Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality* H. Bryant Nguyen, MD, MS; Stephen W. Corbett, MD, PhD; Robert Steele, MD; Jim Banta, PhD, MPH; Robin T. Clark, BS; Sean R. Hayes; Jeremy Edwards; Thomas W. Cho, MD; William A. Wittlake, MD
Objective: The purpose of this study was to examine the outcome implications of implementing a severe sepsis bundle in an emergency department as a quality indicator set with feedback to modify physician behavior related to the early management of severe sepsis and septic shock. Design: Two-year prospective observational cohort. Setting: Academic tertiary care facility. Patients: Patients were 330 patients presenting to the emergency department who met criteria for severe sepsis or septic shock. Interventions: Five quality indicators comprised the bundle for severe sepsis management in the emergency department: a) initiate central venous pressure (CVP)/central venous oxygen saturation (ScvO2) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete early goal-directed therapy at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. Measurements and Main Results: Patients had a mean age of 63.8 ⴞ 18.5 yrs, Acute Physiology and Chronic Health Evaluation II score 29.6 ⴞ 10.6, emergency department length of stay 8.5 ⴞ 4.4 hrs, hospital length of stay 11.3 ⴞ 12.9 days, and in-hospital
P
mortality 35.2%. Bundle compliance increased from zero to 51.2% at the end of the study period. During the emergency department stay, patients with the bundle completed received more CVP/ ScvO2 monitoring (100.0 vs. 64.8%, p < .01), more antibiotics (100.0 vs. 89.7%, p ⴝ .04), and more corticosteroid (29.9 vs. 16.2%, p ⴝ .01) compared with patients with the bundle not completed. In a multivariate regression analysis including the five quality indicators, completion of early goal-directed therapy was significantly associated with decreased mortality (odds ratio, 0.36; 95% confidence interval, 0.17– 0.79; p ⴝ .01). In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p < .01). Conclusions: Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality. (Crit Care Med 2007; 35:1105–1112) KEY WORDS: sepsis bundle; sepsis quality indicators; early goaldirected therapy; emergency department
atients suffering from severe sepsis or septic shock have a mortality rate of 20 –54% (1–3). Among the 751,000 annual cases of severe sepsis in the United States, approximately 458,200 cases (or 61%) are first encountered in the emergency department (ED) (1, 4). Early appropriate antibiotics (5–7), early goal-directed therapy
(EGDT) (8), corticosteroids (9), recombinant human activated protein C (rhAPC) (10), and lung-protective strategies (11) have all been shown to be associated with survival benefits. These and other therapeutic advances led to the development of the Surviving Sepsis Campaign (SSC) management guidelines (12). For the early management of severe sepsis in particular,
*See also p. 1210. From the Department of Emergency Medicine (HBN, SWC, RS, RTC, SRH, JE, TWC, WAW) and Department of Epidemiology and Biostatistics (JB), Loma Linda University, Loma Linda, CA. Presented, in part, at the Society of Critical Care Medicine 34th Critical Care Congress, Phoenix, AZ, January 2005, and the American College of Emergency Physicians Scientific Assembly, Washington, DC, September 2005. The authors received no external funding to perform this study. Dr. Nguyen has received lecture hon-
oraria from Edwards Lifesciences and Eli Lilly and research funding from Edwards Lifesciences. The remaining authors have not disclosed any potential conflicts of interest. For information regarding this article, E-mail:
[email protected] Copyright © 2007 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
Crit Care Med 2007 Vol. 35, No. 4
DOI: 10.1097/01.CCM.0000259463.33848.3D
the SSC and the Institute for Healthcare Improvement recommend implementation of a 6-hr resuscitation bundle (13), especially in the ED, that incorporates early recognition, early antibiotics, and EGDT. Although guidelines provide a roadmap for patient care, their success relies on consistent patterns of clinician practice in order to realize the most optimal outcome. The purpose of this study was to examine the incremental impact of implementing a sepsis management initiative in the ED while integrating quality indicators via a “bundling” approach. Monitoring compliance to the quality indicators serves as a mechanism for clinician feedback and culture change that are needed to achieve uniformity in the process of care. We hoped to show that implementation of a severe sepsis bundle using quality indicators specific to the ED 1105
setting can be accomplished and that compliance to the quality indicators can result in improved patient outcomes.
METHODS AND MATERIALS Design and Setting This was a prospective observational cohort study of patients presenting to the ED meeting criteria for severe sepsis or septic shock and entered in a sepsis registry from October 1, 2003, to September 30, 2005, at an academic tertiary care medical center. The study and sepsis registry were approved by the Institutional Review Board. The ED consists of 47 beds, with approximately 65,000 annual patient visits and 2,490 intensive care unit (ICU) admissions. An additional 30,000 annual visits are seen in an on-campus urgent care department. Staffing in the adult section of the ED at any time includes two attending physicians, two to four resident physicians, and eight to ten nurses. Nurse-to-patient ratio ranges from 2:1 to 1:4, depending on the acuity of patient care. In designing this study, we a priori implemented an ED quality improvement program to deliver a severe sepsis bundle with the existing ED resources.
