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Ventilator Bundle and Its Effects on Mortality Among ICU Patients: A Meta-
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 Review Articles
Ventilator Bundle and Its Effects on Mortality
Among ICU Patients: A Meta-Analysis*
Downloaded from https://journals.lww.com/ccmjournal by 2x1etPFpclCPwq78Y733yAFgT9/JUkE6p5KSS06pP2HML+AQim90HMfF8DqrXU1o/nwXpkSefRhVYmYb49U90SchRCYIvm6tVWi05q7kDLNvz7qN+kDuRF5zN2pq/WLT on 07/19/2018
Claudia Pileggi, MD1, Valentina Mascaro, MD1, Aida Bianco, MD1, Carmelo G. A. Nobile, MD2,3,
Maria Pavia, MD, MPH1
Objectives: To assess the effectiveness of the ventilator bundle in
the reduction of mortality in ICU patients.
Data Sources: PubMed, Scopus, Web of Science, Cochrane
Library for studies published until June 2017.
Study Selection: Included studies: randomized controlled trials or
any kind of nonrandomized intervention studies, made reference
to a ventilator bundle approach, assessed mortality in ICU-venti-
lated adult patients.
Data Extraction: Items extracted: study characteristics, description of
the bundle approach, number of patients in the comparison groups,
hospital/ICU mortality, ventilator-associated pneumonia–related mor-
tality, assessment of compliance to ventilator bundle and its score.
Data Synthesis: Thirteen articles were included. The implementa-
tion of a ventilator bundle significantly reduced mortality (odds
ratio, 0.90; 95% CI, 0.84–0.97), with a stronger effect with a
restriction to studies that reported mortality in ventilator-associ-
ated pneumonia patients (odds ratio, 0.71; 95% CI, 0.52–0.97),
to studies that provided active educational activities was ana-
lyzed (odds ratio, 0.88; 95% CI, 0.78–0.99), and when the role
of care procedures within the bundle (odds ratio, 0.87; 95% CI,
0.77–0.99). No survival benefit was associated with compliance
to ventilator bundles. However, these results may have been con-
*See also p. 1201.
1
Department of Health Sciences, University of Catanzaro “Magna Gracia,”
Catanzaro, Italy.
2
Department of Pharmacy, Health and Nutritional Sciences, University of
Calabria, Arcavacata di Rende, Cosenza, Italy.
3
Department of Health Sciences, University of Catanzaro "Magna Grae-
cia", Catanzaro, Italy.
Drs. Pileggi and Pavia conceived and designed the study. Drs. Pileggi,
Mascaro, and Nobile did the literature review and data collection. Drs.
Mascaro and Bianco did the statistical analysis. Drs. Pileggi and Pavia
wrote the article. All authors contributed to the interpretation of the data
and writing of the article and agree with its content and conclusions.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s website (http://journals.lww.com/ccmjournal).
The authors have disclosed that they do not have any potential conflicts
of interest.
For information regarding this article, E-mail: pavia@unicz.it
Copyright © 2018 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000003136
Critical Care Medicine
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
founded by the differential implementation of evidence-based pro-
cedures at baseline, which showed improved survival in the study
subgroup that did not report implementation of these procedures
at baseline (odds ratio, 0.82; 95% CI, 0.70–0.96).
Conclusions: Simple interventions in common clinical practice
applied in a coordinated way as a part of a bundle care are effective
in reducing mortality in ventilated ICU patients. More prospective
controlled studies are needed to define the effect of ventilator bun-
dles on survival outcomes. (Crit Care Med 2018; 46:1167–1174)
Key Words: critical care; intensive care units; meta-analysis;
mortality; ventilator; ventilator-associated pneumonia
M
echanically ventilated patients are a vulnerable
population because of the risk for a series of pre-
ventable complications. The preventable nature of
most adverse events has promoted the assessment of effective
measures to reduce morbidity and mortality. Traditionally,
most interventions have been focused on the prevention of
ventilator-associated pneumonia (VAP), the most common
hospital-acquired infection (HAI) in the ICU. The impact of
VAP is very high in terms of morbidity, whereas attributable
mortality rates are controversial (1, 2). Therefore, VAP preven-
tion has been proposed as a quality-of-care indicator for ICU
patients, and numerous preventive measures have been tested.
