Oral Hygiene PDF

Oral hygiene care for critically ill patients to prevent
ventilator-associated pneumonia (Review)

Shi Z, Xie H, Wang P, Zhang Q, Wu Y, Chen E, Ng L, Worthington HV, Needleman I, Furness
S
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 8
http://www.thecochranelibrary.com
Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 1 Incidence of VAP. . . . . . .
Analysis 1.2. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 2 Mortality. . . . . . . . . .
Analysis 1.3. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 3 Duration of ventilation. . . . .
Analysis 1.4. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 4 Duration of ICU stay. . . . . .
Analysis 1.5. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 5 Duration of systemic antibiotic
therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 6 Positive cultures. . . . . . . .
Analysis 1.7. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 7 Plaque index. . . . . . . . .
Analysis 1.8. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 8 Adverse effects. . . . . . . .
Analysis 2.1. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 1 Incidence of VAP. . . . . . .
Analysis 2.2. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 2 Mortality. . . . . . . . . .
Analysis 2.3. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 3 Duration of ventilation. . . . .
Analysis 2.4. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 4 Duration of ICU stay. . . . . .
Analysis 2.5. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 5 Colonisation with VAP associated
organisms (Day 5). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.6. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 6 Plaque score. . . . . . . . .
Analysis 3.1. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 1 Incidence of VAP. . . . .
Analysis 3.2. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 2 Mortality. . . . . . . .
Analysis 3.3. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 3 Duration of ventilation. . .
Analysis 3.4. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 4 Duration of ICU stay. . .
Analysis 4.1. Comparison 4 Other oral care solutions, Outcome 1 Incidence of VAP. . . . . . . . . . . .
Analysis 4.2. Comparison 4 Other oral care solutions, Outcome 2 Mortality. . . . . . . . . . . . . . .
Analysis 4.3. Comparison 4 Other oral care solutions, Outcome 3 Duration of ventilation. . . . . . . . . .
Analysis 4.4. Comparison 4 Other oral care solutions, Outcome 4 Duration of ICU stay. . . . . . . . . . .
Analysis 4.5. Comparison 4 Other oral care solutions, Outcome 5 Positive cultures. . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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1
1
2
4
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7
10
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28
33
90
94
96
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i
[Intervention Review]
Oral hygiene care for critically ill patients to prevent

ventilator-associated pneumonia
Zongdao Shi1 , Huixu Xie1 , Ping Wang2 , Qi Zhang3 , Yan Wu4 , E Chen5 , Linda Ng6 , Helen V Worthington7 , Ian Needleman8 , Susan
Furness7
1 Department
of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan
University, Chengdu, China. 2 Department of Dental Implantation, West China College of Stomatology, Sichuan University, Chengdu,
China. 3 Department of Oral Implantology, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan
University, Chengdu, China. 4 Department of Orthodontics, Chongqing Medical University, Chongqing, China. 5 Department of
Paediatric Dentistry, West China College of Stomatology, Sichuan University, Chengdu, China. 6 School of Nursing and Midwifery,
University of Queensland, South Brisbane, Australia. 7 Cochrane Oral Health Group, School of Dentistry, The University of Manchester,
Manchester, UK. 8 Unit of Periodontology and International Centre for Evidence-Based Oral Healthcare, UCL Eastman Dental
Institute, London, UK
Contact address: Susan Furness, Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Coupland III
Building, Oxford Road, Manchester, M13 9PL, UK. Susan.Furness@manchester.ac.uk. suefurness@gmail.com.
Editorial group: Cochrane Oral Health Group.
Publication status and date: Edited (no change to conclusions), published in Issue 11, 2013.
Review content assessed as up-to-date: 14 January 2013.
Citation: Shi Z, Xie H, Wang P, Zhang Q, Wu Y, Chen E, Ng L, Worthington HV, Needleman I, Furness S. Oral hygiene care
for critically ill patients to prevent ventilator-associated pneumonia. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.:
CD008367. DOI: 10.1002/14651858.CD008367.pub2.
ABSTRACT
Background
Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in persons who have received mechanical ventilation for
at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC),
using either a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions may reduce the risk of VAP in these
patients.
Objectives
To assess the effects of OHC on the incidence of VAP in critically ill patients receiving mechanical ventilation in intensive care units
(ICUs) in hospitals.
Search methods
We searched the Cochrane Oral Health Groups Trials Register (to 14 January 2013), CENTRAL (The Cochrane Library 2012, Issue
12), MEDLINE (OVID) (1946 to 14 January 2013), EMBASE (OVID) (1980 to 14 January 2013), LILACS (BIREME) (1982 to
14 January 2013), CINAHL (EBSCO) (1980 to 14 January 2013), Chinese Biomedical Literature Database (1978 to 14 January
2013), China National Knowledge Infrastructure (1994 to 14 January 2013), Wan Fang Database (January 1984 to 14 January 2013),
OpenGrey and ClinicalTrials.gov (to 14 January 2013). There were no restrictions regarding language or date of publication.
Selection criteria
We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, swab, toothbrush or combination) in
critically ill patients receiving mechanical ventilation.
Data collection and analysis

