Implementation of a Diagnostic Stewardship Bundle for Ventilator-associated Pneumonia Among Mechanically-ventilated Patients
Phase: NA
Conditions: VAP - Ventilator Associated Pneumonia
Sponsor: University of Michigan

Study Title: Implementation of a Diagnostic Stewardship Bundle for 
Ventilator-associated Pneumonia among Mechanically-ventilated 
patients: a Pilot/Feasibility trial
National Clinical Trial (NCT) Identified Number: NCT05176353
Principal Investigator: Owen Albin, MD
Protocol Version IRB Approval Date: 3/4/2024

Implementation of a Diagnostic Stewardship 
Bundle for Ventilator-associated Pneumonia 
among Mechanically-ventilated patients: a 
Pilot/Feasibility trial 
Protocol Number: 1 
National Clinical Trial (NCT) Identified Number: NCT05176353 
Principal Investigator: Owen Albin, MD 
Sponsor: University of Michigan Medical School 
Grant Title: CATALYST award 
Grant Number: N/A 
Funded by: Michigan Institute for Clinical & Health Research 
Version Number:  v1.2 
2022-03-22 

VAP Diagnostic Stewardship Intervention 
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Amendments ............................................................................................................................................... 1 
STATEMENT OF COMPLIANCE ............................................................................................................ 2 
1 
PROTOCOL SUMMARY ............................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................. 3 
1.2 
Schema ................................................................................................................................... 4 
1.3 
Study Timeline ....................................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................ 6 
2.1 
Study Rationale ..................................................................................................................... 6 
2.2 
Study Background ................................................................................................................. 6 
4 
OBJECTIVES AND ENDPOINTS .............................................................................................. 10 
5 
STUDY DESIGN ........................................................................................................................... 11 
5.1 
Overall Design ..................................................................................................................... 11 
5.2 
Scientific Rationale for Study Design ............................................................................... 12 
5.3 
Justification for Intervention ............................................................................................... 12 
5.4 
End-of-Study Definition ...................................................................................................... 12 
6 
STUDY POPULATION ................................................................................................................. 12 
6.1 
Inclusion Criteria.................................................................................................................. 12 
6.2 
Exclusion Criteria ................................................................................................................ 12 
7 
STUDY INTERVENTION(S) ....................................................................................................... 12 
7.1 
Study Intervention(s) Administration ................................................................................ 12 
7.2 
Fidelity ................................................................................................................................... 14 
8 
End-of-Intervention/End-of-Study ............................................................................................... 14 
8.1 
Discontinuation of Intervention .......................................................................................... 14 
9 
STATISTICAL CONSIDERATIONS ........................................................................................... 15 
9.1 
General Statistical Approach ............................................................................................. 15 
9.2 
Analysis of the Primary and Secondary Endpoint(s) ..................................................... 15 
9.3 
Exploratory Analyses .......................................................................................................... 15 
9.4 
Other Analyses .................................................................................................................... 16 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 16 
10.1 
Confidentiality and Privacy      ........................................................................................... 16 
10.2 
Safety Oversight .................................................................................................................. 17 
10.3 
Quality Assurance and Quality Control ............................................................................ 17 
11 
REFERENCES .............................................................................................................................. 17 

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AMENDMENTS 
Date 
Version 
Section(s) 
Changes 
22-Mar-
2022
1.2 
5, 1.3 
Modified study timeline to reflect phased roll out of study 
interventions. Removal of study endpoints. 

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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with the protocol, Michigan Institute for Clinical & Health 
Research (MiCHR) Terms and Conditions of Award, applicable local and federal regulatory requirements 
and best research practices. The Principal Investigator will assure that no deviation from, or changes to 
the protocol will take place without prior agreement from the funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. 