To enhance and facilitate the adherence to preventive
guidelines in order to improve clinical outcomes in ventilated
patients, the Institute for Health Improvement (IHI) devel-
oped the “ventilator bundle,” initially consisting of four com-
ponents: 1) elevation of the head of bed (EHB) to 30°–45°, 2)
daily “sedation vacation" (SV) and assessment of readiness
to extubate, 3) peptic ulcer disease prophylaxis, and 4) deep
venous thrombosis prophylaxis (3). In 2010, a fifth bundle ele-
ment, “daily oral care with chlorhexidine,” was added (4).
After the development of the ventilator bundle, studies have
been published reporting results of its implementation in ICUs,
with contrasting findings (5–8); most studies have reported
reduction of VAP occurrence rate, that has not been frequently
associated to reduction of other important outcomes, such as
duration of mechanical ventilation, length of hospitalization, and
www.ccmjournal.org 1167
Pileggi et al
mortality (9–11). These findings have given support to the chal-
lenges posed by VAP detection, given the limitations of the tradi-
tional VAP definition, poorly accurate, and prone to subjectivity
(12), prompting the Centers for Disease Control and Prevention
(CDC) to propose a new paradigm for surveillance purposes, that
measures ventilator-associated events (VAEs), including ventila-
tor-associated complications (VACs) and infectious VAC, even-
tually progressing through “possible” VAP (13). This approach
is challenging, since, although each component of care bundle
is chosen based on best available evidence, bundle components
have been investigated on their effect on VAP and have now to be
evaluated in their effectiveness on VAE and/or VAC.
Furthermore, most studies have not been able to demon-
strate any effect of the ventilator bundle on mortality, probably
because most studies were underpowered (14) and mortality
has often been evaluated as a secondary outcome (15, 16).
The primary aim of our study was to assess, through meta-
analysis of published studies, the effectiveness of the ventilator
bundle in the reduction of mortality in ICU patients.
MATERIALS AND METHODS
Search Strategy and Selection Criteria
A comprehensive systematic bibliographic search of medical
literature published until June 2017 was performed to iden-
tify all studies that investigated the effectiveness of the bun-
dle approach on the prevention of mortality in ICU patients.
The literature search strategy was conducted through elec-
tronic databases, including PubMed, Scopus, Web of Science,
Cochrane Library. In addition, the reference lists from all
retrieved publications were checked to detect additional unrec-
ognized published studies.
We have used text words as well as medical subject head-
ing terms, for example, “ventilator bundle,” “ICU,” “mortal-
ity.” These terms and their variants have been used in several
combinations (Supplemental Table 1, Supplemental Digital
Content 1, http://links.lww.com/CCM/D461).
Two reviewers independently screened the titles and
abstracts of the citations obtained from the search to assess the
eligibility for inclusion in the meta-analysis. Consensus was
reached by discussion if initial assessments differed.
Eligible study designs were randomized controlled trials
(RCTs), quasi-randomized controlled trials (i.e., experimental
studies in which participants are prospectively allocated using
a method that is not random), controlled before-after studies
(i.e., studies in which observations are made before and after
the implementation of an intervention, both in a group that
receives an intervention and in a control group that does not,
with at least two intervention and two control sites), and inter-
rupted time series (i.e., studies that used observations at mul-
tiple time points before and after an intervention, with at least
three data points available before and after the intervention),
complying with the guidelines from the Effective Practice
and Organization of Care (EPOC) Review group (17). Also,
the following additional nonrandomized intervention studies
not adhering to EPOC standards were eligible for inclusion:
1168 www.ccmjournal.org
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
controlled before-and-after studies with less than two inter-
vention and/or control sites, uncontrolled before-and-after
studies, and interrupted time series studies with less than three
data points before and after a clear intervention point.
Included studies also had to make reference to a ventilator
bundle, assess mortality in adults requiring mechanical ven-
tilation in ICU (overall mortality, in-hospital and/or ICU-
mortality, and/or VAP-related mortality), report enough data
to estimate the relative risk or odds ratio (OR) for mortality.
All potentially eligible studies were considered for review,
limited to English, French, German, Spanish, and Portuguese
languages. Studies that examined the implementation of the
ventilator bundle approach in PICU or neonatal ICU or that
evaluated the effectiveness of the bundle interventions for pre-
vention of other HAIs were excluded.