Two review authors independently assessed all search results, extracted data and undertook risk of bias. We contacted study authors
for additional information. Trials with similar interventions and outcomes were pooled reporting odds ratios (OR) for dichotomous
outcomes and mean differences (MD) for continuous outcomes using random-effects models unless there were fewer than four studies.
Main results
Thirty-five RCTs (5374 participants) were included. Five trials (14%) were assessed at low risk of bias, 17 studies (49%) were at high
risk of bias, and 13 studies (37%) were assessed at unclear risk of bias in at least one domain. There were four main comparisons:
chlorhexidine (CHX mouthrinse or gel) versus placebo/usual care, toothbrushing versus no toothbrushing, powered versus manual
toothbrushing and comparisons of oral care solutions.
There is moderate quality evidence from 17 RCTs (2402 participants, two at high, 11 at unclear and four at low risk of bias) that CHX
mouthrinse or gel, as part of OHC, compared to placebo or usual care is associated with a reduction in VAP (OR 0.60, 95% confidence
intervals (CI) 0.47 to 0.77, P < 0.001, I2 = 21%). This is equivalent to a number needed to treat (NNT) of 15 (95% CI 10 to 34)
indicating that for every 15 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP will be
prevented. There is no evidence of a difference between CHX and placebo/usual care in the outcomes of mortality (OR 1.10, 95% CI
0.87 to 1.38, P = 0.44, I2 = 2%, 15 RCTs, moderate quality evidence), duration of mechanical ventilation (MD 0.09, 95% CI -0.84 to
1.01 days, P = 0.85, I2 = 24%, six RCTs, moderate quality evidence), or duration of ICU stay (MD 0.21, 95% CI -1.48 to 1.89 days,
P = 0.81, I2 = 9%, six RCTs, moderate quality evidence). There was insufficient evidence to determine whether there is a difference
between CHX and placebo/usual care in the outcomes of duration of use of systemic antibiotics, oral health indices, microbiological
cultures, caregivers preferences or cost. Only three studies reported any adverse effects, and these were mild with similar frequency in
CHX and control groups.
From three trials of children aged from 0 to 15 years (342 participants, moderate quality evidence) there is no evidence of a difference
between OHC with CHX and placebo for the outcomes of VAP (OR 1.07, 95% CI 0.65 to 1.77, P = 0.79, I2 = 0%), or mortality
(OR 0.73, 95% CI 0.41 to 1.30, P = 0.28, I2 = 0%), and insufficient evidence to determine the effect on the outcomes of duration of
ventilation, duration of ICU stay, use of systemic antibiotics, plaque index, microbiological cultures or adverse effects, in children.
Based on four RCTs (828 participants, low quality evidence) there is no evidence of a difference between OHC including toothbrushing
( CHX) compared to OHC without toothbrushing ( CHX) for the outcome of VAP (OR 0.69, 95% CI 0.36 to 1.29, P = 0.24 , I2
= 64%) and no evidence of a difference for mortality (OR 0.85, 95% CI 0.62 to 1.16, P = 0.31, I2 = 0%, four RCTs, moderate quality
evidence). There is insufficient evidence to determine whether there is a difference due to toothbrushing for the outcomes of duration
of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, microbiological cultures, adverse effects,
caregivers preferences or cost.
Only one trial compared use of a powered toothbrush with a manual toothbrush providing insufficient evidence to determine the effect
on any of the outcomes of this review.
A range of other oral care solutions were compared. There is some weak evidence that povidone iodine mouthrinse is more effective
than saline in reducing VAP (OR 0.35, 95% CI 0.19 to 0.65, P = 0.0009, I2 = 53%) (two studies, 206 participants, high risk of bias).
Due to the variation in comparisons and outcomes among the trials in this group there is insufficient evidence concerning the effects
of other oral care solutions on the outcomes of this review.
Authors conclusions
Effective OHC is important for ventilated patients in intensive care. OHC that includes either chlorhexidine mouthwash or gel is
associated with a 40% reduction in the odds of developing ventilator-associated pneumonia in critically ill adults. However, there is no
evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence
that OHC including both CHX and toothbrushing is different from OHC with CHX alone, and some weak evidence to suggest that
povidone iodine mouthrinse is more effective than saline in reducing VAP. There is insufficient evidence to determine whether powered
toothbrushing or other oral care solutions are effective in reducing VAP.
PLAIN LANGUAGE SUMMARY

Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia
Review question
To assess the effects of oral hygiene care on the incidence of ventilator-associated pneumonia (VAP) in critically ill patients receiving
mechanical ventilation in intensive care units (ICUs) in hospitals (excluding the use of antibiotics). The aim was to summarise all the
available appropriate research in order to facilitate the provision of evidence-based care for these vulnerable patients.
Trials were grouped into four main comparisons.
1. Chlorhexidine antiseptic mouthrinse or gel compared to placebo (treatment without the active ingredient chlorhexidine) or usual
care, (with or without toothbrushing).
2. Toothbrushing compared with no toothbrushing, (with or without chlorhexidine).
3. Powered compared with manual toothbrushing.
4. Oral care with other solutions.
Background
Critically ill people, who may be unconscious or sedated while they are treated in intensive care units often need to have machines
to help them breathe (ventilators). The use of these machines for more than 48 hours may result in VAP. VAP is a potentially serious
complication in these patients who are already critically ill.
Keeping the teeth and the mouth clean, preventing the build-up of plaque on the teeth, or secretions in the mouth may help reduce the
risk of developing VAP. Oral hygiene care, using a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions
may reduce the risk of VAP in these patients.
Study characteristics
This review of existing studies was carried out by the Cochrane Oral Health Group and the evidence is current up to 14 January 2013.
Thirty-five separate research studies were included but only a minority (14%) of the studies were well conducted and described.
All of the studies took place in intensive care units in hospitals. In total there were 5374 participants randomly allocated to treatment.
Participants were critically ill and required assistance from nursing staff for their oral hygiene care. In three of the included studies
participants were children and in the remaining studies only adults participated. Participants had been hospitalised as medical, surgical
or trauma patients. In 13 studies it was not clear which of these three categories the participants belonged to.
Key results
Effective oral hygiene care is important for ventilated patients in intensive care. We found evidence that chlorhexidine either as a
mouthrinse or a gel reduces the odds of VAP in adults by about 40%. So for example for every 15 people on ventilators in intensive
care, the use of oral hygiene care including chlorhexidine will prevent one person developing VAP. However, we found no evidence that
chlorhexidine makes a difference to the numbers of patients who die in ICU, to the number of days of mechanical ventilation or the
number of days in ICU.
The three studies of children (aged birth to 15 years) showed no evidence of a difference in VAP between the use of chlorhexidine
mouthrinse or gel and placebo in children.
Four studies showed no evidence of a difference between toothbrushing (with or without chlorhexidine) and oral care without toothbrushing (with or without chlorhexidine) in the risk of developing VAP. Two studies showed some evidence of a reduction in VAP with
povidone iodine antiseptic mouthrinse.
There was not enough research information available to provide evidence of the effects of other mouth care rinses such as water, saline
or triclosan.
Only two of the included studies reported any adverse effects of the interventions (mild oral irritation (one study) and unpleasant taste
(both chlorhexidine and placebo)), four studies reported that there were no adverse effects and the remaining studies do not mention
adverse effects in the reports.
Quality of the evidence
The evidence presented is of moderate quality. Only 14% of the studies were well conducted and described.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Chlorhexidine (mouthrinse or gel) versus placebo/usual care for critically ill patients to prevent ventilator-associated pneumonia (VAP)
Patient or population: Critically ill patients receiving mechanical ventilation
Settings: Intensive care unit (ICU)
Intervention: Chlorhexidine (mouthrinse or gel)
Comparison: Placebo or usual care
Outcomes
Illustrative comparative risks* (95% CI)
Assumed risk
Control (placebo
usual care)
Relative effect
(95% CI)
No of participants
(studies)

(GRADE)
Comments
This equates to an NNT of

15 (95% CI 10 to 34)
Corresponding risk
or Chlorhexidine
(mouthrinse or gel)
VAP
242 per 1000
Follow-up: mean 1 month
160 per 1000

(130 to 197)
OR 0.60
(0.47 to 0.77)
2402
(17 studies)

moderate1
Mortality
239 per 1000
257 per 1000

(215 to 303)
OR 1.10
(0.87 to 1.38)
2111
(15 studies)

moderate1
Duration of ventilation
Days of ventilation required
The mean duration of

ventilation in the control
groups ranged from 7 to
18 days
The mean duration of ventilation in the intervention

groups was
0.09 higher
(0.84 lower to 1.01
higher)
933
(6 studies)

moderate1
Duration of ICU stay

The mean duration of ICU
Follow-up: mean 1 month stay in the control groups
ranged from 10 to 24
days

stay in the intervention
groups was
0.21 higher
(1.48 lower to 1.89
higher)
833
(6 studies)

moderate1
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; NNT: number needed to treat; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate
1
2
2 studies at high risk of bias, 11 at unclear risk of bias and 4 at low risk of bias
Assumed risk is based on the outcomes in the control groups of the included studies
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BACKGROUND
Description of the condition