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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS
Title: 
Implementation of a Diagnostic Stewardship Bundle for Ventilator-
associated Pneumonia among Mechanically-ventilated patients: a 
pilot/feasibility trial. 
Grant Number: 
Not applicable 
Study Description: 
A pilot/feasibility trial to evaluate the safety and efficacy of a multi-
faceted ventilator-associated pneumonia diagnostic stewardship 
bundle. Trial ICUs will sequentially implement interventions targetting 
the respiratory culture diagnostic testing pathway to minimize 
diagnostic error and overtreatment of ventilator-associated 
pneumonia. 
Objectives: 
Primary Objective: To determine the safety of a multi-faceted 
ventilator-associated pneumonia diagnostic stewardship bundle. 
Secondary Objectives:  
-
To determine the association between a multi-faceted ventilator-
associated pneumonia diagnostic stewardship bundle and ICU
antibiotic utilization rates.
-
To determine the associated between a multi-faceted ventilator-
associated pneumonia diagnostic stewardship bundle and rates of
positive respiratory cultures.
To assess study feasibility and adherence to protocolized intervention. 
Endpoints: 
Primary Endpoints:  
-
Mortality per 1000 mechanically-ventilated patient days
-
Ventilator-associated events (using Centers for Disease
Control/National Healthcare Safety Network definitions) per 1000
patient days
-
Median duration of mechanical ventilation per patient.
Secondary Endpoints: 
-
Positive respiratory cultures per 1000 mechanically-ventilated
patient days.
-
Total ICU antibiotic utilization rates (total antibiotic days of
therapy per 1000 mechanically-ventilated patient days).
-
Broad-spectrum ICU antibiotic utilization rates (broad-spectrum
antibiotic days of therapy per 1000 mechanically-ventilated patient
days).
-
Respiratory cultures ordered per 1000 patient days.
-
Percentage of respiratory cultures obtained by BAL.
-
Percentage of respiratory cultures from BAL samples with alveolar
neutrophils <50% (for Phase 2 only)
Study Population: 
All mechanically-ventilated patients hospitalized within Michigan 
Medicine Cardiac Care Unit (CCU) and Critical Care Medicine Unit 
(CCMU). 

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Phase or Stage: 
Pilot/feasibility trial of a population-based intervention. 
Description of 
Sites/Facilities Enrolling 
Participants: 
2 Michigan Medicine Intensive Care units.   
Description of Study 
Intervention/Experimental 
Manipulation: 
A multi-faceted diagnostic stewardship bundle targeting the ventilator-
associated pneumonia respiratory culture testing pathway. Three 
interventions will be operationalized in sequential intervals at the 
following phases of the diagnostic testing pathway: ordering, 
collection, and reporting. 
Study Duration: 
2 years. 
Participant Duration: 
Not applicable. 
1.2 SCHEMA

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1.3 STUDY TIMELINE 

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2  INTRODUCTION   
2.1 STUDY RATIONALE 
Indiscriminate use of antibiotics is a leading cause of adverse drug events and a catalyst for emergence 
of multidrug-resistant organisms (MDROs), which account for 2.8 million infections and 37,000 deaths 
annually in the US.1,2 Antimicrobial stewardship programs are instrumental in curbing antibiotic overuse, 
but their reach into intensive care units (ICUs)—where antibiotic resistance is most prevalent and 
problematic—is limited.3-5 Treatment for suspected respiratory infection, in particular, ventilator-
associated pneumonia (VAP), accounts for 50-70% of antibiotic use within ICUs.6-9 Studies using 
multidisciplinary expert case review or autopsy findings as reference gold standards demonstrate that a 
majority of ICU patients treated for VAP are misdiagnosed, resulting in excessive and often unnecessary 
antimicrobial exposure, adverse drug events, and generation of MDROs.10-13 There is a pressing need to 
identify strategies to reduce unnecessary antibiotic use against misdiagnosed VAP in ICUs. 
2.2 STUDY BACKGROUND 
Antibiotic overuse is an increasingly recognized problem in intensive care units (ICUs).9,14 A recent 
multinational point-prevalence study of 1150 ICUs determined that 70% of patients surveyed were 
receiving antibiotics; only 54% of these patients had suspected or proven infection and only 35% had 
positive microbiologic cultures supporting a definitive diagnosis of infection.15 Excess antibiotic use 
catalyzes the acquisition and spread of multidrug-resistant organisms (MDROs), which have risen 
precipitously within ICUs in recent decades and are associated with excess morbidity, mortality, and 
healthcare expense.16-23 Antibiotic overuse is also associated with adverse patient outcomes, including 
Clostridioides difficile infection, drug toxicity, and incident sepsis, as well as increases in healthcare costs 
and length of stay.24-28 
Treatment for suspected respiratory infection—in particular, ventilator-associated pneumonia (VAP)—
accounts for 50-70% of antibiotic use within ICUs.6-9 Multidisciplinary case review and autopsy studies 
demonstrate that a substantial number of ICU patients treated for VAP are misdiagnosed, resulting in 
significant antimicrobial overuse.10-13,29,30 For example, a multidisciplinary review of 231 cases diagnosed 
and treated as VAP in 6 ICUs at Johns Hopkins Hospital determined that antibiotics were not indicated in 
59% of cases at the time of diagnosis, resulting in 1,183 days of unnecessary antibiotic use over 1 year.10 
A similar multidisciplinary review of surgical ICUs at Johns Hopkins Hospital found that fewer than 25% of 
patients empirically treated for postoperative VAP met standardized criteria for infection, accounting for 
1,460 days of inappropriate antibiotic therapy over 1 year.11 At Michigan Medicine University Hospital, a 
review of patients with positive respiratory cultures who were treated for nosocomial pneumonia 
determined that 34% were misdiagnosed, account for a median of 12 excess days of unnecessary 
antibiotics per patient.30 

