548

Prevention of Intensive Care Unit-Acquired

Pneumonia
Michael Klompas, MD, MPH1,2

1 Department of Population Medicine, Harvard Medical School and Address for correspondence Michael Klompas, MD, MPH,
Harvard Pilgrim Health Care Institute, Boston, Massachusetts Department of Population Medicine, 401 Park Drive, Suite 401 East,
2 Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215 (e-mail: mklompas@bwh.harvard.edu).
Boston, Massachusetts

Semin Respir Crit Care Med 2019;40:548–557.

Abstract Intensive care unit (ICU) acquired pneumonia is one of the most common and morbid
health care-associated infections. Despite decades of work developing and testing
prevention strategies, ICU-acquired pneumonia remains stubbornly pervasive. Pneu-

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monia prevention studies are difficult to interpret because all are at risk of bias due to
the subjectivity and poor specificity of pneumonia definitions. Interventions associated
Keywords with improvements in objective outcomes in addition to pneumonia, such as length of
► ventilator-associated stay or mortality, should therefore be prioritized. Avoiding intubation, minimizing
pneumonia sedation, implementing early extubation strategies, and mobilizing patients do appear
► ICU-acquired to improve some of these objective outcomes. Many of our other assumptions about
pneumonia how best to prevent ICU-acquired pneumonia, however, have recently been chal-
► spontaneous lenged. Elevating the head of the bed is supported by very little randomized trial data.
breathing trials Early reports suggested that subglottic secretion drainage may decrease time to
► oral care with extubation and ICU length of stay, but more recent analyses refute these findings.
chlorhexidine Novel endotracheal tube cuff designs do not clearly lower pneumonia rates. A large
► subglottic secretion randomized trial of selective digestive decontamination in ICUs with high baseline rates
drainage of antimicrobial resistance did not identify any benefit. Oral care with chlorhexidine
► stress ulcer may increase mortality risk and stress ulcer prophylaxis may facilitate pneumonia. Early
prophylaxis data on probiotics suggest a possible effect but there is no clear signal yet that they
► endotracheal tube shorten duration of mechanical ventilation or lower mortality. Ventilator bundles on
cuff design balance do appear to be beneficial but it is not clear which components are most
► selective digestive important nor how best to implement them. This article will review recent studies that
decontamination have challenged, refined, or complicated our understanding of how best to prevent
► probiotics ICU-acquired pneumonia.

Pneumonia is the most common and morbid hospital-acquired
infection.1 It is associated with a crude mortality rate of
approximately 30%, an attributable mortality rate of 8 to
12%, and prolongs hospital length of stay by approximately
6 days.2–4 Hospital-acquired pneumonia extends length of stay
more than hospital-acquired bloodstream infections and
urinary tract infections and is associated with more years of
life lost and years of disability than any other health care-
associated infection.5,6 Most pneumonia surveillance and
prevention studies to date have focused on patients on
mechanical ventilation. There is increasing appreciation, how-
ever, that nonventilated patients are also at high risk for
nosocomial pneumonia.7 The absolute risk of nosocomial
pneumonia is substantially lower for nonventilated patients

Issue Theme Serious Infections in the
ICU: Evolving Concepts in Management
and Prevention; Guest Editors: Jean
Chastre, MD, Charles-Edouard Luyt, MD,
PhD, and Michel Wolff, MD
Copyright © 2019 by Thieme Medical DOI https://doi.org/
Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1695783.
New York, NY 10001, USA. ISSN 1069-3424.
Tel: +1(212) 584-4662.

