0.09

Fluid resuscitation*


Non-compliant‡ 1.27 (0.86, 1.89) 0.23

Vasopressors


Non-compliant‡ 0.94 (0.63, 1.41) 0.77

Central venous pressure and ScvO2*


Non-compliant‡ 1.71 (1.32, 2.19) <0.0001

Glucose control*


Non-compliant‡ 1.38 (1.08, 1.76) <0.01

Glucocorticoids*


Non-compliant‡ 2.06 (1.62, 2.62) <0.0001 1.76 (1.32, 2.37) <0.001


9

Drotrecogin alfa eligibility assessed*


Non-compliant‡ 2.56 (1.87, 3.49) <0.0001

Use of low tidal volume ventilation, if

mechanically ventilated*


Non-compliant‡ 2.77 (1.98, 3.87) <0.0001 1.84 (1.24, 2.73) <0.01

Total resuscitation bundle

Compliant§ referent

Non-compliant§ 1.46 (1.21, 1.76) <0.0001

Total maintenance bundle


Non-compliant§ 1.80 (1.42, 2.18) <0.0001

Total bundle


Non-compliant§ 1.48 (1.22, 1.79) <0.0001

Abbreviations: ED = emergency department; OR = odds ratio; 95% CI = 95% confidence interval; ScvO2 = central venous oxygen

saturation

* Potential predictors for the final model (p<0.25 on trivariate analysis)

†Covariates for trivariate and multivariate models

‡Compliant = eligible and compliant or ineligible for that single bundle element. Non-compliant = eligible and non-compliant for that

single bundle element.


10

§ Compliant = eligible and compliant or ineligible for all elements in that bundle. Non-compliant = eligible and non-compliant for any

one element in that bundle.


Miller et al., Sepsis Bundle and Mortality Suppl.

1

Supplement: Multicenter Implementation of a Severe Sepsis and Septic Shock Treatment

Bundle

Methods

Data coordinators reviewed all potential subjects. Potential subjects were identified: 1)

prospectively as those meeting criteria for severe sepsis or septic shock at the time of ICU

admission or 2) retrospectively via query of International Classification of Disease-9 (ICD-9) full

text descriptions from an administrative database at hospital discharge. The use of ICD-9 codes

from administrative database is accurate in detecting pneumonia (1) and sepsis (2). The keyword

query was built upon the work of Angus et al. (3) and included a Boolean search for any of the

following terms: %abscess%, %abdominal post-op infection%, %septic%, %sepsis%,

%gangrene%, %infection%, shigellosis, %fever%, and %meningitis%.

All ICUs were subject to the same rules, but not all ICUs were enrolling patients as of

January 1, 2004. Hospital #1 and hospital #11 were not open until October 2007 and August

2010, respectively. Included in the ICU bed totals are two intermediate care units from which

subjects could be included (28 beds at hospital #3 and 16 beds at hospital #4); mechanically

ventilated patients and those with septic shock can be admitted to those units as overflow from

the ICU. All but 16 ICU beds from hospital #2 were “moved” to hospital #1 when the latter

opened in October 2007. Hospital #1’s ICU beds therefore increased from 0 at study start to 84

in late 2007. Additionally, hospitals #5, #9, and #10 did not have electronic records available in

2004 and so the first subject was enrolled at each of those hospitals after 2004, leading to an

actual increase in ICU beds from which subjects might be enrolled from 186 in 2004 to 262 in

2010 (Table E2).



2

References

1. Aronsky D, Haug PJ, Lagor C, Dean NC. Accuracy of administrative data for identifying

patients with pneumonia. American journal of medical quality : the official journal of the

American College of Medical Quality 2005;20:319-328.

2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the united

states from 1979 through 2000. N Engl J Med 2003;348:1546-1554.

3. 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;29:1303-1310.



