Download Survival Benefit and Cost-Savings from Compliance with a

Survival Benefit and Cost-Savings from Compliance with a Simplified 3-Hour Sepsis
Bundle in a Series of Prospective, Multisite, Observational Cohorts
Online-Only Supplemental Material
1. eMethods 1:
2. eMethods 2:
3. eMethods 3:
4. eMethods 4:
5. eMethods 5:
6. eReferences
Version Date: 7/11/16
Quality Improvement (QI) Initiative and Database Abstraction Process –
Financial Data Methods –
Secondary Outcomes and Statistical Analysis for Secondary Outcomes –
Statistical Analysis for Secondary Outcomes –
Definitions for study variables –
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eMethods 1: Quality Improvement (QI) Initiative and Database Abstraction Process
As part of the QI initiative1, each site developed improvement science strategies, including “plan-do-study-act”
(PDSA) cycles, to improve bundle compliance, with assistance of the Health System Improvement Science team. A
centralized data collection process began with initial data collection in 2010, which we used to establish a baseline.
The three-hour bundle was introduced in 2010 and refined in 2011. This initial run-in phase of analysis was intended
to control the initial impacts of Hawthorne effect and denominator expansion as the system adapted to increased
awareness and practice change. In January 2012 bundle elements were finalized.
A dedicated team of data abstractors concurrently entered all 3-hour bundle eligible patients into the QI database
using a standardized data collection form, focused on uniform abstraction of objective variables. All abstractors
received standardized training at the beginning of their involvement. Database managers monitored quality of data
abstraction and monthly abstractor meetings ensured homogeneity in data collection. Abstractors identified eligible
patients by screening all patients who had blood gas or lactate labs ordered in the emergency department (ED).
Abstractors excluded patients from the database who were: less than 18 years old, declined interventions, had
advance directives precluding bundle interventions, were admitted directly from the ED to palliative care or hospice,
or who were enrolled in a precluding IRB-approved clinical trial. Because abstractors did not document when a
potential patient was excluded from the QI database, we are unable to determine how many potential SS/SS patients
met these exclusion criteria.
Demographic and clinical data obtained included patient age, sex, body mass index (BMI), initial lactate, signs of
hypoperfusion or organ dysfunction (manuscript table 1), central line placement, and utilization of central
hemodynamic monitoring by central venous pressure (CVP), central venous oxygenation (ScVO 2), or mixed venous
oxygenation (SVO2). In July, 2014, additional data began to be prospectively collected, including the site of the
source infection (e.g. respiratory, urinary, gastrointestinal, etc.), whether the source infection was nosocomial in
etiology, whether the patient met the criteria specifically for septic shock diagnosis, and the patient’s status for a
number of relevant comorbidities at the time of sepsis identification. Comorbidities documented were: Congestive
heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic renal failure (CRF), liver failure, organ
transplant, metastatic disease, immune modifying medications, and leukemia, lymphoma, or multiple myeloma.
Treatment data included times of intravenous fluid resuscitation initiation, lactate order and result, blood culture
collection, and parenteral broad-spectrum antibiotic administration. Abstractors documented intravenous fluid
resuscitation initiation time as the time that a 0.9% normal saline bolus of at least 30mL/kg was hung – i.e. the time
administration began, not the order time. The use of fluid initiation time, rather than completion time, has been
previously demonstrated2. In the case of patients receiving multiple boluses, the time of the first bolus was used.
Fluid completion times were not reliably documented and subsequently not recorded. Abstractors did not record the
volume administered for much of the data collection period because these data were frequently missing or
unreliable. As such, abstractors recorded initiation times as the time the first bolus began, only for intravenous fluid
administration documented as meeting bundle guidelines – i.e. administered or ordered as a bolus and in volumes
≥30mL/kg. Initiation times for fluids administered as an infusion or in inadequate total volumes as determined by
the abstractor were not recorded. A bolus was defined as volume of at least 500mL, ordered to be administered at a
rate of at least 500mL per 15 minutes. SS/SS patients presenting with comorbid congestive heart failure and/or endstage renal disease were NOT excluded from the fluid resuscitation requirement of the bundle, and the intention was
to administer fully bundle compliant care. Antibiotic administration was the time at which the first antibiotic for the
sepsis episode was administered – not the order time. Blood culture draw times were documented as the time of
collection. Lactate result times were the time the laboratory result became available for review, not the time a
provider actually viewed the result.