Creation of Sepsis Bundle and Quality Indicators The bundle and quality indicators were derived from best practice advances in the early management of severe sepsis and septic shock (8, 9, 14, 15). Additionally, the quality indicators were required to adhere to the following criteria: a) The indicators or interventions are generally accepted clinical practice and supported by evidence; b) the indicators need to be completed in the ED setting; c) the completion of each indicator can be determined by a yes or no on chart review; and d) the completion of the entire bundle can be determined by a yes or no. We identified five quality indicators to comprise the bundle (Table 1). The ED Quality Improvement Committee was asked to approve the bundle before its implementation. A survey questionnaire regarding the validity (evidence-based) and feasibility (practicality) of each quality indicator was given to 23 ED physicians. A score of 1–3 (not acceptable), 4 – 6 (uncertain), or 7–9 (acceptable) was assigned by each physician to rate the validity and feasibility of the quality indicators: a) initiate central venous pressure (CVP)/central venous oxygen saturation (ScvO2) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete EGDT at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. The mean validity score for
1106
Table 1. Severe sepsis bundle and inherent quality indicators 6-hr emergency department severe sepsis bundle 1. Initiate CVP/ScvO2 monitoring within 2 hrs of meeting bundle criteria 2. Give broad-spectrum antibiotics within 4 hrs of meeting bundle criteria 3. Complete early goal-directed therapy (CVP ⱖ8 mm Hg, SBP ⱖ90 mm Hg or MAP ⱖ65 mm Hg, and ScvO2 ⱖ70%) at 6 hrs of meeting bundle criteria 4. Give steroid if patient is on vasopressor or if adrenal insufficiency is suspected 5. Monitor for lactate clearance Completion of the bundle is defined as completion of quality indicators 1, 2, and 3 and one or more of items 4 and 5 The criteria to initiate the bundle are the following 1. Two or more of the following four items a. Temperature ⬎38.3°C or ⬍36.0°C b. Heart rate ⬎90 beats/min c. Respiration ⬎20 breaths/min d. White blood cell count ⬎12,000 or ⬍4000/mm3, or ⬎10% bandemia 2. A suspected infection 3. SBP ⬍90 mm Hg after 20-mL/kg fluid bolus or lactate 肁4 mmol/L CVP, central venous pressure; ScvO2, central venous oxygen saturation; SBP, systolic blood pressure; MAP, mean arterial pressure. Percentage compliance during an implementation phase (i.e., a 3-month period) was defined as the number of patients completing the particular bundle quality indicator (or the numerator) divided by the number of patients meeting the criteria for initiation of the bundle (or the denominator).
each quality indicator was 7.5, 8.6, 8.0, 7.3, 7.4, and the mean feasibility score was 6.7, 8.5, 6.4, 7.3, 5.9, respectively.
Bundle Implementation and Quality Improvement Process The 2-yr implementation program was divided into 3-month quartiles that included baseline, education, and operational, followed by five quality improvement (QI) phases. The baseline phase included data gathering on the current level of care applying a standardized checklist. This checklist was used to gather bundle compliance data (see Data Collection section). Equipment for CVP and ScvO2 monitoring was also acquired during the baseline phase. The education phase consisted of physician, nurse, and residency staff training on sepsis definitions and recognition, hemodynamic monitoring using CVP and ScvO2, EGDT, bundle initiation criteria, and bundle quality indicators. A physician champion and nurse educator provided conference lectures, bedside teaching, and in-services to physicians and nurses during this phase. The operational phase consisted of bundle delivery in the ED setting. Physicians and nurses used a sepsis toolkit (16) and pocket cards as daily reminders of the processes involved in bundle delivery. This phase was considered a trial period without accountability by the physicians and nurses. The QI phase consisted of five quartiles (QI 1 to QI 5). Physician and nursing feedback at the end of each QI quartile was used to increase bundle compliance. An interval summary report was distributed to physicians and nurse managers that included the number of severe sepsis patients who met indications for the bundle, treatments given in
the ED, percentage compliance with bundle quality indicators, and outcome. Individual cases were discussed in a peer-review forum, and a reminder letter from the ED medical director was sent to physicians who did not complete the bundle in patients for whom there were indications.