than ventilated patients (1–2 vs. 5–10%) but the adjusted
mortality rate for nonventilator hospital-acquired pneumonia
(NV-HAP) is equal to or greater than the mortality rate for
ventilator-associated pneumonia (VAP)8,9 and nonventilated
patients account for numerically more cases of nosocomial
pneumonia at the hospital level by virtue of their greater
numbers.1,10
The frequency and morbidity of pneumonia in the ICU
compel providers to implement robust prevention plans. Our
knowledge of how best to prevent nosocomial pneumonia,
however, is patchy and incomplete. Some of our bedrock
assumptions about how best to prevent pneumonia have
been recently been challenged (e.g., oral care with chlorhex-
idine), the evidence base for some widely practiced inter-
ventions remains surprisingly sparse (e.g., head of bed
elevation), one persistent component of many hospitals’
bundles may facilitate pneumonia (e.g., stress ulcer prophy-
laxis), our most powerful potential prevention strategy
remains mired in controversy despite multiple high-quality
trials (i.e., selective digestive decontamination), and rigorous
studies of some very promising interventions have failed to
include pneumonia as an outcome (e.g., minimizing sedation
and spontaneous awakening and breathing trials).
The problem is compounded by the ongoing difficulty the
field faces with accurately identifying pneumonia since the lack
of a sensitive and specific definition exposes all prevention trials
to risk of bias and complicates their interpretation.11–15 This is
true of prospective cohort studies (including before–after and
time-series analyses of ventilator bundle implementations)
since there is a risk that well-meaning surveyors will subcon-
sciously apply the subjective components of pneumonia defi-
nitions more strictly over time leading to a specious impression
of lower pneumonia rates.16,17 It is also true of double-blinded
randomized controlled trials since most interventions designed
to prevent nosocomial pneumonia work in ways that are
circular with pneumonia definitions: the interventions
decrease the frequency of positive respiratory cultures and/or
volume of respiratory secretions leading to a drop in perceived
pneumonias in the intervention arm of the study; but pneumo-
nia clinical criteria correlate imperfectly with histological
pneumonia18 so the drop in observed pneumonias may not
correspond to a true decrease in invasive pneumonias. Both
these potential sources of error allow for the possibility that
investigators can report dramatic decreases in pneumonia rates
that may in fact be spurious.19
One practical solution to the measurement dilemma is to
evaluate the impact of pneumonia prevention strategies on
objective outcomes that are less susceptible to measurement
bias in addition to pneumonia rates.20 These can include
duration of mechanical ventilation, ICU length of stay, antibi-
otic utilization, ventilator-associated events, costs, and mor-
tality. A salutary effect on one or more objective outcomes in
addition to lower pneumonia rates provides corollary evidence
that an intervention is beneficial for patients and that the
observed reduction in pneumonia corresponds to a true
decrease in serious disease.
This review will focus on selected pneumonia prevention
strategies where recent studies have helped modify, and in
Prevention of ICU-Acquired Pneumonia Klompas 549
some cases overturn longstanding beliefs about how best to
prevent pneumonia (►Table 1). In many cases, these studies
have added more nuance and ambiguity than clarity about
how best to prevent pneumonia in critically ill patients.
Avoiding Intubation and Minimizing
Duration of Mechanical Ventilation
Invasive mechanical ventilation is the single greatest risk factor
for hospital-acquired pneumonia. Pneumonia occurs 5 to 10
times more frequently in ventilated patients compared with
nonventilated patients.1,8 It stands to reason then that avoiding
invasive ventilation whenever safe and feasible to do so should
lower ICU-acquired pneumonia rates. There are three primary
strategies for minimizing exposure to invasive mechanical
ventilation: high flow oxygen without intubation for patients
with hypoxemic respiratory failure, noninvasive mechanical
ventilation for patients with hypercapnic respiratory failure,
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and spontaneous breathing trials to identify the earliest possi-
ble moment when patients are likely to tolerate extubation.
High flow oxygen via nasal cannula versus invasive mechanical
ventilation was associated with lower mortality and a trend
toward less nosocomial pneumonia in one prominent study,21
but a subsequent meta-analysis only found nonsignificant
trends toward lower mortality rates and less intubation.22
Initial use of noninvasive ventilation has been associated with
lower pneumonia and lower mortality rates when used in
suitable populations, particularly patients with chronic obstruc-
tive lung disease exacerbations.23–25 Early liberation from
invasive mechanical ventilation by extubating to noninvasive
mechanical ventilation also appears beneficial in reducing total
exposure to invasive ventilation, preventing ICU-acquired
pneumonia and shortening length of stay, but is not associated
with lower mortality rates.26,27 Finally, spontaneous breathing
trials have long been associated with shortening duration of
mechanical ventilation, fewer ventilator-associated events, and
perhaps with lower mortality rates, particularly when per-
formed in conjunction with sedative interruptions.28–31
Minimizing Sedation and Early Mobilization
Deep sedation has repeatedly been associated with a higher risk
for pneumonia, prolonged mechanical ventilation, delirium,
and death.32–34 Amongst 703 patients admitted to 42 ICUs, for
example, there was a stepwise association between depth of
sedation and more time to extubation, more delirium, and
higher 180-day mortality risk.35 Similarly, immobility may lead
to deconditioning, atelectasis, difficulty clearing secretions,
and pneumonia.36 While most observational studies do adjust
for patients’ presenting conditions and severity of illness, it is
difficult to disentangle the specific effects of sedation and
immobility versus underlying disease on the ultimate risk of
pneumonia, duration of mechanical ventilation, and mortality
in observational analyses. It is therefore critical to evaluate the
results of active intervention studies designed to reduce seda-
tion and encourage mobilization to understand the true mag-
nitude of their potential impact on nosocomial pneumonia,
duration of ventilation, and mortality. Intervention studies not
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019
550 Prevention of ICU-Acquired Pneumonia Klompas