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Most efforts to curb inappropriate VAP-directed antibiotic use have focused on therapeutic 
processes, namely antibiotic discontinuation or de-escalation strategies, for patients with an established 
VAP diagnosis.31-39 These strategies have been largely unsuccessful in curbing antibiotic overuse. To 
date, no efforts have instead addressed 
the diagnostic process for VAP—
interventions targeting the pathway of 
ordering, collection, and reporting of 
diagnostic tests to proactively avert 
unnecessary antibiotic use in patients 
with low pretest probabilities of 
infection (Figure 1).40 Interventions 
targeting the diagnostic testing pathway 
for infectious syndromes—collectively 
termed diagnostic stewardship 
approaches—have been shown to avert 
unnecessary antibiotic treatment of conditions such as asymptomatic bacteriuria and Clostridioides 
difficile colonization but remain unexplored in VAP.40-49  
A foundational component of the VAP diagnostic pathway is the collection and interpretation of 
respiratory cultures. Positive respiratory cultures inform the diagnostic probability of VAP, but by 
themselves are not synonymous with infection, owing to the high burden of bacterial colonization of 
endotracheal tubing and distal lung parenchyma in critically ill patients.50-53 Respiratory bacterial 
colonization with pathogenic organisms has been reported in over 50% of patients requiring intensive 
care and in up to 90% of patients with prolonged ventilator-dependence.52,53 Indeed, advances in 
microbiologic techniques have shown that the lungs, once considered sterile, in fact house diverse 
bacterial communities.54 Contemporary respiratory culturing practices frequently identify bacteria 
from the respiratory tract of critically-ill patients without pneumonia and are a major factor in 
incenting unnecessary antibiotic use.10,39,55 Novel interventions targeting the respiratory culture testing 
pathway therefore represent an attractive and, to date, unexplored target for stewardship interventions 
to proactively decrease antibiotic use.  
Using an approach patterned on 
validated diagnostic 
stewardship interventions for 
asymptomatic bacteriuria, our 
group has identified 
interventions at each of the 
three phases of the VAP 
microbiologic diagnostic 
pathway (test ordering, sample 
collection and result reporting) 
to lower antibiotic overuse 
among mechanically-ventilated 
patients (Figure 2, see details 
below): 
Figure 1: Schematic Representation of Diagnostic vs Antimicrobial
Stewardship.  
Figure 2. VAP Diagnostic Stewardship Bundle. EMR=electronic medical record, 
RC=respiratory culture, RT=respiratory therapist, PMN%=polymorphonuclear cell 
percentage of alveolar cytology 