Patient Management Once a patient met bundle initiation criteria, hemodynamic monitoring was initiated with placement of a central venous catheter for CVP and with the internal jugular or subclavian vein approach for ScvO2 monitoring. After radiographic verification of catheter placement, the ED nurse then performed calibration for CVP and ScvO2 monitoring. Broadspectrum antibiotics were administered. Hemodynamic optimization following the EGDT protocol (8) targeting CVP ⱖ8 mm Hg, systolic blood pressure ⱖ90 mm Hg or mean arterial pressure ⱖ65 mm Hg, and ScvO2 ⱖ70% was achieved using fluid resuscitation, red blood cell transfusion, vasopressors, and inotropes at the treating physician’s discretion. Mechanical ventilation was initiated if necessary. Corticosteroid was administered if the patient became vasopressor-dependent or if adrenal insufficiency was suspected. A repeat lactate level was obtained to assess for lactate clearance (15). The bundle was delivered by ED physicians, residents, and nurses as standard care. No additional staffing resources were acquired. All patients were admitted to the ICU. Intensive care consultation was obtained for ICU admission; however, the intensivists were not involved in the delivery of the bundle in the ED before admission. Since the goal of the quality improvement program was completion
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Table 2. Two-level screening process Level 1 screening: Medical charts of patients with the following ICD-9 diagnoses are obtained from the Department of Medical Records 038.0–038.9 Septicemia 790.7 Bacteremia 117.9 Disseminated fungal infection 995.91 Systemic inflammatory response syndrome due to infectious process without organ dysfunction 995.92 Systemic inflammatory response syndrome due to infectious process with organ dysfunction 785.52 Septic shock Level 2 screening: Patient charts obtained from level 1 screening are reviewed for all three of the following criteria occurring during the ED stay 1. Two or more of the following four items a. Temperature ⬎38.3°C or ⬍36.0°C b. Heart rate ⬎90 beats/min c. Respiration ⬎20 breaths/min d. White blood cell count ⬎12,000 or ⬍4000/mm3, or ⬎10% bandemia 2. A suspected infection noted in the physician dictation 3. SBP ⬍90 mm Hg after 20-mL/kg fluid bolus or lactate ⱖ4 mmol/L
p ⬍ .05. Data are presented as mean ⫾ SD. Proportions are presented as percentage and raw data. Patients with missing values were excluded from calculations of means and percentages.
RESULTS There were 1,217 patients meeting level 1 screening criteria during the study period, with 330 patients meeting level 2 screening criteria and entered into the sepsis registry. The mean age was 63.8 ⫾ 18.5, with Acute Physiology and Chronic Health Evaluation II score 29.6 ⫾ 10.6, ED length of stay 8.5 ⫾ 4.4 hrs, hospital length of stay 11.3 ⫾ 12.9 days, and inhospital mortality 35.2%.
ICD, International Classification of Diseases, Ninth Revision; ED, emergency department; SBP, systolic blood pressure.
Comparison of Bundle Implementation Phases and Compliance
of bundle quality indicators in the ED, we did not develop a transfer of care protocol to the intensive care setting. However, the intensivists continued the management of severe sepsis and septic shock in the ICU as recommended by established guidelines (12, 17).
Patient characteristics were similar throughout the bundle implementation phases (Table 3). Bundle compliance showed a progressive improvement from the baseline phase, at zero percentage compliance, to the end of QI 5 phase, at 51.2% compliance (Fig. 1).
Data Collection and Sepsis Registry Patient Selection. A monthly review of patient medical charts was performed to enroll patients. A two-level screening process was used to select patients meeting criteria for initiation of the bundle (Table 2). Level 1 screening included a monthly list of patients from medical records meeting the following criteria: a) admission to the hospital from the ED; and b) sepsisrelated International Classification of Diseases, Ninth Revision diagnosis. Level 2 screening consisted of review of medical charts obtained from level 1 screening. Patients meeting criteria for initiation of the bundle were included in the bundle compliance measurement process and entered into a sepsis registry. Patients with age ⬍18, trauma, seizure, pulmonary edema due to acute heart failure, stroke, active hemorrhage, or do-not-resuscitate orders were excluded during level 2 screening from the compliance measurement process and the sepsis registry. Bundle Compliance Measurement. Trained data abstractors completed a bundle compliance checklist for each patient selected after level 2 screening. The physician champion for the bundle implementation then verified the compliance checklist for correctness. Data obtained included patient demographics, date and time of arrival in the ED, time meeting criteria for initiation of the bundle, sepsis category, completion (yes or no) and time of completion of the bundle quality indicators, completion of the whole bundle, ED length of stay, hospital length of stay, and in-hospital
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mortality. Other data such as vital signs, laboratories, physiologic scores, therapies in the ED, and therapies up to 72 hrs in the ICU were also obtained. The physiologic scores were computed from available data and included Acute Physiology and Chronic Health Evaluation II (18), Mortality in Emergency Department Sepsis (19), Simplified Acute Physiology Score II (20), and Mortality Prediction Model II0 at admission (21). Timing of Bundle (Time Zero). The time from ED arrival that a patient met criteria for initiation of the bundle and the time a physician was accountable for applying the quality indicators of the bundle was defined as time zero. As each chart was reviewed during level 2 screening, time zero was the time systolic blood pressure remained ⬍90 mm Hg after a 20-mL/kg fluid bolus, or the time a lactate result was available and ⱖ4 mmol/L in a patient with systemic inflammatory response syndrome (22) and a chart notation by the physician suspecting a source of infection (Table 2).