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eMethods 2: Financial Data Methods
To obtain financial data for Cohort 2 (MFY 2014) and Cohort 3 (MFY 2015), we extracted data from the health
system’s detailed accounting database and linked data with the research datasets via unique patient encounter
number. This was done at the conclusion of the study periods. These data included discharge diagnosis-related group
(DRG) and corresponding product line (e.g. infectious disease, cardiology), case-mix index (CMI), direct hospital
costs, and adjusted net revenues. CMI, also called service-intensity weight when referring to patient-level data, is an
index measure of a DRG’s typical resource utilization, adjusted for comorbidities and clinical complications.
Originally designed as a financial measure, CMI has been increasingly used a measure of severity of patient illness
during hospitalization3-8. Direct costs are costs allocated to departments that provide patient care (e.g. cardiology,
laboratory). Indirect costs are those allocated to departments that do not provide care (e.g. maintenance). We
considered only direct costs in our analyses. Total direct cost (TDC) represents the sum of fixed and variable direct
costs. Fixed costs do not vary based on practice patterns (e.g. provider salaries). Variable costs include costs affected
by practice patterns (e.g. pharmaceuticals, medical supplies). Physician costs are allocated by department, and
adjusted for time spent with the patient and DRG. Adjusted net revenue (ANR) describes total reimbursement
received for an encounter, reflecting payer costs.
𝐴𝑁𝑅 = (𝐶𝑜𝑛𝑡𝑟𝑎𝑐𝑡𝑢𝑎𝑙 𝑅𝑒𝑣𝑒𝑛𝑢𝑒) + (𝑃𝑜𝑜𝑙𝑠) − (𝐵𝑎𝑑 𝐷𝑒𝑏𝑡 + 𝐶ℎ𝑎𝑟𝑖𝑡𝑦 𝐶𝑎𝑟𝑒) − (𝐵𝑎𝑑 𝑅𝑒𝑐𝑜𝑣𝑒𝑟𝑖𝑒𝑠) − (𝐷𝑒𝑛𝑎𝑖𝑙𝑠 + 𝐷𝑜𝑤𝑛𝑔𝑟𝑎𝑑𝑒𝑠)
Pools comprise graduate and direct medical education, indigent, and statewide compensation. Government resident
education dollars are spread based on days and CMI to the appropriate payer-mix. The data does not account for
patients who have exhausted coverage benefits. For multiply insured patients, revenue is modeled based on primarypayer only. Contribution margin (CM) reflects the hospital’s financial gain or loss for the encounter before indirect
costs.
𝐶𝑀 = 𝐴𝑁𝑅 − 𝑇𝐷𝐶
eMethods 3: Secondary Outcomes
Secondary outcomes included intensive care unit (ICU) utilization, need for mechanical ventilation, need for
vasopressor administration, and hospital length of stay (hLOS). Mechanical ventilation was defined as either
endotracheal intubation or bi-level positive airway pressure. In Cohort 2 and Cohort 3, secondary financial outcomes
were the ANR and the CM for the encounter. The ANR is a detailed measure of reimbursement for an encounter and
reflects the payer-costs of care. CM is a measure of the hospital’s profit or loss for the encounter before indirect
costs.
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eMethods 4: Statistical Analyses for Secondary Outcomes
We report categorical secondary outcomes as frequencies and proportions, and financial secondary outcomes as both
means standard deviations and medians with interquartile ranges. We constructed 95% confidence intervals about
means and group differences. We report hLOS using Kaplan-Meier curve assessment with log-rank test, with 95%
confidence intervals. We do not report p-values for unadjusted outcomes. As with we did with the primary clinical
and financial outcome respectively, we assess bundle compliance as a predictor of categorical outcomes with
multivariable logistic regression, and continuous outcomes with linear regression, adjusting for potentially
confounding demographic and clinical variables. We assessed goodness-of-fit for logistic models with HosmerLemeshow test, where the null hypothesis that the model adequately fit the data was accepted for p>0.05. We use
adjusted r2 to assess model fit for linear regression. Analysis of Cohorts 2 and 3 tested compliance as a predictor of
hLOS with proportional hazard (Cox) models censoring for mortality. Because a subject being discharged alive was
the “event” in the model, a hazard ratio >1.0 indicates faster rate of live discharge (shorter LOS), and the inverse
hazard ratio (HR-1) is the hLOS ratio between groups.
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eMethods 5: Definitions for Composite Clinical Variables
Subject Baseline Characteristics
Acute Kidney Injury – serum creatinine greater than 2.0 mg/dL or a 50% increase from a known baseline in the
absence of chronic kidney disease9,10.
Acutely Altered Mental Status – new altered mentation unrelated to the patient’s prior medical history10.
Coagulopathy – international normalized ratio (INR) greater than 1.5, or a partial thromboplastin time greater than
60 seconds, or an activated partial thromboplastin time greater than 30 seconds, not otherwise explained by the
subject’s medical history (e.g. subjects on anticoagulation with therapeutic INR > 1.5 would not be considered to
have coagulopathy)10.