To appraise the quality of the research included in the meta-
analysis, each study was read and scored by two independent
investigators, who were blinded to authors, institutions, coun-
try, and journal for the purpose of decreasing the detection bias.
The Cochrane study quality assessment tool (18) was identified
to assess RCTs quality, and the Downs and Black scale to assess
nonrandomized intervention studies quality (19). Consensus
was reached by discussion if initial assessments differed.
Data Analysis
Two reviewers independently examined the article and
extracted for each study the following items: study character-
istics (authors, year of publication, objective, geographic set-
ting, type of ICU, design); description of the bundle approach;
number of patients in the comparison groups; hospital/ICU
mortality; VAP-related mortality; VAP occurrence rate; length
of stay (LOS) in ICU and in hospital; duration of mechanical
ventilation; days of antibiotic therapy; assessment of compli-
ance to ventilator bundle and its score, according to IHI cri-
teria (4); and strategies for the implementation of the bundle
categorized using the taxonomy developed by EPOC, includ-
ing educational activities (e.g., educational meetings, semi-
nars, workshops, teaching sessions), audit and feedback, and
reminders (e.g., checklists with bundle elements, daily goal
sheets, insertion, charts) (20).
Differences between reviewers were resolved by discussion
with consultation of the third reviewer when necessary.
The effectiveness of a ventilator bundle implementation
to reduce mortality in ICU patients was estimated in several
meta-analyses by combining the values from the single studies
and was expressed as OR and its related 95% CI.
OR and 95% CIs were obtained using the random effect model
by DerSimonian and Laird (21), to incorporate heterogeneity
within and between studies. The method by Mantel-Haenszel
(22) (fixed effects model) was also used when heterogeneity
was less than 25%. Heterogeneity among studies was calculated
using the Cochrane Q test and the inconsistency index (I2) (23).
Heterogeneity was classified as low (25–50%), moderate (50–
75%), or high (> 75%), on the basis of an I2 statistic (24).
In order to investigate eventual causes of observed heteroge-
neity and robustness of results, separate sensitivity analyses were
July 2018 • Volume 46 • Number 7

planned by pooling studies with similar characteristics, such as
implementation of evidence-based practices for VAP prevention
at baseline, presence of an education program, characteristics of
bundle components, compliance, and quality score. We also per-
formed a univariate meta-regression to assess the role of compli-
ance to the ventilator bundle on mortality reduction.
Finally, the presence of publication bias was assessed by
Egger’s test (25) and Begg’s rank correlation test (26). All sta-
tistical analyses were performed using Stata software, Version
14 (Stata Corporation, College Station, TX).
The reporting of study’s findings was in accordance with
the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) statement (27). The research proto-
col was registered on the International prospective register of
systematic reviews (CRD42017054268).
RESULTS
Two-hundred forty-seven citations were identified through
research in electronic database and scanning reference lists.
One-hundred ninety-six publications were reviewed as
potentially relevant, and, after examining the studies, 94 were
Figure 1. Flow chart of the included studies in the meta-analysis. IHI = Institute for Health Improvement, VAP = ventilator-associated pneumonia.
Critical Care Medicine
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Review Articles
considered eligible for inclusion. Of these, 13 articles (5–11,
28–33) met all inclusion criteria and were available for the
meta-analysis. A flow chart summarizes and shows the reasons
of exclusion of the other studies (Fig. 1). Supplemental Table 2
(Supplemental Digital Content 2, http://links.lww.com/CCM/
D462) describes the principal features and information of the
included studies.