Statistical Analysis The Statistical Analysis System software (SAS Institute, Cary, NC) was used to perform data analysis. Patients enrolled in the sepsis registry after meeting level 2 screening were analyzed. The sepsis registry was maintained in an Access database (Microsoft, Redmond, WA). Chisquare, Fisher’s exact test, and unpaired Student’s t-test were used when appropriate in testing for differences between groups. The outcome measurements included bundle percentage compliance, hospital length of stay, and inhospital mortality. Univariate and multivariate logistic regression models were performed, with mortality as the dependent variable and individual bundle quality indicators as independent variables. Statistical significance was defined as
Comparison of Bundle Completed With Bundle Not Completed There was no difference in patient characteristics between those with the bundle completed compared with patients with the bundle not completed (or only received some of the bundle quality indicators), except that patients with the bundle completed had lower lactate (3.3 ⫾ 2.4 vs. 4.3 ⫾ 3.6 mmol/L, p ⫽ .03) and higher ScvO2 (70.1 ⫾ 11.6 vs. 63.3 ⫾ 18.4%, p ⱕ .01) than those with the bundle not completed (Table 4). Patients with the bundle completed had higher percentage compliance of all quality indicators compared with patients with the bundle not completed (all p ⬍ .01). During the ED stay, patients with the bundle completed received more CVP/ ScvO2 monitoring (100.0 vs. 64.8%, p ⬍ .01), more antibiotics (100.0 vs. 89.7%, p ⫽ .04), and more corticosteroid (29.9 vs. 16.2%, p ⫽ .01). There was no difference in ED length of stay and hospital length of stay between patients with the bundle completed compared with patients with the bundle not completed. In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p ⬍ .01). 1107
Table 3. Patient characteristics from October 2003 (baseline) to September 2005 (quality improvement [QI] phase 5)
No. of patients (level 1 screening) No. of patients (level 2 screening) Age, yrs CVP, mm Hg SBP, mm Hg DBP, mm Hg ScvO2, % Lactate, mmol/L Hgb, g/dL APACHE II, score MEDS, score SAPS II, score MPM II0, % mortality Septic shock, % (n) Blood cx pos, % (n) Culture pos, % (n) Time zero, hrs
Baseline Oct–Dec 03
Education Jan–Mar 04
Operational Apr–Jun 04
QI 1 Jul–Sep 04
QI 2 Oct–Dec 04
QI 3 Jan–Mar 05
QI 4 Apr–Jun 05
QI 5 Jul–Sept 05
164
144
133
148
134
142
186
166
37
50
46
46
35
41
34
41
70.1 ⫾ 15.1 9.3 ⫾ 3.3 74.2 ⫾ 22.1 38.0 ⫾ 11.2 64.2 ⫾ 22.0 4.9 ⫾ 3.9 11.9 ⫾ 2.0 30.9 ⫾ 9.4 13.5 ⫾ 4.7 59.7 ⫾ 21.9 53.2 ⫾ 25.1 89.2 (33) 40.5 (15) 62.2 (23) 3.0 ⫾ 3.4
64.6 ⫾ 19.0 9.4 ⫾ 3.7 78.3 ⫾ 14.8 38.9 ⫾ 9.6 65.5 ⫾ 10.2 3.6 ⫾ 3.2 11.7 ⫾ 2.7 27.0 ⫾ 9.2 13.3 ⫾ 4.7 49.1 ⫾ 20.0 41.6 ⫾ 26.8 74.0 (37) 50.0 (25) 56.0 (28) 1.6 ⫾ 1.9