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1. Ordering (preanalytic) phase:
•
Current state: At present, there are no preconditions for ordering respiratory cultures; as a
result, respiratory cultures are often ordered indiscriminately and in scenarios of uncertain
or low utility: for surveillance purposes following tracheostomy placement, following
transient clinical decompensations which resolve expediently with supportive care (i.e.
mucous plugging events), for isolated changes in endotracheal secretion character, as as
part of a “pan-culture” workup in response to fever or leukocytosis.30,56,57,58 We have
demonstrated that these practices incent unnecessary antibiotic use and are common at our
institution.30 Additionally, approximately 10% of respiratory cultures ordered in ICUs are
“repeat cultures”—tests that are drawn within 72 hours of an identical test (internal data).
While a positive respiratory culture in the context of fever informs the diagnostic
probability of pneumonia, it is exceedingly unlikely to indicate VAP in patients without
localizing pulmonary features of infection. For example, if one assumes a VAP prevalence of
10% among mechanically-ventilated patients,21 those with fever but without new
radiographic infiltrates, alterations in gas exchange or purulent sputum have a pretest
probability of VAP prior to respiratory culture of 2.6%; a positive respiratory culture would
increase the posttest probability of VAP to 3.7%, rendering the test minimally beneficial at
best.50 Our group has shown that procuring respiratory cultures in patients identified above
is associated with excessive antibiotic utilization within just one week of respiratory culture
collection.59
2. Collection (analytic) phase:
•
Current state: There is wide variability in ICU practice patterns for acquiring respiratory
specimens. 60% of respiratory cultures in ICUs at our institutional are obtained from
proximal lung samples, most frequently via endotracheal aspiration (ETA). ETAs are
convenient to acquire, but growth of microorganisms from ETA adds little to the diagnostic
specificity of VAP, as pathogenic organisms often colonize endotracheal material within
hours of intubation.60-62 ETA samples demonstrate low concordance with organisms isolated
from the lung itself in both animal models and human studies.62,63 Distal lung sampling, via
bronchoalveolar lavage (BAL), offers the advantage of directly sampling the alveolar space
and can be performed without bronchoscopic guidance by Respiratory Therapists at
Michigan Medicine for equivalent supply and labor cost to ETAs. In multiple randomized
controlled trials, use of BAL rather than ETA for respiratory collection in suspected VAP has
been associated with lower rates of antibiotic use, without increased rates of mortality or
ventilator-dependence.64-67
3. Reporting (postanalytic) phase:
•
Current state: Physicians routinely utilize the number and proportion of white blood cells
recovered from bodily fluid to determine the significant of positive culture results (for
example, this is considered standard of care in ascites fluid, pleural fluid and urine). Using
this data from clinical specimens helps providers to differentiate infection from
contamination when a clinical culture grows bacteria. For example, if a patient grows
bacteria from a urine specimen, but the patient’s urine has few to no white blood cells
present, it virtually assures that the bacteria recovered is not causing a clinical infection. In a
VAP enriched population of 851 ICU patients, our collaborators have demonstrated that BAL
neutrophil percentage <50% has a negative predictive value of 92% for ruling out VAP.68
Autopsy studies have similarly shown that BAL neutrophil percentage <50% approaches a
sensitivity of 100% in ruling out infection.69 Despite this, alveolar neutrophilia has never
been adopted for diagnostic stewardship purposes. Similarly, all respiratory cultures include

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a gram stain to identify bacteria under a microscope. If one assumes a VAP prevalence of 20-
30%, the negative predictive value of a negative gram stain for VAP diagnosis is 91%. Despite 
this, negative gram stains are not routinely used by providers to inform interpretation of 
respiratory cultures. 
The manner in which test results are reported by microbiology labs has been shown to 
significantly impact antibiotic use. Strategies such as “cascading” and selective reporting of 
antimicrobial susceptibility results, adding comments to microbiologic test results (to 
“nudge” providers towards appropriate antimicrobial prescriptions), and censoring tests 
results in certain clinical scenarios (such as growth of likely contaminant organisms from 
blood cultures or growth of pathogenic bacteria in urine without pyuria) have all shown 
success as diagnostic stewardship strategies.41,70  
Our goal is to conduct a pilot/feasibility trial of this VAP diagnostic stewardship bundle within Michigan 
Medicine ICUs to 1) demonstrate concept feasibility, 2) gauge and address protocol adherence, and 3) 
collect preliminary data pertaining to intervention efficacy and safety. A successful VAP diagnostic 
stewardship bundle has the potential to significantly lower inappropriate ICU antibiotic use and 
consequent rates of antimicrobial resistance while simultaneously providing an innovative blueprint 
for future ICU stewardship interventions. 
3 RISK/BENEFIT ASSESSMENT 
3.1.1 Known Potential Risks  
This study’s intervention is aimed at reducing overtesting/overdiagnosis and their consequent harms to 
patients. A potential concern for any intervention aimed at lowering overdiagnosis is the possibility of 
underdiagnosis. This is of particularly importance for VAP which is a condition associated with 
substantial morbidity and mortality.21 Expedient performance of respiratory cultures and receipt of 
susceptibility test results is a key component of VAP management and delays in effective antimicrobial 
therapy are important determinants of outcomes.71,72  
3.1.2 Known Potential Benefits 
Reduction of unnecessary antibiotic use has been associated with significant benefits to patients and 
healthcare systems. For patients, these include lower rates of Clostridioides difficile infection, adverse 
drug events and incident sepsis. For healthcare systems, reduction of unnecessary antibiotic use has been 
consistently associated with decreases in hospital-wide rates of multi-drug resistant organisms, as well as 
hospital costs and inpatient lengths of stay. 
3.1.3 Assessment of Potential Risks and Benefits  
While the possibility of underdiagnosis VAP is a theoretical concern, this trial does not prohibit ordering 
of diagnostic tests, prescription of antibiotics or microbiology lab culture workflows. Rather, it 1) utilizes 
behavioral “nudges” to disincentivize ordering diagnostic tests which do not meaningfully alter Bayesian 
diagnostic probability; 2) improves/standardizes sampling methods for respiratory cultures to decrease 
the frequency of false positive test results; and 3) provides frontline providers with data (degree of 
alveolar neutrophilia) to better inform culture interpretation and management decisions. All of these 
interventions components are within what is considered the standard of care and supported by expert 
consensus guidelines to inform clinical decision making, however they have not been 