Patients in intensive care units in hospital frequently require mechanical ventilation because their ability to breathe unassisted is
impaired due to trauma, or as the result of a medical condition
or recent surgery. These critically ill patients are also dependent
on hospital staff to meet their needs for nutrition and hygiene,
including oral hygiene.
Overall the research suggests that oral health deteriorates following admission to a critical care unit (Terezakis 2011). Intubation
and critical illness reduce oral immunity, may be associated with
mechanical injury of the mouth or respiratory tract, increase the
likelihood of dry mouth and the presence of the endotracheal
tube may also make access for oral care more difficult (Alhazzani
2013; Labeau 2011). Dental plaque accumulates rapidly in the
mouths of critically ill patients and as the amount of plaque increases, colonisation by microbial pathogens is likely (Fourrier
1998; Scannapieco 1992). Plaque colonisation may be exacerbated
in the absence of adequate oral hygiene care and by the drying of
the oral cavity due to prolonged mouth opening which reduces
the buffering and cleansing effects of saliva. In addition, the patients normal defence mechanisms for resisting infection may be
impaired (Alhazzani 2013; Terpenning 2005). Dental plaque is
a complex biofilm which, once formed, is relatively resistant to
chemical control, requiring mechanical disruption (such as toothbrushing) for maximum impact (Marsh 2010).
One of the complications which may develop in ventilated patients is ventilator-associated pneumonia (VAP). VAP is generally
defined as a pneumonia developing in a patient who has received
mechanical ventilation for at least 48 hours (ATS Guideline 2005).
It is thought that the endotracheal tube, which delivers the necessary oxygen to the patient, may also act as a conduit for pathogenic
bacteria which multiply in the oral cavity and move down the tube
into the lungs. Micro-aspiration of pharyngeal secretions may also
occur around an imperfect seal of the cuff of the endotracheal tube
in a ventilated patient. Several studies have shown that micro-aspiration contributes to the development of nosocomial pneumonia
(Azoulay 2006; Scannapieco 1992; Mojon 2002).
There is increasing evidence in the literature to suggest a link between colonisation of dental plaque with respiratory pathogens
and VAP (Azarpazhooh 2006; Estes 1995; Fourrier 1998;
Garrouste-Orgeas 1997; Scannapieco 1992). Scannapieco et al
conducted a survey where 65% of 34 patients in intensive care
units (ICUs) were found to have respiratory pathogen colonisation
in the plaque or oral mucosa or both, compared with only 16%
of 25 patients in dental clinics (Scannapieco 1992). Treloar and
co-workers reported that 37.5% of oropharyngeal cultures taken
from orally intubated patients had the same pathogens as sputum
specimens (Treloar 1995). In another study, pathogens from the
respiratory tract of patients with hospital-acquired pneumonia genetically matched those from dental plaque (El-Solh 2004).
Ventilator-associated pneumonia is a relatively common nosocomial infection in critically ill patients, with a reported prevalence
ranging between 6% and 52% (Apostolopoulou 2003; Edwards
2009) with some indications that incidence is decreasing as understanding of the risk factors and preventative measures improves.
A recent study estimated that the attributable mortality of VAP
to be 10% (Melsen 2011). Cohort studies (Apostolopoulou 2003;
Cook 1998) have found that duration of ICU stay is increased in
patients who develop VAP but it is unclear whether this is cause
or effect.
Antibiotics, administered either intraorally as topical pastes or
systemically have been used to prevent VAP and these interventions are evaluated in other Cochrane systematic reviews (DAmico
2009; Selim 2010). Topical antibiotic pastes have been shown to
be effective but are not widely used because of the risk of developing antibiotic resistant organisms (Panchabhai 2009). However
overuse of antibiotics is associated with the development of multidrug resistant pathogens and therefore there is merit in using
other approaches for preventing infections such as VAP.
Description of the intervention

This systematic review evaluates various types of oral hygiene care
as a means of reducing the incidence of VAP in critically ill patients
receiving mechanical ventilation. Oral hygiene care is promoted
in clinical guidelines as a means of reducing the incidence of VAP
but the evidence base is limited (Tablan 2004).
Oral hygiene care includes the use of mouthrinses (water, saline,
antiseptics) applied either as sprays, liquids or with a swab, with
or without toothbrushing (either manual or powered) and toothpaste, to remove plaque and debris from the oral cavity. Oral hygiene care also involves suction to remove excess fluid, toothpaste
and debris and may be followed by the application of an antiseptic
gel. Antiseptics are broadly defined to include saline, chlorhexidine, povidone iodine, cetylpyridium and possibly others, (but
exclude antibiotics).
How the intervention might work

Patients on mechanical ventilation often have a very dry mouth
due to prolonged mouth opening which may be exacerbated by
the side effects of medications used in their treatment. In healthy
individuals, saliva functions to maintain oral health through its
lubricating, antibacterial and buffering properties (Labeau 2011)
but patients on ventilators lack sufficient saliva for this to occur,
and the usual stimuli for saliva production are absent.
Routine oral hygiene care is designed to remove plaque and debris as well as replacing some of the functions of saliva, moistening and rinsing the mouth. Toothbrushing, with either a man-
ual or powered toothbrush, removes plaque from teeth and gums

and disrupts the biofilm within which plaque bacteria multiply
(Whittaker 1996; Zanatta 2011). It is hypothesised that using an
antiseptic, such as chlorhexidine gluconate or povidone-iodine, as
either a rinse or a gel may further reduce the bacterial load or delay
a subsequent increase in bacterial load.
However, it is important that during oral hygiene care, the plaque
and debris are removed from the oral cavity with care in order to
avoid aspiration of contaminated fluids into the respiratory tract.
Raising the head of the bed, and careful use of appropriately maintained closed suction systems, together with an appropriately fitted cuff around the endotracheal tube are other important aspects
of care of critically ill patients that are not part of this systematic
review.
Why it is important to do this review

Other Cochrane systematic reviews have evaluated the use of topical antibiotic pastes applied to the oral cavity (selective oral decontamination DAmico 2009), the use of probiotics (Hao 2011)
and systemic antibiotics (Selim 2010) to prevent VAP. Other published reviews have evaluated aspects of oral hygiene care, such as
toothbrushing (Alhazzani 2013) or use of chlorhexidine (Pineda
2006), and broader reviews have noted the lack of available evidence (Berry 2007; Shi 2004). Clinical guidelines recommend
the use of oral hygiene care but there is a lack of available evidence as a basis for specifying the essential components of such
care (Muscedere 2008; Tablan 2004). The goal of this Cochrane
systematic review was to evaluate all oral hygiene care interventions (excluding the use of antibiotics) used in ICU for patients
on ventilators to determine the effects of oral hygiene care on the
development of VAP. We planned to summarise all the available
research in order to facilitate the provision of evidence-based care
for these vulnerable patients.
OBJECTIVES
To assess the effects of oral hygiene care on prevention of VAP in
critically ill patients receiving mechanical ventilation in hospital
settings.
We included in the review all randomised controlled trials (RCTs)