64.1 ⫾ 20.5 10.8 ⫾ 2.9 81.0 ⫾ 17.2 40.1 ⫾ 9.4 71.8 ⫾ 7.3 3.9 ⫾ 3.9 12.5 ⫾ 2.3 28.6 ⫾ 8.9 11.5 ⫾ 4.9 56.0 ⫾ 24.8 45.6 ⫾ 28.4 80.4 (37) 50.0 (23) 60.9 (28) 2.6 ⫾ 2.6
60.5 ⫾ 18.6 11.2 ⫾ 4.1 81.0 ⫾ 21.7 40.0 ⫾ 8.5 69.2 ⫾ 17.8 3.4 ⫾ 2.8 11.4 ⫾ 2.2 26.8 ⫾ 9.4 11.8 ⫾ 4.4 49.3 ⫾ 18.6 43.2 ⫾ 26.5 76.1 (35) 39.1 (18) 65.2 (30) 2.5 ⫾ 2.2
64.5 ⫾ 16.8 11.0 ⫾ 3.5 78.9 ⫾ 13.3 42.1 ⫾ 8.9 65.0 ⫾ 11.0 3.9 ⫾ 2.6 11.9 ⫾ 2.7 32.6 ⫾ 12.0 12.3 ⫾ 3.7 51.4 ⫾ 20.0 59.1 ⫾ 31.7 80.0 (28) 40.0 (14) 34.3 (12) 2.4 ⫾ 1.6
62.8 ⫾ 17.3 10.7 ⫾ 3.3 79.4 ⫾ 14.9 36.7 ⫾ 10.4 65.6 ⫾ 18.9 4.0 ⫾ 3.7 12.1 ⫾ 2.3 27.4 ⫾ 12.5 11.4 ⫾ 3.3 44.6 ⫾ 18.1 50.5 ⫾ 29.0 75.6 (31) 36.6 (15) 31.7 (13) 3.0 ⫾ 2.5
61.0 ⫾ 21.0 11.4 ⫾ 3.1 75.0 ⫾ 19.7 36.7 ⫾ 11.4 61.9 ⫾ 14.3 4.9 ⫾ 4.0 11.8 ⫾ 2.0 31.4 ⫾ 11.8 13.5 ⫾ 3.6 48.7 ⫾ 19.4 55.6 ⫾ 27.2 64.7 (22) 29.4 (10) 61.8 (21) 3.2 ⫾ 3.1
63.1 ⫾ 18.2 11.5 ⫾ 2.2 76.6 ⫾ 11.8 39.9 ⫾ 9.2 64.0 ⫾ 21.9 4.4 ⫾ 2.6 11.3 ⫾ 3.1 33.7 ⫾ 10.5 13.9 ⫾ 2.0 64.0 ⫾ 20.2 75.9 ⫾ 24.5 85.4 (35) 63.4 (26) 68.3 (28) 3.0 ⫾ 3.0
CVP, central venous pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; ScvO2, central venous oxygen saturation; Hgb, hemoglobin; APACHE, Acute Physiology and Chronic Health Evaluation; MEDS, Mortality in Emergency Department Sepsis; SAPS, Simplified Acute Physiology Score; MPM, Mortality Prediction Model; cx, culture; pos, positive. Patient characteristics of hemodynamic variables and laboratories are values first available during the ED length of stay. Values are presented as mean ⫾ SD. Proportions are presented as percentage (number of patients).
interval [CI], 0.18 – 0.80; p ⫽ .03); completed EGDT at 6 hrs (OR, 0.55; 95% CI, 0.32– 0.93; p ⫽ .03); had lactate clearance (OR, 0.49; 95% CI, 0.31– 0.78; p ⬍ .01); and had the bundle completed (OR, 0.40; 95% CI, 0.22– 0.74; p ⬍ .01). After adjustment for unequal lactate and ScvO2 between patients with bundle completed and patients with bundle not completed, patients with bundle completed had an OR for mortality of 0.36 (95% CI, 0.16 – 0.78; p ⬍ .01). A multivariate logistic regression analysis including the five quality indicators as independent variables was performed. Completing EGDT at 6 hrs was the only quality indicator with a significant OR for decreased mortality (OR, 0.36; 95% CI, 0.17– 0.79; p ⫽ .01). The in-hospital mortality in patients who completed EGDT compared with those who did not complete EGDT was 25.8 vs. 38.8% (p ⫽ .03).
DISCUSSION Figure 1. Bundle percentage compliance from baseline through the quality improvement phases. Each phase represents percentage compliance in the bundle quality indicators over a 3-month period. QI, quality improvement; CVP, central venous pressure; ScvO2, central venous oxygen saturation; EGDT, early goal-directed therapy.