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operationalized/implemented in a standardized fashion as proposed by this study.9,10 Counterbalanced 
with the significant harms of overuse of antibiotics, on the whole the potential benefits of this study 
intervention significantly outweigh its potential risks. 
This study’s endpoints have been calibrated to reflect safety concerns and will track rates of mortality, 
ventilator usage and ventilator-associated events to monitor for important safety signals. Importantly, 
systematic reviews of other antimicrobial stewardship interventions in ICUs (predominantly prospective 
audit and feedback) have shown stewardship interventions to be safe.73 In total, there are multiple 
immediate potential benefits to patients exposed to this intervention and the potential long-term 
benefits to patients from information gained from this trial are significant. 
4 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
To determine the safety of a multi-
faceted ventilator-associated 
pneumonia diagnostic stewardship 
bundle. 
Mortality per 1000 
mechanically-ventilated 
patient days 
Ventilator-associated 
events (using Centers 
for Disease 
Control/National 
Healthcare Safety 
Network definitions) per 
1000 patient days 
Median duration of 
mechanical ventilation 
per patient. 
The goal of this study is to 
demonstrate preliminary safety of a 
diagnostic stewardship bundle for 
ventilator-associated pneumonia.   
Secondary 
To determine the association 
between a multi-faceted ventilator-
associated pneumonia diagnostic 
stewardship bundle and ICU 
antibiotic utilization rates. 
Total ICU antibiotic 
utilization rates (total 
antibiotic days of 
therapy per 1000 
mechanically-ventilated 
patient days). 
Broad-spectrum ICU 
antibiotic utilization 
rates (broad-spectrum 
antibiotic days of 
therapy per 1000 
Our preliminary data suggests that a 
bundled diagnostic stewardship 
intervention can successfully reduce 
antibiotic use in mechanically-
ventilated patients.   

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
mechancially-ventilated 
patient days). 
To determine the association 
between a multi-faceted ventilator-
associated pneumonia diagnostic 
stewardship bundle and rates of 
positive respiratory cultures. 
Positive respiratory 
cultures per 1000 
mechanically-ventilated 
patient days. 
To assess study feasibility and 
adherence to protocolized 
intervention. 
Respiratory cultures 
ordered per 1000 
mechcanically-
ventilated patient days 
Percentage of 
respiratory cultures 
obtained by BAL 
Percentage of 
respiratory cultures 
from BAL samples with 
alveolar neutrophils 
<50% 
Adherence to study intervention is 
crucial to evaluating study efficacy 
and potentially recalibrating 
approach to intervention prior to 
multi-center implementation.   
5 STUDY DESIGN 
5.1 OVERALL DESIGN
We plan to conduct a quasi-experimental, single-arm pilot/feasibility trial of a VAP diagnostic 
stewardship bundle in the MM Critical Care Medicine Unit (CCMU) and Cardiac Care Unit (CCU). This is a 
population-based rather than individual intervention. Both the CCMU and CCU will designate team 
leaders (one faculty member, fellow, and unit nurse), who will be instructed on study design and 
rationale, to disseminate study information and education in concert with study PI to colleagues through 
use of infographics and powerpoint-based sessions.  
The study intervention will consist of interventions at all 3 phases of the diagnostic testing pathway (see 
Section 7 for full details). The bundle’s first two interventions (ordering & collection phase interventions) 
will be implemented at the onset of the study period. The final bundled intervention (reporting phase) 
will be implemented 6 months after study onset (see Study Timeline (section 1.2)). 