of oral hygiene care interventions.
Types of participants
Critically ill patients in hospital settings receiving mechanical ventilation, without ventilator-associated pneumonia or respiratory
infection at baseline. Trials where only some of the participants
were receiving mechanical ventilation were included if
the outcome of ventilator-associated pneumonia was
reported,
data for those who had been treated with mechanical
ventilation for a minimum of 48 hours and then developed
nosocomial pneumonia were available.
Trials where participants were undergoing a surgical procedure
that involved mechanical ventilation (e.g. cardiac surgery) were
only included in this review if the oral hygiene care was given during the period of mechanical ventilation which had a minimum
duration of 48 hours. Trials where pre-operative patients received
a single dose of antibacterial rinse or gargle, and received mechanical ventilation only for the duration of the surgery, with no further mechanical ventilation and oral hygiene care during the postoperative period were excluded.
Types of interventions
Intervention group: received clearly defined oral care
procedures such as nurse-assisted toothbrushing, oral and
pharyngeal cavity rinse, decontamination of oropharyngeal
cavities with antiseptics.
Control group: received no treatment, placebo, usual care
or a different specific oral hygiene care procedure.
Trials where the intervention being evaluated was a type of suction
system or variation of method, timing, or place where mechanical
ventilation was introduced (e.g. emergency room or ICU) were
excluded.
We excluded trials of selective decontamination using topical
antibiotics administered to the oral cavity or oropharynx because these interventions are covered in another Cochrane review
(DAmico 2009). Trials of probiotics administered to prevent respiratory infections were also excluded as these are covered in a
separate review (Hao 2011).
Types of outcome measures
METHODS
Primary outcomes
Criteria for considering studies for this review

Types of studies
1. Incidence of VAP (defined as pneumonia developing in a

patient who has received mechanical ventilation for at least 48
hours).
2. Mortality (either ICU mortality if these data were available,
or 30-day mortality).
Secondary outcomes
1. Duration of mechanical ventilation or ICU stay or both.

2. Systemic antibiotic use.
3. Colonisation of dental plaque, saliva, oropharyngeal
mucosa or endotracheal aspirates by VAP-associated organisms.
4. Oral health indices such as gingival index, plaque index,
bleeding index, periodontal index etc.
5. Adverse effects of the interventions.
6. Caregivers preferences for oral hygiene care.
7. Economic data.
Search methods for identification of studies

For the identification of studies included or considered for this
review, we developed detailed search strategies for each database
searched. These were based on the search strategy developed for
MEDLINE (OVID) but revised appropriately for each database.
Electronic searches
We searched the following electronic databases:
Cochrane Oral Health Groups Trials Register (to 14
January 2013) (Appendix 1)
The Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library 2012, Issue 12) (Appendix
2)
MEDLINE via OVID (1946 to 14 January 2013)
(Appendix 3)
EMBASE via OVID (1980 to 14 January 2013) (Appendix
4)
CINAHL via EBSCO (1980 to 14 January 2013)
(Appendix 5)
LILACS via BIREME Virtual Health Library (1982 to 14
Chinese Biomedical Literature Database (1978 to 14
China National Knowledge Infrastructure (1994 to 14
Wan Fang Database (1984 to 14 January 2013) (Appendix
9)
OpenGrey (1980 to 14 January 2013) (Appendix 10)
ClinicalTrials.gov (14 January 2013) (Appendix 11).
The search strategy used a combination of controlled vocabulary
and free text terms, details of the MEDLINE search are provided in
Appendix 3. The search of EMBASE was linked with the Cochrane
Oral Health Group filter for identifying RCTs (Appendix 4). All
relevant publications were included irrespective of language.
Searching other resources
All the references lists of the included studies were checked manually to identify any additional studies.
We contacted the first author of the included studies, other experts

in the field and manufacturers of oral hygiene products to request
unpublished relevant information.
Data collection and analysis
Selection of studies
Two review authors independently examined the title and abstract
of each article obtained from the searches. If they disagreed with
the inclusion of any study, there was group discussion with other
members of the review team until consensus was achieved. Multiple reports from a study were linked and the report with more
complete follow-up data was the primary source of data.
Full-text copies of potentially relevant reports were obtained and
examined in detail to determine whether the study fulfilled the
eligibility criteria. Any queries were once again resolved by discussion. Attempts were made to contact study authors to obtain
additional information as necessary.
Data extraction and management
Two review authors independently extracted data from the included studies into the pre-designed structured data extraction
forms. Any disagreements were resolved by discussion. Contents
of the data extraction included the following items.
(1) General characteristics of the study
Authors, year of publication, country where the study was performed, funding, language of publication, study duration, citation, contact details for the authors and identifier.
(2) Specific trial characteristics
Basic study design characteristics: sequence generation, allocation
sequence concealment, blinding, incomplete outcome data and
selective outcome reporting etc were collected and presented in
the table of Characteristics of included studies. Verbatim quotes
on the first three issues from original reports were adopted.
Participants: total number, setting, age, sex, country, ethnicity,
socio-demographic details (e.g. education level), diagnostic criteria
of VAP and the presence of co-morbid conditions.
Interventions: we collected details of all experimental and control
interventions, such as dosages for drugs used and routes of delivery, format for oral hygiene care, timing and duration of the oral
care procedures. In addition, information on any co-interventions
administered were also collected.
Outcomes: incidence of VAP or other respiratory diseases and
mortality (directly and indirectly attributable), adverse outcomes
resulting from the interventions, quantity of pathogenic microorganisms from culture of oropharyngeal materials or tracheal aspirates, indices of the plaque, inflammation of the gum or periodontal tissues etc were collected. All outcome variables were specified
in terms of definition, timing, units and scales.
Other results: we also collected summary statistics, sample size,