Completion of Bundle Quality Indicators and Associated Mortality Benefit Univariate comparisons of mortality in patients receiving the individual bundle 1108
quality indicators and those patients not receiving the indicators were performed (Fig. 2). There was a statistically significant decreased odds ratio for mortality in patients who received antibiotics by 4 hrs (odds ratio [OR], 0.38; 95% confidence
The application of evidence-based guidelines to the patient bedside is often difficult. Recently, a few studies have shown the feasibility of providing the level of care recommended by the SSC guidelines for severe sepsis patients, with suggested outcome benefits in small samples of patients (23–27). The limitation remains a comprehensive implementation of the sepsis bundle in the ED setting. Our study suggests that a severe Crit Care Med 2007 Vol. 35, No. 4
Table 4. Comparisons between patients with bundle completed and patients with bundle not completed Bundle Completed (n ⫽ 77)
Bundle Not Completed (n ⫽ 253)
p Value
64.2 ⫾ 19.3 10.8 ⫾ 2.8 78.6 ⫾ 16.1 40.0 ⫾ 9.3 70.1 ⫾ 11.6 3.3 ⫾ 2.4 16.2 ⫾ 9.9 12.1 ⫾ 2.7 277.3 ⫾ 182.7 2.0 ⫾ 1.5 1.6 ⫾ 2.7 3.4 ⫾ 4.4 173.4 ⫾ 99.0 29.0 ⫾ 11.1 13.2 ⫾ 3.1 48.0 ⫾ 17.7 51.6 ⫾ 27.5 81.8 (63) 48.1 (37) 54.6 (42) 2.7 ⫾ 2.2
63.7 ⫾ 18.2 10.6 ⫾ 3.6 78.1 ⫾ 17.6 38.8 ⫾ 10.0 63.3 ⫾ 18.4 4.3 ⫾ 3.6 15.2 ⫾ 9.9 11.7 ⫾ 2.4 258.1 ⫾ 161.3 2.3 ⫾ 1.8 2.5 ⫾ 7.1 2.9 ⫾ 2.5 158 ⫾ 85.1 29.8 ⫾ 10.5 12.3 ⫾ 4.4 52.7 ⫾ 21.6 50.1 ⫾ 28.9 77.1 (195) 43.1 (109) 55.7 (141) 2.6 ⫾ 2.7
.82 .57 .83 .37 ⬍.01 .03 .48 .22 .38 .15 .30 .26 .18 .60 .22 .13 .73 .43 .70 .08 .75
52.0 (40) 50.6 (39) 5.2 (4) 6.5 (5) 3.9 (3) 3.9 (3) 15.6 (12) 11.7 (9)
44.7 (113) 37.9 (96) 7.9 (20) 7.5 (19) 3.6 (9) 0.8 (2) 14.2 (36) 19.0 (48)
.30 .06 .62 .96 .89 .09 .85 .17
100.0 (77) 100.0 (77) 100.0 (77) 100.0 (77) 100.0 (77) 77.9 (60) 79.2 (61)
51.8 (131) 87.4 (221) 35.6 (90) 63.2 (160) 22.9 (58) 58.5 (148) 39.1 (99)
⬍.01 ⬍.01 ⬍.01 ⬍.01 ⬍.01 ⬍.01 ⬍.01
100.0 (77) 1.0 ⫾ 1.5 100.0 (77) 1.0 ⫾ 1.2 2755 ⫾ 1477 14.3 (11) 50.7 (39) 23.4 (18) 29.9 (23) 7.8 (6)
64.8 (164) 1.4 ⫾ 2.0 89.7 (227) 1.5 ⫾ 1.8 2807 ⫾ 2091 12.7 (32) 43.8 (111) 26.5 (67) 16.2 (41) 1.6 (4)
⬍.01 .07 .04 .02 .84 .70 .30 .66 .01 .01
100.0 (77) 7766 ⫾ 5206 24.7 (19) 66.2 (51) 19.5 (15) 39.0 (30) 14.3 (11)
94.5 (239) 7947 ⫾ 6097 26.5 (67) 59.7 (151) 28.9 (73) 31.2 (79) 5.6 (14)
.21 .82 .88 .35 .11 .22 .03
8.4 ⫾ 4.1 8.6 ⫾ 4.3 11.2 ⫾ 10.9 11.2 ⫾ 9.9 54.6 (42)
8.6 ⫾ 4.5 9.2 ⫾ 4.6 11.4 ⫾ 13.4 12.9 ⫾ 13.9 54.6 (138)
.69 .36 .90 .38 1.00
Patient characteristics Age, yrs CVP, mm Hg SBP, mm Hg DBP, mm Hg ScvO2, % Lactate, mmol/L WBC, ⫻103/mm3 Hgb, g/dL Platelets, 103/L Creatinine, mg/dL Total bilirubin, mg/dL Albumin, g/dL Glucose, mg/dL APACHE II, score MEDS, score SAPS II, score MPM II0, % mortality Septic shock, % (n) Blood cx pos, % (n) Culture pos, % (n) Time zero, hrs Source of infection, % (n)a Pneumonia Urinary tract infection Intra-abdominal Soft tissue infection Line infection Meningitis Other Unknown Bundle compliance, % (n) CVP/ScvO2 by 2 hrs Antibiotics by 4 hrs CVP goal met at 6 hrs SBP/MAP goal met at 6 hrs ScvO2 goal met at 6 hrs Appropriate steroid Lactate clearance Therapies in ED CVP/ScvO2 monitoring, % (n) Time to CVP/ScvO2, hrs Antibiotics, % (n) Time to antibiotics, hrs Fluids, mL Transfusion, % (n) Vasopressor, % (n) Inotropes, % (n) Corticosteroids, % (n) rhAPC, % (n) Therapies in ICU (72 hrs) Antibiotics, % (n) Fluids, mL Transfusion, % (n) Vasopressor, % (n) Inotropes, % (n) Corticosteroids, % (n) rhAPC, % (n) Resource consumption ED LOS all patients, hrs ED LOS survivors, hrs Hospital LOS all patients, days Hospital LOS survivors, days Mech vent in ED or ICU, % (n)
CVP, central venous pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; ScvO2, central venous oxygen saturation; WBC, white blood cell count; Hgb, hemoglobin; APACHE, Acute Physiology and Chronic Health Evaluation; MEDS, Mortality in Emergency Department Sepsis; SAPS, Simplified Acute Physiology Score; MPM, Mortality Prediction Model; cx, culture; pos, positive; MAP, mean arterial pressure; rhAPC, recombinant human activated protein C; ED, emergency department; LOS, length of stay; mech vent, mechanical ventilation; ICU, intensive care unit. a Individual patients may have multiple sources of infection: others (source of infection) included bacteremia, fungemia, and endocarditis. Patient characteristics of hemodynamic variables and laboratories are values first available during the ED length of stay. Values are presented as mean ⫾ SD. Proportions are presented as percentage (number of patients).