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5.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The majority of antimicrobial stewardship interventions are system-based interventions, operationalized 
at the level of individual hospital, hospital units or outpatient clinics. Thus, quasi-experimental pre/post 
study designs are a widely utilized and validated approach for studies of large-scale antimicrobial 
stewardship interventions. 
5.3 JUSTIFICATION FOR INTERVENTION 
VAP is overdiagnosed and overtreated, resulting in ICU antibiotic overuse which degrades patient care. 
Novel antimicrobial stewardship approaches to combat ICU antimicrobial overuse are required. 
5.4 END-OF-STUDY DEFINITION
The study will conclude after 1 year of intervention operationalization (February 2023). 
6 STUDY POPULATION 
6.1 INCLUSION CRITERIA 
This pilot/feasibility trial will occur within the Michigan Medicine Cardiac Care Unit (CCU, 7D) and the 
Michigan Medicine Critical Care Medicine Unit (CCMU, 6D). This study will not be screening or enrolling 
individual patients, but rather instituting system-based interventions in the diagnostic testing workflow 
that providers engage with as part of routine clinical care. Study subjects in this trial are therefore all 
patients hospitalized in the aforementioned Michigan Medicine ICUs during the study period requiring 
invasive mechanical ventilation, as well as healthcare providers providing care to said patients in the 
aforementioned ICUs during the study period. 
6.2 EXCLUSION CRITERIA 
For the study intervention requiring performance of bronchoalveolar lavage rather than endotracheal 
aspirate for respiratory culture collection, the following are exclusion criteria for performance of 
bronchoalveolar lavage: INR>2, platelet count <50, gross blood in endotracheal secretions, P/F ratio<80, 
major lung surgery in prior 30 days. There are no exclusion criteria for study interventions at the ordering 
and reporting phases of the diagnostic testing pathway. 
7 STUDY INTERVENTION(S)    
7.1 
STUDY INTERVENTION(S) ADMINISTRATION 
7.1.1 Study Intervention Description 
This study’s VAP diagnostic stewardship bundle will include interventions that occur at discrete phases 
in the diagnostic testing pathway: 1) the preanalytic phase, in which tests are ordered; 2) the analytic 

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phase, in which diagnostic specimens are collected and laboratory tests are performed; and 3) the 
postanalytic phase. 
Trial Interventions 
Diagnostic 
Testing 
Phase 
Intervention 
Implementation 
method 
Details 
Respiratory 
culture 
ordering 
CDS tool requiring providers to 
select a valid indication for 
respiratory culture performance: 
• New radiographic infiltrate on 
CXR or chest CT 
• Purulent endotracheal 
secretions 
• Worsening PEEP and/or FiO2 
Interruptive EHR 
alert triggered 
upon respiratory 
culture order, 
tagged to custom 
CDS order set. 
The following prompts were given to providers using the CDS 
order set: 
• Fever or leukocytosis without aforementioned culture 
indications is unlikely to indicate pneumonia. 
• Radiographic infiltrates consistent with atelectasis or 
pulmonary edema do not require respiratory cultures. 
• Purulent secretions are different than thickened or 
increased nonpurulent secretions (the latter do not require 
cultures). 
• Transient worsening of PEEP or FiO2 that rapidly improves 
is unlikely to indicate pneumonia 
Respiratory 
culture 
collection 
CDS tool requiring providers to use 
non-bronchoscopic BAL (performed 
by respiratory therapists) when no 
contraindications present.  
All BAL specimens automatically sent 
for quantitative respiratory culture 
& cell count/differential. 
Interruptive EHR 
alert triggered 
upon respiratory 
culture order, 
tagged to custom 
CDS order set 
Contraindications to BAL were as follows: 
• major lung surgery in prior 30 days
• gross blood in endotracheal secretions
• INR>2
• platelet count <50k
• P/F ratio <80.
Consideration of bronchoscopy was recommended for 
sampling upper lobe infiltrates. 
Respiratory 
culture 
result 
reporting 
Respiratory culture results 
automatically released in EHR only 
for BAL samples with a PMN% of 
>50%. 
Respiratory culture results for BAL 
samples with PMN% <50% released 
upon direct primary team request to 
Clinical Microbiology Lab. 
Modification to 
Clinical 
Microbiology 
Laboratory 
workflows. 
The following prompt was provided for suppressed respiratory 
culture results:  
• “Culture results suppressed due to <50% PMNs seen in 
BAL, which has a sensitivity of 95% for diagnosis of 
bacterial pneumonia in non-neutropenic patients. Please 
call the Microbiology Laboratory within 7 days if 
identification/antimicrobial susceptibility testing are 
needed.” 
CDS=clinical decision support; EHR=electronic health record; CXR=chest X-ray; CT=computed tomography; BAL=bronchoalveolar 
lavage; PMN%=percentage of polymorphonuclear neutrophils observes on BAL cell count/differential. 
1.
Ordering (preanalytic) phase:
•
Study intervention: In participating ICUs, all providers who order respiratory cultures will be
automatically routed to a custom study order set within the electronic medical record. This
order set will require providers to select a valid clinical indication for respiratory culture
performance (worsening hypoxia, new infiltrate on chest imaging, purulent sputum
production), but will not include aforementioned scenarios in which respiratory culture
collection is not indicated (fever or leukocytosis without features localizing infection to the
respiratory tract, changes in secretions that are not purulent, transient respiratory
decompensations that rapidly improve without supportive care.
2.
Collection (analytic) phase:
•
Study intervention: In participating ICUs, all providers who order respiratory cultures will be
automatically routed to a custom study order set within the electronic medical record. This
order set will require physician or RT-guided BAL for respiratory collection rather than
endotracheal aspiration for mechanically-ventilated patients, provided there are no specific
exclusion criteria for individual patients (see Section 4.1 for specific patient exclusion
criteria). Importantly, Respiratory Therapists are trained in the use of BAL for respiratory
collection and routinely perform these procedures hundreds of times a year for precisely