The studies were undertaken between 2005 and 2017, six in
Europe (5, 9, 11, 28, 31, 32), six in United States (6–8, 10, 30, 33),
and one in Brazil (29). According to the Cochrane Handbook
for Systematic Interventions (34), they were classified as
uncontrolled before-after studies, except two (29, 32) that
were interrupted time series studies. Investigated ICUs were
heterogeneous, and in two studies (7, 30), trauma ICUs were
involved. Number of patients ranged from 85 to 1,527 in the
preintervention group and from 89 to 1,534 in the postint-
ervention group. Although none of the studies was designed
to investigate mortality in ventilated patients, data on ICU or
in-hospital mortality could be retrieved in all but one study
(29), and in four studies (5, 6, 11, 29), VAP-related mortality
was available.
www.ccmjournal.org 1169
Pileggi et al
In six studies (8, 11, 28, 31–33), no mention of evidence-
based procedures for VAP prevention was reported at baseline,
and their implementation was made during the study period,
whereas in seven studies (5–7, 9, 10, 29, 30), evidence-based
practices for VAP prevention were already performed at base-
line, and a subsequent active implementation of a ventilator
bundle was made (Supplemental Table 2, Supplemental Digital
Content 2, http://links.lww.com/CCM/D462).
Bundle components chosen for the intervention were very
different among studies, both quantitatively, ranging from
three to six components, and qualitatively, and in five stud-
ies (7, 9, 10, 28, 32), no mention of IHI ventilator bundle
was found. A matrix identifying which components of the
ventilator bundle were implemented in each study is shown
in Supplemental Table 3 (Supplemental Digital Content 3,
http://links.lww.com/CCM/D463).
As described in Supplemental Table 4 (Supplemental
Digital Content 4, http://links.lww.com/CCM/D464), the
mean duration of mechanical ventilation was reported in
six studies (6, 7, 10, 11, 28, 32), as well as the mean ICU LOS
(6, 7, 10, 11, 28, 30), hospital LOS was reported in three stud-
ies (6, 10, 30), VAP occurrence rate was reported in 11 studies
(5–11, 29–32), and the mean antimicrobial days in one study (6).
In nine studies (5–9, 11, 29, 31, 32), the intervention of the
ventilator bundle was accompanied by educational activities,
Figure 2. Forest plot of the association of implementation of a ventilator bundle and mortality. OR = odds ratio, VAP = ventilator-associated pneumonia.
1170 www.ccmjournal.org
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
whereas four studies (10, 28, 30, 33) used audit and feedback and
reminders as strategies for the implementation of the bundle.
Compliance was assessed in all but one study (33) ranging,
after the intervention implementation, from 20% to 99.8%.
The OR for mortality in ICU varied from 0.76 to 1.30, but
only in one study (31), the postintervention mortality was sig-
nificantly reduced (OR, 0.80; 95% CI, 0.66–0.98).
Quality assessment of the included studies was made using
the Downs and Black scale scoring system, as they were all non-
randomized intervention studies. The quality scores ranged
from 13/28 to 20/28, with a median of 18/28, and studies were
all classified as of poor quality.
Quality of reporting was similar among almost all studies
because the aim of the studies, the main outcomes, and the
characteristics of patients were often clearly described. Internal
validity scores were low because the presence of educational
interventions precluded blinding to the intervention and/or
blinding of researchers was not achieved. Only one study (33)
had a statistical power calculation.
The results of the meta-analysis that compared mortality
among ICU patients with the implementation of ventilator
bundle approach are shown in Figure 2.
On average, the implementation of a ventilator bundle sig-
nificantly reduced mortality; the pooled OR when comparing the
group with the implementation of the bundle with the control
July 2018 • Volume 46 • Number 7
 Review Articles

group was 0.90 (95% CI, 0.84–0.97), with low observed hetero-
geneity (p = 0.304; I2 = 14%) (Fig. 2A). The analysis restricted to
studies that reported mortality in VAP patients showed a stronger
effect (OR, 0.71; 95% CI, 0.52–0.97) (Fig. 2B).
To examine the stability of the overall results, we carried out
sensitivity analyses that substantially confirmed the primary
meta-analysis (Table 1).
When we restricted the analysis to only studies in which no
mention of evidence-based practices for VAP prevention was
present at baseline, the pooled OR was 0.86 (95% CI, 0.76–
0.96), with low observed heterogeneity (p = 0.24; I2 = 25.4%),
whereas there was no more a significant reduction of mortality
in the restricted analysis to studies in which evidence-based
practices for VAP prevention were already performed at base-
line (OR, 0.94; 95% CI, 0.85–1.03).
Indeed, when we restricted the analysis to the studies that
provided educational activities to healthcare workers, there
was still a significant reduction of mortality after bundle
implementation (OR, 0.89; 95% CI, 0.80–0.99), whereas this
was no more significant in the meta-analysis involving stud-
ies that provided other strategies for the implementation of
bundle (OR, 0.88; 95% CI, 0.73–1.05).