Table 1 Potential measures to prevent ICU-acquired pneumonia and their impact on objective outcomes

Intervention ICU Ventilator- Days of ICU or Mortality

acquired associated invasive hospital
pneumonia events mechanical length
ventilation of stay
High flow oxygen via nasal cannula21,22 ↓ or $ Unknown ↓ $ ↓ or $
23–25
NIPPV to avoid intubation in suitable patients ↓ Unknown ↓ ↓ ↓
NIPPV to speed extubation26,27 ↓ Unknown ↓ ↓ $
28–31
Spontaneous breathing trials ↓ or $ ↓ ↓ ↓ ↓ or $
37–39
Minimizing sedation (SAT or sedation protocols) ↓ or $ ↓ ↓ ↓ $
39,40
Early mobility ↓ or $ Unknown ↓ $ $
Head of bed elevation49 ↓ Unknown $ $ $
55,60
Conical (tapered) endotracheal tube cuffs $ $ $ $ $
58,59,111
Ultrathin polyurethane endotracheal tube cuff ↓ or $ Unknown $ $ $
Frequent or automated cuff pressure monitoring61,62 ↓ or $ $ $ $ $

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69,112
Subglottic secretion drainage ↓ $ $ $ $
72,73,80,82,83
Selective digestive decontamination ↓ Unknown $ ↓ ↓a
Oral care with chlorhexidine31,73,85–88 $ " or $ $ $ " or $
31,96,101
Stress ulcer prophylaxis " or $ " or $ $ $ $
102
Probiotics ↓ Unknown $ $ $

Abbreviations: ICU, intensive care unit; NIPPV, non-invasive positive pressure ventilation; SAT, spontaneous awakening trials.
a
For regimens that include parenteral antibiotics in settings with low baseline rates of antibiotic resistance.

only assess the impact of these strategies on patient outcomes,
but also lend insight into the practical feasibility of limiting
sedation or mobilizing critically ill patients.
Reassuringly, the balance of studies suggests that protocols
to limit sedation and mobilize patients are associated with less
time to extubation, more hospital-free days, and possibly with
lower VAP rates.37–40 There is no clear mortality signal in
randomized trials of sedation or mobility protocols, but some
implementation studies have reported lower mortality rates,
particularly with high adherence to integrated sedation and
mobility bundles (although these observations are at risk of
confounding as high bundle performance rates may be more
feasible in less ill patients).39–43
One challenge in applying the evolving literature on seda-
tion, mobility, and liberation from mechanical ventilation is
that most studies of these interventions do not include HAP,
VAP, or ventilator-associated events amongst their outcomes.
This limits our capacity to directly relate lighter sedation and
higher mobility to lower pneumonia rates. Nonetheless, the
ultimate purpose in implementing prevention practices in the
ICU is not to prevent VAP, HAP, or ventilator-associated events
per se but to improve patient-centered outcomes. The empha-
sis then of sedation and mobility studies on time to extubation,
ICU discharge, survivors’ quality of life, and short- and long-
term mortality is informative even in the absence of specific
data on pneumonia.
Elevating the Head of the Bed
Elevating the head of the bed is the most widely practiced
pneumonia prevention strategy in the United States and much
of the world.44 Over 98% of US hospitals report routinely
elevating the head of the bed of patients on mechanical
ventilation to prevent VAP.45 Notwithstanding widespread
adoption of this practice, the evidence associating head-of-
bed elevation with better outcomes is surprisingly sparse. Only
three randomized controlled trials have been published in the
English language literature.46–48 The first trial only included 86
patients but reported significantly fewer VAPs in patients
randomized to head-of-bed elevation (8 vs. 34%).46
The second trial only included 30 patients and found numeri-
cally fewer VAPs in the intervention group but the effect was
not statistically significant.48 The third and most rigorous study
to date included 221 patients and found no difference in VAP
rates between patients randomized to 45 degrees head-of-bed
elevation versus 10 degrees.47 Importantly, this study included
continuous measures of backrest elevation and reported that
the ICU team had difficulty in both achieving and maintaining
the target backrest elevation position: initial average backrest
elevation in the intervention group was 28 degrees and de-
creased to 23 degrees by day 7. While this may account for this
study’s lack of impact on VAP rates, it also attests to the practical
difficulties ICUs face with achieving reliable backrest elevation.
Of note, none of the three studies reported any differences
in corollary outcomes such as duration of mechanical venti-
lation, ICU length of stay, or mortality.46–48 Chinese inves-
tigators subsequently published a Cochrane review that
included these three studies plus five additional randomized
trials from the Chinese language literature.49 Even with these
additional studies, however, there were only 739 patients
available for evaluation. On meta-analysis amongst these
patients, backrest elevation was associated with a significant

Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019


drop in VAP incidence (14 vs. 40%, risk ratio [RR]: 0.36; 95%
confidence interval [CI]: 0.25–0.50). Only a subset of the
studies in the meta-analysis included data on other out-
comes: collectively they found no significant differences in
ICU length of stay or mortality (3 studies, 346 patients).49
Notably, some investigators have challenged the notion
that elevating the head of the bed is the best way to prevent
VAP.50 Li Bassi and colleagues hypothesized that the lateral
Trendelenburg position may be a more effective station to
prevent VAP since this position uses gravity to draw orogas-
tric secretions in the upper aerodigestive tract away from the
lungs rather than facilitating their entry into the lungs.51
They tested this hypothesis by randomizing 401 patients to
the lateral Trendelenburg position versus the semirecum-
bent position.52 Patients randomized to the lateral Trende-
lenburg position did indeed develop fewer microbiologically
confirmed VAPs (0.5 vs. 4.0%) but the trial was stopped early
because of a higher rate of serious adverse events amongst
patients randomized to the lateral Trendelenburg position
including oxygen desaturation, severe hypotension, sus-
tained bradycardia, extubation, intracranial hemorrhage,
and brachial plexus injury.
Despite the lack of robust data supporting the semirecum-
bent position, practitioners are still advised to elevate the head
of the bed whenever safe and feasible to do so. This is because
of observational data showing a strong association between
the supine position and VAP particularly in patients receiving
enteral nutrition, radiolabeling and orogastric biomarker
studies documenting that ventilated patients routinely aspi-
rate oropharyngeal and gastric secretions, and observational
studies of ventilator bundle components suggesting that head-
of-bed elevation may indeed be associated with shortening
duration of mechanical ventilation.31,46,53–55 All told this
intervention is already ubiquitous in practice, inexpensive,
possibly helpful, and unlikely to be harmful for most
patients.20
Endotracheal Tube Cuff Design and Pressure
Monitoring
Investigators have proposed several innovations in endotra-
cheal tube cuff materials, shape, and design to prevent
VAP.56,57 Conventional polyvinyl chloride cylindrical endotra-
cheal tube cuffs conform imperfectly to the shape of the
trachea; they develop vertical microfolds that create passage-
ways that can allow microbe-laden secretions above the cuff to
flow across the cuff and into the lungs. Innovators have tried to
block this pathway to aspiration by switching to ultrathin cuff
materials such as polyurethane, changing the shape of the cuff
from a cylinder to a cone, and by monitoring and adjusting cuff
pressures more frequently and/or consistently using either
manual or automated methods. Ultrathin polyurethane better
conforms to the shape of the trachea and thus decreases the
number and size of channels along the tracheal wall.58 Tapered
cuffs are thought to approximate the tracheal wall more evenly
and consistently at the point of maximum cuff diameter
compared with conventional cylindrical cuffs. And more con-
sistent cuff pressure monitoring is intended to protect against
Prevention of ICU-Acquired Pneumonia Klompas 551
unappreciated drops in cuff pressure that could facilitate
increased passage of secretions around the cuff.
Unfortunately, none of these innovations have thus far
been proven to prevent VAP or improve objective patient
outcomes. Philippart and colleagues randomized 621
patients expected to require >2 days of mechanical ventila-
tion to four groups: cylindrical polyvinyl chloride cuffs,
cylindrical polyurethane cuffs, conical polyvinyl chloride
cuffs, and conical polyurethane cuffs.59 They found no differ-
ence between any of the four groups in tracheal colonization
or VAP rates. Similarly, Jaillette and colleagues randomized
326 patients to endotracheal tubes with conical versus
cylindrical cuffs.55 They documented microaspiration
rates of over 50% in both groups regardless of cuff shape
by assaying tracheal aspirates for pepsin and α-amylase
(proxies for gastric and oropharyngeal secretions, respec-
tively). They found no difference between groups in VAP,
ventilator-associated events, mechanical ventilation-free
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days, antibiotic-free days, ICU length of stay, or ICU mortality.