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this purpose. Performance of BAL is considered standard of care by national and 
international VAP expert guidelines.9,10 
3.
Reporting (postanalytic) phase:
•
Study intervention: In participating ICUs, all providers who order respiratory cultures will be
automatically routed to a custom study order set within the electronic medical record. This
order set will require performance of BAL for all patients without exclusion criteria (see
Section 4.1) in whom respiratory cultures are ordered. The order set will include not only an
order for respiratory culture from BAL (performed by the Michigan Medicine Clinical
Microbiology lab), but also a BAL cell count and differential. The Michigan Medicine Clinical
Microbiology lab will work up all respiratory cultures according to current practices, but will
not release the culture reports to providers for samples in which the BAL neutrophil % is less
than 50%. When providers examine the culture result in the electronic medical record, an
automated message will indicate that the BAL neutrophil % is low on the sample, making
pneumonia exceedingly unlikely. Providers will be informed in this automated message that
they can call the Michigan Medicine Clinical Microbiology lab and manually request release
of the results if they feel it is indicated.
7.2 FIDELITY
7.2.1 Provider Training 
Providers will be counseled on CDST use during bimonthly educational sessions over a 3-month trial 
rollout period and via subsequent monthly email reminders thereafter. Each ICU will designate a nursing 
and physician champion to facilitate implementation. 
7.2.2 Intervention Delivery 
Interventions 1 and 2 will be operationalized through an interruptive clinical decision support tool, 
triggered within the electronic health record whenever a respiratory culture is ordered in a 
mechanically-ventilated study ICU patient. Intervention 3 will be operationalized through modifications 
in Clinical Laboratory workflows. 
8 END-OF-INTERVENTION/END-OF-STUDY    
8.1 DISCONTINUATION OF INTERVENTION 
The full diagnostic stewardship intervention will be discontinued at the primary study completion date 
(February 2023). The study interventions will also be halted for prespecified increases in adverse safety 
outcomes (noted previously). 

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9 STATISTICAL CONSIDERATIONS       
9.1 GENERAL STATISTICAL APPROACH      
9.1.1 Descriptives  
We will compare categorical variables by reporting frequencies and percentages and assess statistical 
significance using a chi-square test. Subject-level continuous variables will be compared compared using 
Kruskal-Wallis tests. Rate variables (e.g., deaths per 1,000 MVPDs) will be compared using a z-score test. 
9.1.2 Hypotheses 
The primary study hypothesis was that implementation of a bundled DSI targeting the respiratory 
culturing pathway would not associate with significant increases in adverse safety outcomes. 
The secondary study hypotheses were that implementation of a bundled DSI targeting the respiratory 
culturing pathway would associate with reductions in rates of respiratory culture positivity (RCP) and 
ICU-antimicrobial utilization rates (ICU-AURs). 
 
9.2 ANALYSIS OF THE PRIMARY AND SECONDARY ENDPOINT(S) 
Primary and secondary study outcomes will be compared between patient cohorts before and after DSI 
implementation. All primary/secondary study outcomes will compare patients admitted to study ICUs 
over the course of the year-long study intervention (Feb 2022-23) versus those admitted in the pre-
intervention historical control period (Feb 2017-22). As above, rate variables will be compared using a z-
score test. A p-value of 0.05 will be utilized for statistical significance. 
9.3 EXPLORATORY ANALYSES 
In addition to unadjusted pre- vs post- outcome comparisons, we will utilize additional analytic 
approaches to explore exposure-outcome relationships between the study DSI and ICU antimicrobial 
use. These will include: 1) interrupted time series analyses of rates at the calendar month level to 
account for changes in temporal trends antecedent to the time of the intervention, 2) individual subject-
level negative binomial analyses with a covariate for admitted pre vs. post intervention date. 
For the interrupted time series analysis, will treat each calendar month (beginning as the unit of 
analysis. Each month will have an average antibiotic DOT per mechanically-ventilated patient per day. 
Linear regression will be used to model change over time, as well as an interaction for the change over 
time before and after the start of the trial intervention date.  
 