key conclusions, comments and any explanations provided for
unexpected findings by the study authors. The lead authors of
included studies were contacted if there were issues to be clarified.
Assessment of risk of bias in included studies
Two review authors assessed the risk of bias of all included studies, independently and in duplicate, using The Cochrane Collaborations domain-based, two-part tool as described in Chapter 8
of the Cochrane Handbook for Systematic Reviews of Interventions (
Higgins 2011). Study authors were contacted for clarification or
missing information where necessary. Any disagreements concerning risk of bias were resolved by discussion. A Risk of bias table
was completed for each included study. For each domain of risk
of bias, we described what was reported to have happened in the
study in order to provide a rationale for the second part, which
involved assigning a judgement of Low risk of bias, High risk
of bias, or Unclear risk of bias.
For each included study, we assessed the following seven domains
of risk of bias.
Random sequence generation (selection bias): use of simple
randomisation (e.g. random number table, computer-generated
randomisation, central randomisation by a specialised unit),
restricted randomisation (e.g. random permuted blocks),
stratified randomisation and minimisation were assessed as low
risk of bias. Other forms of simple randomisation such as
repeated coin tossing, throwing dice or dealing cards were also
considered as low risk of bias (Schulz 2002). Where a study
report used the phrase randomised or random allocation but
with no further information we assessed it as unclear for this
domain.
Allocation concealment (selection bias): use of centralised/
remote allocation, pharmacy-controlled randomisation and
sequentially numbered, sealed, opaque envelopes were assessed as
low risk of bias. If a study report did not mention allocation
concealment we assessed it as unclear for this domain.

Blinding of participants and personnel (performance bias):
participants in included studies were in intensive care and on
mechanical ventilation and were therefore unlikely to be aware of
the treatment group to which they were assigned. Where no
placebo was used, caregivers would be aware of the assigned
intervention and it is unclear whether this would introduce a risk
of performance bias. If a study was described as double blind,
and a placebo was used we assumed that caregivers and outcome
assessors were blinded to the allocated treatment. If blinding was
not mentioned, and if no placebo was used we assumed that no
blinding of caregivers occurred and we assessed this domain as at
unclear risk of bias.
Blinding of outcome assessment (detection bias): if
outcome assessor blinding was not mentioned in the trial report
we assessed this domain as at unclear risk of bias.
Incomplete outcome data (attrition bias): where the overall
rate of attrition was high the risk of attrition bias was assessed as
high. Alternatively if the numbers of participants, and/or the
reasons for exclusion were different in each arm of the study, risk
of attrition bias was assessed as high. If numbers of participants
randomised or evaluated in each arm of the study were not
reported we assessed this domain as unclear.
Selective reporting (reporting bias): if the study did not
report outcomes stated in the methods section, or reported
outcomes without estimates of variance, we assessed this as at
high risk of reporting bias.
Other bias: any other potential source of bias which might
feasibly alter the magnitude of the effect estimate e.g. baseline
imbalance between study arms in important prognostic factors
(e.g. clinical pulmonary infection scores (CPIS), antibiotic
exposure), early stopping of the trial, or co-interventions or
differences in other treatment between study arms. Other
potential sources of bias were described and risk of bias assessed.
We summarised the risk of bias as follows.
Risk of bias
Interpretation
In outcome
Low risk of bias
Plausible bias unlikely to seriously Low risk of bias for all key domains Most information is from studies at
alter the results
low risk of bias
Unclear risk of bias
Plausible bias that raises some Unclear risk of bias for one or more Most information is from studies at
doubt about the results
key domains
low or unclear risk of bias
High risk of bias
Plausible bias that seriously weak- High risk of bias for one or more The proportion of information
ens confidence in the results
key domains
from studies at high risk of bias is
sufficient to affect the interpretation of results
In included studies
We presented the risk of bias graphically by: (a) proportion of

studies with each judgement (Low risk, High risk, and Unclear
risk of bias) for each risk of bias domain (Figure 1), and (b) crosstabulation of judgements by study and by domain (Figure 2).
Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies
10
Figure 2. Risk of bias summary graph: review authors judgements about each risk of bias item for each
included study
11
1997 (continuous outcome) and Rcker 2008 (dichotomous outcome) (such analysis would have been done in STATA 11.0).
Measures of treatment effect

For dichotomous outcomes, we computed the effect measure the
odds ratio (OR) together with the 95% confidence interval. For
continuous outcomes, mean difference (MD) with 95% confidence interval was used to estimate the summary effect.
Unit of analysis issues

The unit of analysis was the patient. The indices of plaque and
gingivitis were measured as mean values for the patients. Episodes
of care were also related back to individual patients.
Data synthesis
Meta-analyses were undertaken for the similar comparisons and
same outcomes across studies. We decided to use random-effects
models providing there were four or more trials in any one metaanalysis. If different scales were used, standardised mean differences were calculated.
Subgroup analysis and investigation of heterogeneity