Maertens and colleagues further evaluated tapered versus
conventional cuffs by combining these two trials with
four others (total 1,324 patients).60 On meta-analysis, they
found no difference between cuff shapes in the frequency of
hospital-acquired pneumonia nor any signals in the individ-
ual studies suggesting differences in duration of mechanical
ventilation (three trials), ICU length of stay (four trials), or
mortality (three trials). There is a paucity of additional
studies on polyurethane cuffs that include data on clinical
outcomes, but for the present at least there is no clear signal
of clinical benefit.58
Recent studies on endotracheal tube cuff pressure moni-
toring frequency and method have also failed to suggest clear
benefits. Letvin and colleagues quasi-randomized 305
patients to frequent manual cuff pressure checks (and infla-
tion adjustment if needed) versus infrequent checks.61 Both
groups of patients had their cuff pressures checked immedi-
ately following intubation. Patients allocated to frequent
checks subsequently had their cuff pressures re-evaluated
every 8 hours. Patients allocated to infrequent checks were
evaluated for cuff pressure loss only if the tube migrated or if
the patient developed a clinically apparent cuff leak. The
investigators found no difference in ventilator-associated
event rates, hospital length of stay, or 30-day mortality.
Nseir and colleagues, by contrast, conducted a patient
level meta-analysis of three nonblinded randomized studies
comparing automated cuff pressure monitoring systems
versus usual care amongst 543 patients.62 Automated cuff
pressure monitoring was associated with a 53% decrease in
the hazard ratio for VAP, but there was no difference between
groups in duration of mechanical ventilation, ICU length of
stay, duration of antibiotics, or mortality. The discrepancy
between the marked decrease in VAP rates in this analysis
versus the lack of difference in antibiotic prescribing, dura-
tion of mechanical ventilation, or death may simply have
been due to limited power, but the mismatch does under-
score the risk of drawing misleading conclusions about the
effectiveness of VAP prevention strategies when looking at
VAP rates alone as the sole measure of success.
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019
552 Prevention of ICU-Acquired Pneumonia Klompas
Subglottic Secretion Drainage
Subglottic secretion drainage has received a great deal of
attention as a potential strategy to prevent VAP.63 Secretions
pooling above the endotracheal tube cuff create an inflamma-
tory milieu where excess mucin production can impair host
defenses and create a reservoir for pathogenic organisms that
can seep across the endotracheal tube cuff and infect the
lungs.64 Routine or continuous drainage of subglottic secretions
would therefore appear to be an attractive strategy to mitigate
this risk. Multiple studies both in isolation and on meta-analysis
have reported that subglottic secretion drainage may lower VAP
rates by as much as 45%.65–69 The corollary data on objective
outcomes, however, are complicated and contradictory.
Initial meta-analyses reported that subglottic secretion
drainage was associated with a significant decrease in dura-
tion of mechanical ventilation and ICU length of stay in
addition to VAP.65–67 On the basis of these encouraging
corollary outcomes, the Society for Healthcare Epidemiology
of America recommended subglottic secretion drainage as a
basic strategy to prevent VAP in 2014.20 On re-evaluation of
the supporting data, however, the meta-analyses suggesting
significant decreases in duration of mechanical ventilation
and ICU length of stay had high levels of heterogeneity
suggesting large discrepancies in the underlying popula-
tions, methods, or reporting of component studies (indeed,
one key study was abstracted as showing a large decrease in
mean duration of mechanical ventilation,67 whereas the
original trial reported no difference in this outcome70).
When the meta-analysis was updated by excluding ques-
tionable studies and adding some newly published studies,
the positive association between subglottic secretion drain-
age and lower VAP rates remained but there was no longer
any association between subglottic secretion drainage and
improvements in duration of mechanical ventilation, venti-