A significant role of high compliance on reduction of mor-
tality was highlighted in the pooled analysis of studies in which

TABLE 1. Sensitivity Analysis Results on Ventilator Bundle Effectiveness in the Prevention

of Mortality Among ICU Patients
Sensitivity Analysis

No. of No. of Heterogeneity

Variables Studies Patients Overall OR 95% CI Test (p; I2,%)

Implementation of evidence-based procedures

at baseline
No 6 5,575 0.86 0.76–0.96 0.24; 25.4
Yes 7 6,241 0.94 0.85–1.03 0.4; 3.9
Strategies for the implementation
Educational activities 9 9,528 0.89 0.8–0.99 0.16; 32.2
Others (audit and feedback, reminders) 4 2,288 0.88 0.73–1.05 0.57; 0
Compliance to bundle program (all studies)a
< 70 % 5 3,740 0.9 0.76–1.07 0.2; 34
≥ 70 % 7 7,689 0.92 0.84–1 0.31; 15.7
Compliance to bundle program (studies with no
implementation of evidence-based procedures
at baseline)
 < 70 % 2 2,297 0.95 0.78–1.16 0.04; 75.7
≥ 70 %
  3 2,891 0.82 0.7–0.96 0.81; 0
Compliance to bundle program (studies with implementation
of evidence-based procedures at baseline)
< 70 % 2 863 0.81 0.64–1.02 0.45; 0
≥ 70 % 5 5,378 0.97 0.87–1.07 0.41; 0
Bundle components
All components 4 3,664 0.98 0.88–1.09 0.28; 21.4
Others 9 8,152 0.85 0.77–0.94 0.5; 0
All the following: deep venous thrombosis prophylaxis- 3 2,089 0.98 0.82–1.17 0.26; 25.3
EHB-peptic ulcer disease prophylaxis-SV
Others 10 9,727 0.89 0.82–0.96 0.36; 9.4
All the following: EHB, daily assessment of 7 7,168 0.87 0.77–0.99 0.18; 32
readiness to extubate, daily oral care, SV
Others 6 4,648 0.9 0.79–1.03 0.4; 2.4
EHB = elevation of the head of the bed, OR = odds ratio, SV = sedation vacation.
Compliance to bundle program was calculated according to Institute for Health Improvement criteria when it was not already reported by the author.
a

Critical Care Medicine www.ccmjournal.org 1171

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Pileggi et al
no mention of a ventilator bundle was reported at baseline
(OR, 0.82; 95% CI, 0.70–0.96) (Table 1), whereas no signifi-
cant role of compliance could be evidenced when we examined
all included studies, since there was no significant mortality
reduction both in the analysis restricted to high (OR, 0.92;
95% CI, 0.84–1.00) and low compliance studies (OR, 0.90;
95% CI, 0.76–1.07) (Supplemental Table 5, Supplemental
Digital Content 5, http://links.lww.com/CCM/D465).
The role of care procedures within the ventilator bundle
(EHB, daily assessment of readiness to extubate, daily oral care,
SV) showed to be significantly related to a lower risk of mortal-
ity (OR, 0.87; 95% CI, 0.77–0.99).
Funnel plots showed no significant asymmetry for studies
exploring the effectiveness of the ventilator bundle on the pre-
vention of mortality (p = 0.393 by the Begg and Mazumdar
(26) adjusted rank correlation test; p = 0.409 by Egger et al (25)
regression asymmetry test).
In order to bolster our primary finding, when we assessed
the effectiveness of the ventilator bundle on other outcomes,
its implementation has confirmed to be significantly related
to the reduction of the occurrence of VAP (OR, 0.54; 95% CI,
0.49–0.59), the patients’ ICU LOS (standardized mean dif-
ference [SMD], –0.17; 95% CI, –0.21 to –0.12), hospital LOS
(SMD, –0.12; 95% CI, –0.18 to –0.6), and the duration of
mechanical ventilation (SMD, –0.18; 95% CI, –0.23 to –0.13)
(Supplemental Fig. 1, Supplemental Digital Content 6, http://
links.lww.com/CCM/D466).