Dealing with missing data
We contacted the lead author of studies requesting that they supply any missing data. Missing standard deviations were to be obtained using the methods outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011).
One subgroup analysis was proposed a priori when discussing how

to structure the data comparisons. It was decided to undertake a
subgroup analysis for whether the patients teeth were cleaned or
not as it was hypothesised that antiseptics would be less effective
if toothbrushing was not used to disrupt dental plaque biofilm.
Sensitivity analysis
Assessment of heterogeneity
Chi2
To detect heterogeneity among studies in a meta-analysis, a

test with a 0.01 level of significance as the cut-off value was applied.
The impact of statistical heterogeneity was quantified using the
I2 statistic. The thresholds of I2 recommended by the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011)
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity
were used for interpretation of the results. If considerable heterogeneity existed then it was investigated. We used subgroup analyses to investigate possible differences between the studies.
Assessment of reporting biases

Only a proportion of research projects conducted are ultimately
published in an indexed journal and become easily identifiable for
inclusion in systematic reviews. Reporting biases arise when the reporting of research findings is influenced by the nature and direction of the findings of the research. We investigated and attempted
to minimise potential reporting biases including publication bias,
time lag bias, multiple (duplicate) publication bias and language
bias in this review.
Where there were more than 10 studies in one outcome we constructed a funnel plot. We planned to investigate the asymmetry
in the funnel plot (indicating possible publication bias) by undertaking statistical analysis using the methods introduced by Egger
To determine whether the intervention effects of oral hygiene care

were robust, sensitivity analyses were planned to determine the
effect of those factors, such as exclusion of some studies with questionable diagnostic criteria for VAP, excluding studies with high
risk of bias, or changing assumptions about missing data on the
estimates of effect.
If the results did not change substantially in sensitivity analyses,
then the conclusion would have been regarded as stable with a
higher degree of certainty. Where sensitivity analyses identified
particular factors that greatly influenced the conclusions of the
review, the plausible causes of the uncertainties would have been
explored, and the results would be interpreted with caution.
Summary of findings
The GRADE system for evaluating quality of the evidence of systematic reviews (Guyatt 2008; Higgins 2011) was adopted using
the software GRADEprofiler. The quality of the body of evidence
was assessed with reference to the overall risk of bias of the included
studies, the directness of the evidence, the inconsistency of the
results, the precision of the estimates, and the risk of publication
bias. The quality of the body of evidence was classified into four
categories: high, moderate, low and very low.
RESULTS
12
Description of studies
Results of the search

After removal of duplicates, the electronic search strategies identified 774 records from English language databases and 234 from
Chinese language databases, which were screened by at least two
review authors against the inclusion criteria for this review. Of
these 937 were discarded and full-text copies of 71 references were

requested. These papers were assessed by at least two review authors to determine their eligibility, and from these 35 studies were
identified which met the inclusion criteria for this review. One ongoing study was identified and a further four studies are awaiting
classification because we have not yet obtained full-text copies or
they require translation or both.
The flow diagram is shown in Figure 3.
13
Figure 3. Study flow diagram
14
Included studies
and in the remaining 13 studies it was not clearly stated whether

participants were medical, surgical or trauma cases.
We included 35 RCTs in this review.

Classification of the interventions
Setting
Nine of the included studies were conducted in the USA (Bopp

2006; DeRiso 1996; Fields 2008; Grap 2004; Grap 2011; McCartt
2010; Munro 2009; Prendergast 2012; Scannapieco 2009), seven
in China (Chen 2008; Feng 2012; Hu 2009; Long 2012; Xu 2007;
Xu 2008; Zhao 2012), four in Brazil (Bellissimo-Rodrigues 2009;
Caruso 2009; Jacomo 2011; Kusahara 2012), three in each of
France (Fourrier 2000; Fourrier 2005; Seguin 2006) and Spain
(Lorente 2012; Pobo 2009; Roca Biosca 2011), two in India
(Panchabhai 2009; Sebastian 2012), and one in each of Australia
(Berry 2011), Croatia (Cabov 2010), Taiwan(Yao 2011), Thailand (Tantipong 2008), Turkey (Ozcaka 2012), the Netherlands
(Koeman 2006), and the United Kingdom (Needleman 2011).
All of the studies took place in intensive care units in hospitals.
Most of the studies were two-arm parallel group RCTs, but six
studies had three arms (Berry 2011; Grap 2004; McCartt 2010;
Scannapieco 2009; Seguin 2006; Xu 2007) and one study had
four arms (Munro 2009).
Participants
In total there were 5374 participants randomly allocated to treatment in 34 RCTs included in this review and the other trial did
not state how many patients were included (Fields 2008). The criteria for inclusion in these studies generally specified no prior intubation, no clinically apparent pneumonia at baseline (except for
Sebastian 2012, where most of the children admitted to ICU had
pneumonia already and criteria of the Centers for Disease Control
(CDC) were strictly applied to diagnose subsequent VAP) and an
expected requirement for mechanical ventilation for a minimum
of 48 hours. Participants were critically ill and required assistance
from nursing staff for their oral hygiene care. In three of the included studies participants were children (Jacomo 2011; Kusahara
2012; Sebastian 2012) and in the remaining studies only adults
participated.
In four studies (Koeman 2006; McCartt 2010; Munro 2009;
Panchabhai 2009) participants were either medical or surgical
patients, in another four studies participants were described as
trauma patients (Grap 2011; Prendergast 2012; Scannapieco
2009; Seguin 2006), six studies recruited surgical patients only
(Chen 2008; DeRiso 1996; Jacomo 2011; Kusahara 2012; Yao
2011; Zhao 2012), eight studies recruited medical patients
only (Cabov 2010; Fields 2008; Fourrier 2000; Fourrier 2005;
Needleman 2011; Ozcaka 2012; Sebastian 2012; Tantipong 2008)
The interventions in the included studies were in three broad