lator-associated events, ICU length of stay, or mortality.69
Subglottic secretion drainage, like most VAP prevention
initiatives, is at high risk of bias in prevention studies because
removing subglottic secretions can decrease the perceived
volume and frequency of pulmonary secretions and possibly
lower microbial colonization rates. These in turn may lead to
fewer patients in the intervention arm that meet VAP surveil-
lance criteria, but these criteria are not specific for histological
pneumonia so it is possible to see lower rates of perceived
pneumonia that might not correspond to a true decrease in
invasive disease.13,71 The lack of a clear association between
subglottic secretion drainage and objective outcomes suggests
that this intervention should be treated with caution, particu-
larly as there are some downsides to subglottic secretion
drainage tubes including larger external diameters compared
with similar caliber conventional tubes, increased risk for
clogging, and higher cost.
Selective Oral and Digestive
Decontamination
Selective oral and digestive decontamination continues to
vex quality-improvement advocates. On the one hand,
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019
these are amongst the very few prevention strategies in
critical care that are not only associated with lower VAP
rates but have repeatedly been associated with lower
mortality rates in large, rigorous, randomized trials.72–74
On the other hand, antibiotic stewards continue to worry
that widespread use of oral or digestive decontamination
will ultimately lead to higher levels of antibiotic resistance
that will eventually outweigh the short-term mortality
benefit associated with decontamination. Paradoxically,
some studies suggest that digestive decontamination
may be associated with less net antibiotic use and lower
rates of resistant organisms, presumably because decon-
tamination prevents some infections and thus saves some
patients from needing treatment courses of antibiotics.75
And indeed, a few hospitals have reported persistently low
rates of antibiotic-resistant organisms sustained for many
years after implementing selective digestive decontamina-
tion.76–78 Nonetheless, active surveillance for resistant
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pathogens amongst all ICU patients (not just those receiv-
ing digestive or oral decontamination) does suggest that
selective decontamination is associated with small but
significant and sustained increases in the unit-wide preva-
lence of antibiotic-resistant organisms.79,80
Most of the large cluster randomized trials of oral and
digestive decontamination were conducted in the
Netherlands, a country with low prevalence of resistant
organisms and low rates of antibiotic utilization compared
with many other countries; commentators therefore worry
that the effect of digestive decontamination on resistance
rates may be magnified in settings with higher baseline rates
of resistant pathogens and antibiotic utilization. The most
recent European guidelines on the management of HAP and
VAP consequently issued a weak recommendation in favor of
selective oral decontamination alone, not selective digestive
decontamination, and only for settings with low rates of
antibiotic-resistant bacteria and low rates of antibiotic
consumption.81
The recent publication of the R-GNOSIS trial suggests
this recommendation was prescient. The R-GNOSIS
investigators assessed the impact of oral care with 2%
chlorhexidine versus selective oral decontamination versus
selective digestive decontamination on ICU-acquired
bloodstream infections with resistant organisms and 28-
day mortality in a cluster randomized crossover trial
amongst 13 European ICUs with moderate to high rates
of antibiotic resistance at baseline.82 They found no differ-
ences between arms in either bloodstream infections or
28-day mortality.
Importantly, the selective digestive decontamination arm
of the R-GNOSIS trial only included antibiotics administered
via a nasogastric tube to the stomach, but not a course of
parenteral antibiotics. Some analyses have suggested that a
brief course of parenteral antibiotics may be critical to the
success of selective digestive decontamination.83 Thus
despite the completion of yet another large, rigorous cluster
randomized trial, questions about the role of digestive
decontamination in preventing VAP and improving outcomes
for ICU patients persist.