3

Table E1. Severe Sepsis and Septic Shock Management Bundle Elements by Bundle Type

Resuscitation Bundle

1) Serum lactate measured within 3 hours of emergency department admission

2) Blood cultures obtained prior to antibiotic administration within 3 hours of emergency department admission

3) Broad-spectrum antibiotics administered within 3 hours of emergency department admission

4) If hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) or lactate ≥4mmol/L, resuscitated with

minimum of 20-40 mL/kg (predicted body weight) crystalloid

5) If hypotension persists after adequate fluid resuscitation, vasopressors given

6) If septic shock or lactate ≥4 mmol/L, central venous pressure (CVP) and central venous oxygen saturation (ScvO2) obtained at

regular intervals via central catheter with tip in superior vena cava; CVP goal ≥8 cm H2O and ScvO2 goal ≥70%

7) If CVP ≥8 cm H2O and ScvO2 <70%, inotropes and/or packed red cells (if hematocrit <30%) given

Maintenance Bundle

8) Mean glucose ≤180 mg/dL between 12-24h following emergency department admission

9) If after adequate fluid resuscitation (CVP ≥8 cm H2O) the patient was still on more than one vasopressor or a higher than normal

dose of a single vasopressor, glucocorticoids given

10) Drotrecogin alfa eligibility assessed per hospital guideline



4

11) If mechanically ventilated, lung protective strategy with tidal volume 6 mL/kg predicted body weight



5

Table E2. Study Hospital Intensive Care Unit Beds and Enrollment Start Date

Hospital ICU Beds, 2004 First Subject Enrolled Enrollable ICU Beds, 2004 ICU Beds, 2010

1 0 October 2007 0 84

2 64 January 2004 64 16

3 46 January 2004 46 46

4 49 January 2004 49 49

5 24 January 2005 0 24

6 8 January 2004 8 8

7 15 January 2004 15 15

8 4 January 2004 4 4

9 6 December 2007 0 6

10 6 January 2005 0 6

11 0 October 2010 0 4

Total 222 186 262



6

Results

Number of subjects enrolled by study hospital and the percentage of those subjects with septic shock are indicated in Table E4.

Number of subjects enrolled by study hospital and percent total bundle compliance are indicated in Table E5. Ineligibility for later

bundle elements is indicated in Table E6.



7

Table E3. Comparison of Study Subject Characteristics and Outcomes by Study Period

Variable

2004

(n=325)

2005-2007

(n=1348)

2008-2010

(n=2656)

Overall

(n=4329)

P value*

Mean (±SD) age, y 62.7 (17.6) 62.7 (17.4) 62.8 (17.1) 62.7 (17.2) 0.99

Mean (±SD) Acute Physiology Score 16.0 (8.1) 15.4 (8.4) 16.7 (8.4) 16.3 (8.4) <0.0001†

Mean (±SD) Charlson Comorbidity Index Score 4.9 (3.2) 4.9 (3.5) 5.1 (3.6) 5.0 (3.6) 0.42

Female, n (%) 163 (50.2) 696 (51.6) 1306 (49.2) 2165 (50.0) 0.27

Race/Ethnicity, n (%)

White, non-Hispanic

Black

White, Hispanic

Other

282

3

21

18

(87.0)

(0.9)

(6.5)

(5.5)

1204

11

66

67

(89.3)

(0.8)

(4.9)

(5.0)

2352

32

148

122

(88.6)

(1.2)

(5.6)

(4.6)

3838

46

235

207

(88.7)

(1.1)

(5.4)

(4.8)

0.35

Severity of sepsis,‡ n (%)

Septic shock in first 24h

Severe sepsis in first 24h

183

58

(75.9)

(24.1)

426

892

(32.3)

(67.7)

849

1747

(32.7)

(67.3)

1426

2655

(34.9)

(65.1)

<0.0001

Median (IQR) hospital length of stay, d 7.4 (4.1, 14.9) 5.9 (3.6, 10.5) 5.6 (3.5, 9.5) 5.8 (3.6, 10.0) <0.0001