DISCUSSION
To the best of our knowledge, this is the first meta-analysis
demonstrating a significant reduction of overall mortality and
of VAP-related mortality in ICU-ventilated patients after real-
world implementation of the ventilator bundle.
This result is strengthened by the overall stability of results
in all sensitivity analyses performed according to bundle com-
ponents included in the implementation programs, compli-
ance, and eventual education programs.
Several systematic reviews and meta-analyses have dem-
onstrated the effectiveness of single components (15, 16) or
of the overall ventilator bundle (35, 36) on VAP prevention in
ICU patients, whereas in none of them, ventilator bundle was
able to reduce mortality. Most of the studies on single compo-
nents were randomized trials (37–39), while ventilator bundle
effectiveness has been mostly investigated in implementation
studies, aiming to translate evidence-based findings into real-
world delivered healthcare. These controversial results have
questioned the opportunity to consider VAP as a quality-of-
care indicator for ICU patients (40), stimulating the introduc-
tion of the new CDC VAE definition (13) and advocating the
need for randomized clinical trials to investigate the effective-
ness of the single ventilator bundle components on these new
outcomes and on mortality (41). However, it is well known
that bundles have been widely accepted among the safety inter-
ventions practices in ICUs. In these cases, it is very difficult to
randomize patients to the arm not receiving the routinely used
1172 www.ccmjournal.org
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
practice. Furthermore, a recently published large retrospective
cohort study found that at least three of five components of the
ventilator bundle were effective on VAE (42).
Our meta-analysis has allowed overcoming this issue, since
the outcome we chose, mortality, is not definition dependent.
Furthermore, it is worth noting that none of the included stud-
ies had been specifically designed to evaluate the effect of ven-
tilator bundle on mortality, and none except one study had
found a significant effect, since they were probably underpow-
ered for this aim. Therefore, our study once more highlights the
fundamental role of meta-analysis in the detection of the effects
of interventions on the so called “hard” outcomes, such as mor-
tality, that do not pose any problem as regard to subjectivity of
case definition but need very large samples to detect significant
differences of effects between intervention and control groups.
The extent of mortality reduction is not very large, but
when the outcome is so important, even small reductions may
be of great interest in the evaluation of ICU performance.
Furthermore, mortality in ICU is only partially attributable to
mechanical ventilation, since severe conditions of ICU patients
are frequently related to the underlying disease; indeed, in two
of the included studies performed in trauma ICUs, the absence
of an effect on mortality after ventilator bundle implementa-
tion was explained by the high incidence of severe traumatic
brain injuries and exsanguination that were the main causes of
mortality (7, 30).
Although the bundle approach has already shown to be use-
ful in the improvement of selected clinical outcomes (43–45),
it crucially depends on the level of compliance to the bundle
procedures, with IHI recommending 95% compliance calcu-
lated through the “all or nothing” measurement (4). However,
it should be noted that extrapolating data on compliance from
the included studies was not straightforward, and, in some
instances, it was not possible to deduct how compliance was
calculated. This could partly explain the difficulty of our meta-
analysis to find a major role of higher compliance with bundle
effectiveness in reducing mortality. Indeed, only the analysis
restricted to studies in which no mention of ventilator bundle
at baseline was reported highlighted a significant role of high
compliance on the reduction of mortality, whereas no other sen-
sitivity analyses showed a significant role of higher compliance.
It is reasonable to assume that the performance monitor-
ing mode could be one of the several factors that influenced
compliance rates. Checklist is a useful tool to ensure that all
care team members provide the evidence-based intervention
for every patient, and it has been widely used in the manage-
ment of patients undergoing mechanical ventilation. In this
complex process of care, a lot of checklists were created (e.g.,
diagnosis checklist, treatment checklist, monitoring check-
list) (46). Although the use of checklists is promising in the
improvement of safety of care, it is possible that if they are too
many, clinicians tend to underuse them (46). Therefore, there
may be a discrepancy between the actual provided care and
that reported by the checklists, with a consequent reduction in
compliance assessment, whereas the correct processes of care
have actually been performed.