Subject-level analyses will also be performed to account for confounding clinical variables impacting ICU 
antimicrobial use. We will utilize patient-level data from pre-intervention historical control data to 
construct a multivariate model predictive of ICU-AURs. For these analyses, all study subjects will have a 
calculated rate of ICU-AURs (e.g., total antibiotic DOTs on mechanical ventilation divided by total 
number of person days on mechanical ventilation). Multiple imputation using fully conditional 
specification will be performed to create 25 imputation data sets to account for missing data, and 
negative binomial regression models were constructed for each data set using backwards selection. 
Covariates will be retained in a final multivariate master model if they are retained in 100% of negative 

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binomial regression models, after evaluation for multicollinearity. Admission before or after the study 
intervention will then be to the final model as a covariate to determine the independent effect of the 
study intervention on antibiotic use.  
9.4 OTHER ANALYSES 
9.4.1 Safety Analyses 
This study will utilize a Data and Safety Monitoring Board (DSMB) comprised of study personnel (the 
study PI, biostatistician, and ICU medical directors, Drs. Hyzy and Thomas), as well as an independent 
medical monitor (Dr. Keith Kaye, Chief of Division of Allergy, Immunology and Infectious Diseases at 
Robert Wood Johnson University Hospital). Dr. Kaye has served on data safety and monitoring 
committees for multiple federally- and industry-funded clinical trials, many of which have involved the 
study of ventilator-associated pneumonia. 
The DSMB will meet every two months to review the following safety metrics: 1) Mortality per 1000 
mechanically-ventilated patient days per ICU, Ventilator- associated events (using Centers for Disease 
Control/National Healthcare Safety Network definitions) per 1000  mechanically-ventilated patient days 
per ICU, Median duration of mechanical ventilation per patient per ICU. All safety outcomes will be 
compared to preintervention ICU data collected over the last 5 years to ensure that postintervention 
values fall within 2 standard deviations of preintervention controls. The study will be halted if any 
safety outcome is increased by more than 2 standard deviations relative preintervention control data. If 
safety outcomes are decreased by more than 2 standard deviations relative to preintervention control 
data (i.e. in a favorable direction following the intervention), the study intervention will be continued 
as this is a single-arm study trial design.  
9.4.2 Sub-Group Analyses 
We will also perform a series of prespecified confirmatory subgroup analyses for all study outcomes, 
stratified by individual study ICU and DSI implementation phase (for the latter, in order to account for 
seasonality, outcomes in the post-intervention cohort were compared to historical control patients 
admitted to study ICUs during analogous months in the pre-intervention control period). 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS    
10.1 CONFIDENTIALITY AND PRIVACY
10.1.1 Data sharing 
Sharing of data generated by this project is an essential part of our proposed activities and will be 
carried out in several different ways. We would wish to make our results available both to the 
community of scientists interested in ventilator-associated pneumonia to avoid unintentional 

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duplication of research. Conversely, we would welcome collaboration with others who could make use 
of protocols developed in this project. Data generated from this projects will be shared at national 
meetings and conferences and in peer-reviewed publications. 
We will share the final data in accordance with NIH policy. The final dataset will be stripped of patient 
identifiers prior to release for sharing. Because of the remote possibility of deductive disclosure of 
subjects’ identities, we will make data available to interested parties under a data sharing agreement 
that includes commitments to the following: (a) use of data for research purposes only; (b) use of 
appropriate electronic safeguards to ensure information security; (c) destruction or return of the 
data after the analysis has been completed; (d) agreement to not use data for any commercial purposes; 
and (e) agreement to not redistribute the data to third parties. Interested parties will be able to request 
access to unpublished data from the Principal Investigators by email using the following contact 
information: oalbin@med.umich.edu. 
10.2 SAFETY OVERSIGHT 
10.2.1 Key Roles and Study Governance 
Principal Investigator 
Medical Monitor or 
Independent Safety Monitor 
Owen 
Albin, 
MD, 
Assistant 
Professor of Medicine 
Keith Kaye, MD, MPH, Professor 
of Medicine and Chair of the 
Division of Allergy, Immunology 
& Infectious Diseases  
University of Michigan Medical 
School  
Robert Wood Johnson School of 
Medicine 
1500 E. Medical Center Drive, Ann 
Arbor, MI 48109 
125 Paterson St, New Brunswick, 
NJ 08901 
734-232-1871
N/A 
oalbin@med.umich.edu 
Kk1116@rwjms.rutgers.edu 
10.3 QUALITY ASSURANCE AND QUALITY CONTROL
10.3.1 Data Handling and Record Keeping  
All study data will be maintained on HIPPA-complaint, secure servers through the University of Michigan 
Advanced Research Computing (ARC) core. 
11 . REFERENCES 
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