8

Median (IQR) ICU length of stay, d 2.8 (1.2, 5.6) 2.3 (1.2, 4.6) 2.5 (1.5, 4.7) 2.5 (1.4, 4.7) 0.17

Died, n (%) 69 (21.2) 191 (14.2) 266 (10.0) 526 (12.2) <0.0001

Abbreviations: SD = standard deviation; IQR = interquartile range; ICU = intensive care unit

* According to analysis of variance, Mantel-Haenszel, or Kruskal-Wallis test, as appropriate

† For 2005-2007 versus 2008-2010, p<0.0001. Otherwise, all otherwise pairwise comparisons were not significant.

‡ There were 84 subjects in 2004, 30 subjects in 2005-2007, and 60 subjects in 2008-2010 for which severity of

sepsis was missing. Percentages listed are for non-missing data only.



9

Table E4. Number of Enrolled Subjects and Percent Septic Shock* by Hospital and Study

Period

2004 (n=325) 2005-2007 (n=1348) 2008-2010 (n=2656) Total (n=4329)

Hospital n Shock n Shock n Shock n Shock

1 0 - 36 27.8% 776 32.9% 812 32.7%

2 158 91.8% 364 35.3% 253 29.8% 775 45.1%

3 58 65.2% 181 56.8% 414 20.9% 653 33.0%

4 50 30.0% 213 18.5% 326 32.2% 589 27.1%

5 0 - 275 29.8% 291 52.4% 566 41.4%

6 12 0.0% 121 15.0% 210 29.8% 343 24.1%

7 31 55.0% 76 56.9% 165 52.5% 272 53.9%

8 16 42.9% 77 9.6% 96 23.2% 189 18.3%

9 0 - 1 100.0% 75 11.1% 76 12.5%

10 0 - 4 66.7% 33 10.0% 37 17.4%

11 0 - 0 - 17 29.4% 17 29.4%

Total Enrolled 325 75.9% 1348 32.3% 2656 32.7% 4329 35.1%

* Excludes subjects with missing severity of sepsis



10

Table E5. Number of Enrolled Subjects and Percent Total Bundle Compliance by

Hospital and Study Period

2004 (n=325) 2005-2007 (n=1348) 2008-2010 (n=2656)

Hospital n Compliance n Compliance n Compliance

1 0 - 36 30.6% 776 52.7%

2 158 7.6% 364 33.2% 253 59.3%

3 58 0.0% 181 66.3% 414 92.3%

4 50 8.0% 213 32.4% 326 61.0%

5 0 - 275 13.8% 291 74.5%

6 12 0.0% 121 26.5% 210 64.3%

7 31 0.0% 76 2.6% 165 67.3%

8 16 0.0% 77 29.9% 96 60.4%

9 0 - 1 0.0% 75 77.3%

10 0 - 4 0.0% 33 72.7%

11 0 - 0 - 17 0.0%

Total Enrolled 325 4.9% 1348 30.9% 2656 65.6%



11

Table E6. Ineligibility for Later Bundle Elements by Study Period

Element

2004

(n=325)

2005-2007

(n=1348)

2008-2010

(n=2656)

All

(n=4329)

Fluid Resuscitation 80 (25%) 476 (35%) 774 (29%) 1330 (31%)

Vasopressors 120 (37%) 772 (57%) 1715 (65%) 2607 (60%)

CVP and ScvO2 116 (36%) 911 (68%) 1894 (71%) 2921 (67%)

Inotropes and/or red cell transfusions 132 (41%) 1056 (78%) 2311 (87%) 3499 (81%)

Glucocorticoids 120 (37%) 819 (61%) 2090 (79%) 3029 (70%)

Lung protective ventilation 186 (57%) 1055 (78%) 2278 (86%) 3519 (81%)

Abbreviations: CVP = central venous pressure; ScvO2 = central venous oxygen saturation


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