Chronic Renal Failure – chronic stage III or stage IV kidney disease with or without peritoneal or hemodialysis.
Compromised Oxygenation – a new increased O2 requirement to maintain SaO2 greater than 90% or a PaO2/FiO2
ratio less than 30010.
Diabetes – Type I or type II diabetes mellitus
Hypotension – systolic blood pressure less than 90 mmHg or decrease in systolic blood pressure ≥40% from a
known baseline or a mean arterial pressure less than 65 mmHg.
Immune Modifying Medications – cytostatics/chemotherapy within 30 days or oral glucocorticoids, calcineurin
inhibitors, or mycophenalte concomitant with presentation.
Leukemia, Lymphoma, Multiple Myeloma – active (i.e. non-remission) acute or chronic lymphocytic or
myelogenous leukemia or Hodgkin or non-Hodgkin lymphoma, or multiple myeloma.
Metastatic Disease – active (non-remission) malignancy explicitly indicated as stage IV, or explicitly indicated as
metastatic, or explicitly indicated to exhibit multi-organ involvement; excludes leukemia, lymphoma, and multiple
myeloma.
Nosocomial Infection – a sepsis episode’s source infection that was confirmed or considered highly likely to have a
hospital or healthcare acquired etiology. For data abstraction purposes, this was an infection explicitly described as
hospital or healthcare acquired, or an infection not explicitly described as community acquired for patients who were
discharged from a preceding hospitalization within 72 hours of presenting with sepsis at a study site.
Severe Sepsis – a source of infection in addition to 2 or more SIRS criteria, as well 1 or more organ dysfunction
criteria, or who met 2 or more “Super-SIRS” criteria at triage. Organ dysfunction criteria were hypotension, lactate
greater than or equal to 2.2 mmol/L, acute kidney injury, coagulopathy, thrombocytopenia, a total bilirubin greater
than 2.0 mg/dL, compromised oxygenation, or acutely altered mental status. These criteria applied only when not
otherwise explained by the patient’s medical history (e.g., an end-stage renal disease patient with an infection and 2
SIRS, who had a serum creatinine greater than 2.0 mg/dL and no other organ dysfunction criteria would not meet
our severe sepsis or septic shock definition).
Septic Shock – a source of infection in addition 2 or more SIRS criteria, as well as either a lactate greater than 4.0
mmol/L or hypotension that was refractory to intravenous fluid resuscitation.
Suspected Infection Source – site of suspected source infection for a subject’s sepsis episode. Coded as urinary,
respiratory, gastrointestinal, dermatologic, central nervous system, other, or unknown.
“Super-SIRS” – locally developed consensus-criteria employed at triage, where meeting 2 or more criteria was a
“time-zero” entry point for three-hour bundle care. “Super-SIRS” criteria were: (1) heart rate greater ≥ 120, (2)
respiratory rate ≥ 24, (3) systolic blood pressure < 90 mmHg or mean arterial pressure < 65 mmHg, (4) temperature
≥ 38.0° C (101.0° F) or (5) ≤ 36.0° C (96.8° F), and (6) acutely altered mental status.
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“Time-zero” – entry point for three-hour bundle care; the time of the earliest laboratory result or vital sign
measurement that first caused a patient to meet sufficient criteria to be classified as a severe sepsis or septic shock
patient.
Thrombocytopenia – platelet count less than 150,000 cells/μm3.10
Treatment and Outcome Characteristics
Antibiotic Administration Time – the time of administration, not order, of the first intravenous antibiotic for the
current sepsis episode.
Bundle Compliance – The accomplishment of all four three-hour bundle objectives’ within their specified time
allotment. Failure to complete any part of any bundle element with 100% adherence to the bundle specification was
considered bundle non-compliant care.
Blood Culture Draw Time – The time of collection of a blood sample for laboratory culture.
ICU Admission – admission to a critical care unit at any point during a subject’s hospitalization.
Intravenous Fluid Resuscitation Initiation Time – the time of administration, not order, of a 0.9% normal saline
bolus of at least 30mL/kg. In the case of patients receiving multiple boluses, the time of administration for the first
bolus was used. Initiation times for fluids administered as an infusion were not recorded. A bolus was defined as
volume of at least 500mL, ordered to be administered at a rate of at least 500mL per 15 minutes.
Mechanical Ventilation – endotracheal intubation or bilevel positive airway pressure at any point during a subject’s
hospitalization. We did not include continuous positive airway pressure in this definition.
Lactate Order to Result Time – the time from when the physician ordered a lactate, which was done for all possible
sepsis patients per algorithm specifications, to when the test result became available for review by the clinician.
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