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sepsis bundle can be implemented as standard care among ED physicians and nurses at our institution through the use of compliance measurements and feedback. Our quality improvement effort included the largest single-center cohort of patients and required 2 yrs to achieve ⬎50% completion of the bundle, with 82.9% of patients having the bundle initiated (i.e., receiving CVP/ScvO2 monitoring) at the end of the study period. Although we had hoped to achieve ⬎80% completion of the bundle by the end of the study period, our results are similar to those shown by Gao et al (26). They prospectively observed the compliance of a modified SSC 6-hr sepsis bundle at two hospitals in the UK, using hemoglobin target 7–9 g/dL and hypotension after fluid resuscitation instead of ScvO2 as a threshold for initiating inotrope therapy. They noted a 52% compliance with the 6-hr sepsis bundle and a 26% absolute decrease in mortality. Using a more stringent bundle and quality indicators, requiring CVP and ScvO2 monitoring, our current compliance is also relatively higher than with other therapies for severe sepsis. Lung-protective strategies have been achieved only in 39% of patients on day 2 of acute lung injury (28). Tight glucose control was achieved in 19% of the time with routine insulin protocols (29). The administration of rhAPC ranged from 4% to 33% of patients in other studies (14.3% in patients with bundle completed in this study) examining the effectiveness of a sepsis protocol (23–25). The bundle is unique in that it is applicable during the earliest hours of severe sepsis presentation. The items of the bundle are treatment goals that can be abstracted from the medical chart with a yes or no answer for completion. The items themselves are inherent quality indicators with supporting evidence associated with improved outcome: early antibiotics (14), EGDT (8), appropriate corticosteroid (9), and lactate clearance (15). Most important, the bundle quality indicators were accepted by the implementing physicians as valid and feasible a priori bundle implementation. Although the implementation of the bundle was an ED-based process of care improvement initiative targeting the quality indicators, and not a controlled clinical trial, our study showed a few interesting results. First, time zero or the time from ED arrival to meeting criteria for severe sepsis (lactate ⱖ4 mmol/L) or 1109
Figure 2. Odds ratio for in-hospital mortality relative to completion of each bundle quality indicator and completion of the bundle. CVP, central venous pressure; ScvO2, central venous oxygen saturation; EGDT, early goal-directed therapy.
septic shock (refractory hypotension) ranged from immediate to 17.0 hrs. This observation supports the concept of “cryptic shock.” Septic patients with significant systemic hypoperfusion may initially present with normal or high blood pressure in the ED and may require a few hours before the fluid refractory hypotension (vasodilation) occurs. In the original EGDT study, 18% of enrolled patients had mean arterial pressure ⬎100 mm Hg, and 14% of these later died from sudden cardiovascular collapse or vasodilatory shock in the ICU (8, 30). Second, patients with the bundle completed had a lower lactate and higher ScvO2 compared with the patients with the bundle not completed. Perhaps these patients met their hemodynamic goals with an associated lower mortality because they had less disease severity. However, both groups had similar percentages of patients with septic shock, suggesting that most patients received the bundle based on hypotension refractory to fluids rather than lactate criterion. Physiologic scores, culture results, and other laboratories were similar between patients with the bundle completed and patients with bundle not completed. After adjustment for unequal lactate and ScvO2, patients with the bundle completed still had decreased odds ratio for mortality. Third, the patients with the bundle completed had no difference in fluids, transfusion, vasopressor, or inotrope administration compared with patients with the bundle not completed. These results were different from the original EGDT study, where more fluids, transfusion, and inotrope were administered, with less vasopressor usage in the treatment 1110
group. Perhaps the physicians in clinical practice tended to use more vasopressor than fluids to achieve the hemodynamic goals compared with the researchers in the original EGDT study who used more fluids, transfusion, and inotrope. Furthermore, mean CVP was consistently ⬎8 mm Hg throughout the study period, suggesting that patients in this study were not as hypovolemic and required less fluid resuscitation compared with patients in the original EGDT study. Regardless, the primary aim of the bundle was for clinicians to achieve the quality indicators rather than target a specific resuscitation strategy. Although we do not claim that EGDT compliance was the limiting factor in decreased mortality, we surmise that EGDT completion may be the most important quality indicator associated with improved outcome when examined in a multivariate analysis including the other bundle quality indicators. Finally, although rhAPC administration was not a quality indicator in the bundle, patients with the bundle completed received more rhAPC compared with patients with the bundle not completed. Thus, patients who had the bundle completed tended to be evaluated for and to receive rhAPC. This phenomenon may have resulted from variability in clinical practice among physicians completing the bundle compared with those physicians not completing the bundle.