Oral Care with Chlorhexidine
Oral care with chlorhexidine has come under scrutiny in
recent years because of a series of studies associating oral
chlorhexidine with a possible increased risk of mortality and
ventilator-associated events.84 This signal has been noted on
meta-analyses of randomized trials,73,85 observational anal-
yses of associations between ventilator bundle components
and outcomes,31,86,87 and in one hospital-wide observational
analysis of prescribed medications.88 In addition, doubt has
been cast on whether oral care with chlorhexidine truly
prevents VAP. While meta-analyses of randomized trials
have reported that oral care with chlorhexidine lowers VAP
rates by approximately 30%, this signal is only evident in
open-label studies.85 If one restricts the meta-analysis to
double-blind studies, the signal is diminished and no longer
significant (yet another reminder of the risk of bias in VAP
prevention studies and the importance of looking at objec-
tive outcomes for corollary evidence of benefit).85
Despite the array of independent signals suggesting possible
harm, there are important limitations to the existing evidence.
First, no single randomized trial has reported an association
between oral care with chlorhexidine and higher mortality
rates. Second, the meta-analyses that reported a possible
increase in mortality combined studies performed in different
populations with different preparations of chlorhexidine.
Third, all observational studies are at risk of confounding.
Fourth, the hospital-wide analysis suggesting an association
between chlorhexidine and higher mortality rates specifically
did not find this association amongst ventilated patients and
may not have adequately controlled for confounding by indica-
tion insofar as oral chlorhexidine was selectively prescribed for
frail and dependent patients.88 Fifth, the mechanism by which
oral care with chlorhexidine may increase ventilator-associat-
ed events and mortality risk is unclear. Investigators speculate
that it may be because some patients aspirate the antiseptic
which in turn might precipitate acute lung injury and the acute
respiratory distress syndrome; however, none of the random-
ized trials of chlorhexidine have specifically evaluated this
hypothesis.84 Note that the recent publication of a large cluster
randomized trial of different oral decontamination strategies
(the R-GNOSIS trial) failed to resolve the question of oral
chlorhexidine’s safety.82 The trial reported that 6 months of
routine care with 2% oral chlorhexidine was associated with an
adjusted 28-day mortality hazard ratio of 1.13 (95% CI: 0.68–
1.88) compared with baseline care; however, baseline care in
11 of the 13 study ICUs included oral care with 0.12% chlorhex-
idine. Thus the trial provided a comparison of high-concentra-
tion chlorhexidine versus low-concentration chlorhexidine but
not a comparison of oral chlorhexidine versus placebo. The
study did document a high rate of oral mucosal reactions to 2%
oral chlorhexidine but these resolved when the investigators
switched to a 1% chlorhexidine preparation.89
At the end of the day, the data suggesting that oral care
with chlorhexidine may pose a safety risk are far from
certain. At the same time, however, the evidence that oral
care with chlorhexidine prevents VAP is equally tenuous (no
signal in the vast majority of individual trials, no signal on
Prevention of ICU-Acquired Pneumonia Klompas 553
meta-analysis of double-blinded studies).85 Faced with these
two uncertainties, the better part of valor is to follow the
precautionary principal: it is best for now to remove chlor-
hexidine from oral care regimens given the absence of clear
evidence of benefit and the possible suggestion of harm.90
Unfortunately, this recommendation does leave hospitals in a
quandary regarding whether and what to use instead of
chlorhexidine. There is no clear answer to this question since
chlorhexidine is by far the best studied oral antiseptic in
ventilated patients. There are very little data on other oral
antiseptics and some concern that aspiration triggering
acute lung injury could be a class effect for oral antiseptics
rather than an isolated effect of chlorhexidine alone. Indeed,
a randomized trial of one possible alterative (povidone-
iodine) documented higher rates of acute respiratory distress
syndrome in patients randomized to povidone-iodine versus
placebo.91 For the time being, toothbrushing and oral care
with sterile water alone may be the most prudent course
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until more data are available.
Stress Ulcer Prophylaxis
Stress ulcer prophylaxis has long been an integral compo-
nent of ventilator bundles on the rationale that mechani-
cally ventilated patients are at increased risk for
gastrointestinal bleeding (which in turn could lead to
aspiration pneumonitis and pneumonia).92 The net risk
versus benefit of stress ulcer prophylaxis has lately been
called into question. Modern series report much lower
rates of gastrointestinal bleeding compared with historical
patterns and there is increasing appreciation that gastric
acid suppression may be a risk factor for hospital-acquired
pneumonia and Clostridioides difficile infections.93–95
Huang and colleagues conducted a meta-analysis of seven
randomized trials of stress ulcer prophylaxis versus place-
bo in 889 patients and reported significantly higher rates of
hospital-acquired pneumonia in patients receiving stress
ulcer prophylaxis and no difference in gastrointestinal
bleeding rates (or C. difficile rates).96
Renewed interest in determining the necessity and safety
of stress ulcer prophylaxis has catalyzed several randomized
controlled trials comparing different stress ulcer prophylaxis
regimens to one another or to placebo.97–100 Many of these
are still recruiting but one large randomized trial has been
published. Krag and colleagues randomized 3,298 patients in
33 European intensive care units to daily intravenous pan-
toprazole versus placebo.101 Patients randomized to panto-
prazole had a lower rate of clinically notable gastrointestinal
bleeding (2.5 vs. 4.2%) but no difference in the rates of red