July 2018 • Volume 46 • Number 7

According to a recent systematic review aimed at the assess-
ment of the best strategy to implement care bundles in ICUs
(47), mortality rate decrease was more pronounced in studies
using educational activities, independently of the single imple-
mented procedures. Therefore, the introduction or the modi-
fication of evidence-based procedures in the clinical setting
should always be supported by continuous quality-improve-
ment interventions that possibly include active and multifac-
eted education programs, as we found in this meta-analysis.
The results of this meta-analysis should be viewed within
certain limitations. First, almost all included studies were
before-and-after interventions. This study design is prone to
bias, since it may not be excluded that postintervention results
are the consequence of changes in the outcome influenced
by secular trends (48). However, comparisons of ventilated
patients’ mortality at baseline yielded similar findings across the
studies included in the meta-analysis and conducted between
2005 and 2017. In particular, the mortality rate among the ear-
lier studies, performed from 2005 to 2009, ranged from 21% to
30%, and in more recent studies, completed between 2013 and
2017, it ranged from 23% to 32%. Indeed, there seems to be no
substantial secular improvement of mortality at baseline over
time and no evidence for changes in practice and outcomes
resulting from other contemporaneous quality-improvement
efforts; therefore, these considerations lend indirect support
to the hypothesis that the mortality decline may be related to
ventilator bundle implementation. Another factor influencing
the decrease in mortality could be the change in the case-mix
of ventilated patients. Furthermore, most studies provided
statistical analysis to adjust for changes in patient mix and to
offer insight into the pace of change. No significant differences
in the underlying conditions and situation of the populations
in either period in most of the included studies were detected
although, in some cases, there was an insufficient statistical
power to determine if both groups were comparable. Also,
before-and-after studies were designed without concurrent
controls. However, since components of the ventilator bundle
are widely spread in the clinical practice and are included in the
guidelines to perform in ventilated patients (4), it could appear
unethical to have control patients who do not receive these pro-
cedures (35). Furthermore, a recently published meta-analysis
investigating the role of quality-improvement interventions
on the prevention of central catheter–associated blood stream
infections underlined the role of before-after studies to iden-
tify the effect of strategies such as bundles and checklists in the
translation of evidence-based practices in the clinical settings
(49). Second, there were differences among studies in the num-
ber and types of procedures included in the intervention, and
in some of them, no mention of bundle was found. Therefore,
particularly for the studies that implemented additional com-
ponents outside the IHI ventilator bundle definition, it appears
difficult to assess to what extent the outcome is attributable to
the bundle or to the other preventive measures. Third, as for
all meta-analysis, the results rely on the quality of the underly-
ing included studies, and it is well known that implementation
Critical Care Medicine
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Review Articles
and quality-improvement studies are challenging as regard to
design and reporting (50). However, since in certain situations
they are the only way to assess real-world effectiveness of inter-
ventions, relying on robust study designs and standardized
study reporting represents an imperative scientific challenge
for implementation science.
The strengths of the present meta-analysis include the
extensive search strategy that allowed including studies with-
out strict language restriction; furthermore, heterogeneity was
not an issue in this meta-analysis, and it is well known that
heterogeneity represents one of the major drawbacks of the
meta-analysis, since its presence hampers a straightforward
interpretation of the results. Finally, publication bias was not
detected in our study; indeed, publication bias is generally
caused by the higher likelihood of publication of “positive”
studies compared with “negative” studies, and this could not
be the case of this meta-analysis, since almost all studies did
not report any effect of ventilator bundle on mortality of ICU-
ventilated patients. However, it should be noted that low het-
erogeneity and absence of publication bias are often secondary
to small number of studies and small sample size; therefore,
these results should be interpreted cautiously.
CONCLUSIONS
The results of this meta-analysis support the effectiveness of
the introduction in the clinical practice of evidence-based
procedures organized in a bundle, independently of the single
implemented procedures and also of the educational activities
in the improvement of acute care. Both strategies, implemen-
tation of evidence-based procedures organized in a bundle and
educational activities, are necessary to ensure that ventilated
ICU patients receive the most appropriate care to improve
important outcomes and in particular mortality.
Efforts to find effective methods to enhance adherence to
the best strategies to implement care bundles and applica-
tion of robust study methods in implementation or quality-
improvement research are key areas of further research.
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July 2018 • Volume 46 • Number 7