Limitations Our study was nonrandomized; therefore, the implementation of the bundle and quality indicators were at best associated with a mortality benefit and not causal. However, given the quality im-
provement initiatives advocating the implementation of severe sepsis bundles, we were limited by the ethical constraints of performing a randomized trial examining the utility of the bundle (or standard care). Our use of corticosteroid as a quality indicator and its association with a decreased odds ratio for mortality should be interpreted with caution. We adopted the SSC guidelines recommendation that in a patient requiring vasopressor therapy after fluid resuscitation, corticosteroid should be started without waiting for the adrenocorticotropic hormone stimulation result (12). Thus, we do not know how many patients receiving corticosteroid in our study actually have relative adrenal insufficiency and are the patients with the most benefit from corticosteroid administration (9, 31). However, one study showed that 19% of hemodynamically unstable vasopressor-dependent patients in the ED have relative adrenal insufficiency (32). We did not measure the variables involved in process improvement. What were the barriers in bundle compliance? How do we know individual physicians changed their behaviors? How effective was physician feedback in improving compliance? What role does administrative leadership play in effecting compliance (33, 34)? Although we did not explicitly study these factors, we observed that completion of the EGDT hemodynamic goals was the limiting factor in achieving compliance. In a busy ED with the ED physician continually multitasking, it is difficult to initiate vasopressor, inotrope, and transfusion in a timely way to meet the CVP, mean arterial pressure, and ScvO2 goals at 6 hrs. Other factors Crit Care Med 2007 Vol. 35, No. 4
may include simple lack of documentation. As compliance was measured by chart review, an optimal but undocumented CVP at 6 hrs would equate to noncompliance to the bundle. These process barriers may be inherent to our attempt at a culture change in the standard care. Perhaps a “shock team” approach with a physician at bedside (35) and concurrent measurement of compliance during the bundle completion would have further increased our compliance. However, we believe that physician education, physician buy-in as shown by our initial survey on the bundle validity and feasibility, and regular physician and nursing feedback were as important.
questions, we have already begun the process of providing better care for patients with severe sepsis or septic shock. 12.
ACKNOWLEDGMENTS We thank the emergency department physicians, nurses, students, and staff for their contribution to this study, especially Carlos Mejia, RN, who provided the sepsis education to the nursing staff. We also thank Jacqueline Abernathy from Department of Medical Records for providing us with monthly listings of patients meeting the level 1 screening criteria.
REFERENCES
13.
14.
15.
CONCLUSIONS We showed that a severe sepsis bundle could be feasibly implemented in the ED setting by an ED-centralized model with no additional staffing resources. Clinician feedback was crucial in achieving compliance, and successful completion of the bundle quality indicators may be associated with improved outcome. As a result of this effort, we have increased our awareness of severe sepsis and the importance of early recognition and intervention even though the patient may appear stable. With unavoidable prolonged ED length of stays, the physicians and nurses were committed to providing the level of intensive care required by the bundle to avoid the potential cardiovascular demise that may occur before ICU bed availability. Although other institutions are implementing similar quality improvement programs with the use of the sepsis bundles and sharing their results, we pose a few questions for future studies. Can bundle implementation be generalized in most institutions, such as community vs. academic tertiary care centers? Are these quality indicators applicable in other ED settings, on the medical ward, or in the ICU? What component of the bundle is most effective, or will a partial bundle be just as effective as a complete bundle? What efforts and time are needed to increase bundle completion to ⬎95%? What resource limitations prevent bundle compliance? What strategies are most effective in overcoming implementation barriers? What implementation model is best (ED centralized, ICU centralized, or a multidisciplinary team model)? While we and others await answers to these Crit Care Med 2007 Vol. 35, No. 4
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