blood cell transfusions, pneumonia, C. difficile infections, or
90-day mortality. While this trial somewhat tempers the
concern that stress ulcer prophylaxis may increase the risk of
pneumonia in critically ill patients, it simultaneously failed
to provide clear evidence that stress ulcer prophylaxis
improves objective patient outcomes. The results of the
additional large trials currently underway are eagerly
awaited to shed further light upon risk–benefit balance of
stress ulcer prophylaxis.
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019
554 Prevention of ICU-Acquired Pneumonia Klompas
Probiotics
Probiotics are hypothesized to moderate the microbiome of the
aerodigestive tract, decrease colonization with pathogenic
organisms, and therein protect patients from aspirating the
organisms that lead to hospital-acquired pneumonia. Many
studies have been conducted to test this hypothesis but most
have been small, variably blinded, single-center assess-
ments with discrepant results. A recent meta-analysis of
13 randomized trials with 1,969 adults and children did
report a significant association between probiotics and
lower VAP rates (RR: 0.73; 95% CI: 0.60–0.89) but no
difference in duration of mechanical ventilation, ICU length
of stay, or mortality.102 Notably, the meta-analysis did
report near-significant trends toward lower mortality rates
(RR: 0.84; 95% CI: 0.70–1.02; p ¼ 0.09) and shorter duration
of mechanical ventilation (3.32 days, 95% CI: 6.74 to
þ0.09, p ¼ 0.06) in patients randomized to probiotics, so
future studies may reveal clearer evidence of net benefit.102
There is a large multicenter randomized trial of this inter-
vention underway that may be helpful in this regard.103
Note that there is some risk associated with probiotics. There
are multiple case reports of bloodstream infections with
probiotic strains following exposure to these agents.104–106
Probiotics are therefore contraindicated in patients with
impaired immunity, severe pancreatitis, and short-gut syn-
drome. There have also been reports of airborne transmission of
probiotic strains within intensive care units.107,108
Ventilator Bundles
One bright note is that ventilator bundle implementations do
appear on balance to be beneficial for patients. Many hospitals
have reported lower VAP rates after implementing prevention
bundles.109 These have always been subject to question
because of the difficulty knowing if lower VAP rates in these
before–after or time-series analyses were due to true decreases
in disease versus stricter application of subjective and nonspe-
cific VAP definitions over time.19 A recent meta-analysis,
however, addressed this question by evaluating the association
between bundle implementations and mortality.110 Using data
from 13 hospitals, the authors reported that ventilator bundle
implementations were associated with a 10% decrease in the
odds of death. While the before–after/time-series design of all
the contributing studies still makes it possible that some of the
signal may be due to temporal trends unrelated to bundles,17
this study at least allows for the possibility that our many
efforts to prevent pneumonia in critically ill populations are
proving beneficial. In light of the foregoing analysis of individ-
ual strategies to prevent ICU-acquired pneumonia, it is most
likely that the salutary impact of bundles is primarily being
driven by the sedation management and early extubation
components (i.e., minimizing sedation, spontaneous awaken-
ing, and breathing trials).31 This is further borne out by the
complementary results of “ABCDE” bundle implementation
reports (minimizing sedation, daily coordinated spontaneous
awakening and breathing trials, delirium screening, and early
mobilization).39–43
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 4/2019
Summary and Practical Recommendations
Much still remains unclear about how best to prevent
pneumonia in critically ill patients. Recent studies have
challenged many favored interventions without clearly iden-
tifying a bundle of interventions that does work. Head-of-
bed elevation is widely practiced but there are very little
randomized controlled trial data supporting its use. Novel
endotracheal tube cuff shapes and materials do not lower
VAP rates and continuous control of cuff pressure remains
understudied. An updated meta-analysis of subglottic secre-
tion drainage reported no impact on duration of mechanical
ventilation, ICU length of stay, or mortality. Selective diges-
tive decontamination has historically been the one pneumo-
nia prevention strategy repeatedly associated with lower
mortality rates, but a recent cluster randomized trial in ICUs
with a high baseline prevalence of resistant organisms did
not find a mortality benefit. Oral care with chlorhexidine has
Downloaded by: University of Alabama at Birmingham. Copyrighted material.
a limited effect on VAP and may increase mortality rates.
Stress ulcer prophylaxis is associated with higher pneumonia
risk in some studies. Probiotics are associated with lower VAP
rates but sometimes cause bloodstream infections and do
not clearly impact more objective outcomes.
Large multicenter studies on stress ulcer prophylaxis,
probiotics, and oral care with chlorhexidine are underway,
so more clarity may be forthcoming. In the interim, a
practical way forward is to prioritize interventions with
the best safety records and the most convincing (albeit still
imperfect) data suggesting a favorable impact on objective
outcomes. These might include avoiding intubation when-
ever possible using high flow oxygen or noninvasive me-
chanical ventilation as appropriate, minimizing sedation,
implementing daily spontaneous breathing trials, mobilizing
patients early, providing oral care with sterile water alone,
and elevating the head of the bed. Other strategies such as
digestive decontamination, continuous monitoring of endo-
tracheal tube cuff pressures, and probiotics may prove
beneficial but more data on their safety and effectiveness
are needed before advocating widespread adoption.
Conflict of Interest
Dr. Klompas reports personal fees from UpToDate Inc.,
outside the submitted work.
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