groups.
Chlorhexidine.
Chlorhexidine solution (applied as mouthrinse, spray

or on a swab).
Chlorhexidine gel.
Toothbrushing.
Powered.
Manual.
Other solutions.
Saline.
Bicarbonate.
Povidone iodine.
Triclosan.
These interventions were used either singly or in combinations.
We evaluated the following comparisons.
1. Chlorhexidine versus placebo/usual care with or without
toothbrushing (20 studies: Bellissimo-Rodrigues 2009; Berry
2011; Bopp 2006; Cabov 2010; Chen 2008; DeRiso 1996;
Fourrier 2000; Fourrier 2005; Grap 2004; Grap 2011; Jacomo
2011; Koeman 2006; Kusahara 2012; McCartt 2010; Munro
2009; Ozcaka 2012; Panchabhai 2009; Scannapieco 2009;
Sebastian 2012; Tantipong 2008).
2. Toothbrushing versus no toothbrushing (in addition to
usual care) (eight studies: Bopp 2006; Fields 2008; Lorente
2012; Munro 2009; Needleman 2011; Pobo 2009; Roca Biosca
2011; Yao 2011).
3. Powered toothbrushing versus manual toothbrushing (one
study: Prendergast 2012).
4. Other solutions (nine studies).
i) Saline (Caruso 2009; Hu 2009; Seguin 2006; Xu
2007; Xu 2008).
ii) Bicarbonate (Berry 2011).
iii) Povidone iodine (Feng 2012; Long 2012; Seguin
2006).
iv) Triclosan (Zhao 2012).
Three studies (Berry 2011; Bopp 2006; Munro 2009) are included
in two comparisons.
Placebos used included saline (Chen 2008; Feng 2012; Hu 2009;
Ozcaka 2012; Seguin 2006; Tantipong 2008; Xu 2007; Xu 2008),
potassium permanganate (Panchabhai 2009), half-strength hydrogen peroxide (Bopp 2006), water/alcohol mixture (DeRiso
1996; Jacomo 2011), placebo gel (Fourrier 2005; Koeman 2006;
15
Kusahara 2012;Sebastian 2012), base solution (Scannapieco 2009)

or water (Berry 2011). In one trial the nature of the placebo was
not specified (Bellissimo-Rodrigues 2009). In some of these studies the intervention described as placebo may have had some antibacterial activity but this was considered to be negligible compared to the active intervention.
In nine studies the control group received usual/standard care (
Caruso 2009; Fields 2008; Fourrier 2000; Grap 2004; Grap 2011;
McCartt 2010; Munro 2009; Seguin 2006; Yao 2011) (for specific
details see Characteristics of included studies), and in four studies
there was a head to head comparison between two potentially
active interventions (Needleman 2011; Pobo 2009; Prendergast
2012; Roca Biosca 2011).
Measures of primary outcomes
Incidence of VAP
The primary outcome of our review is ventilator-associated pneumonia (VAP) defined as pneumonia developing in a person who
has been on mechanical ventilation for at least 48 hours. VAP was
fully reported by 28 of the included studies (Bellissimo-Rodrigues
2009; Berry 2011; Bopp 2006; Cabov 2010; Caruso 2009; Chen
2008; DeRiso 1996; Feng 2012; Fourrier 2005; Grap 2011;
Hu 2009; Jacomo 2011; Koeman 2006; Kusahara 2012; Long
2012; Lorente 2012; Ozcaka 2012; Panchabhai 2009; Pobo 2009;
Prendergast 2012; Scannapieco 2009; Sebastian 2012; Seguin
2006; Tantipong 2008; Xu 2007; Xu 2008; Yao 2011; Zhao 2012),
one study reported only that there was no difference in VAP between the two arms of the study (Roca Biosca 2011) and in another study it was reported that the VAP rate dropped to zero in
the intervention group but the control group event rate was not
reported (Fields 2008). Two studies (Fourrier 2000; Hu 2009)
reported the outcome of nosocomial pneumonia but it was not
clear in the trial reports whether all those who developed this outcome had been on mechanical ventilation for at least 48 hours.
One study reported mean CPIS score per group but did not record
cases of VAP (McCartt 2010). We sought clarification from the
trial authors but to date no further data have been received.
Diagnostic criteria for the outcome of ventilator-associated pneumonia were specified in 21 of the studies which reported the outcome of VAP (60%). Sixteen studies (Berry 2011; Cabov 2010;
Caruso 2009; Fourrier 2000; Fourrier 2005; Grap 2004; Grap
2011; Koeman 2006; Kusahara 2012; McCartt 2010; Munro
2009; Pobo 2009; Scannapieco 2009; Seguin 2006; Tantipong
2008; Yao 2011) used Pugins criteria (Cook 1998; Pugin 1991)
which form the basis of the CPIS score, based on the presence of
an infiltrate on chest radiograph, plus two or more of the following: temperature greater than 38.5 C or less than 35 C, white
blood cell count greater than 11,000/mm3 or less than 4000/mm
3 , mucopurulent or purulent bronchial secretions, or more than
20% increase in fraction of inspired oxygen required to maintain

saturation above 92%. In Ozcaka 2012 no specific criteria were
reported, but communication from the author confirmed that patients with new pulmonary infiltrates or opacities on the chest Xray were pre-diagnosed VAP and lower tracheal mini-bronchoalveolar lavage (mini-BAL) samples were taken and then subjects were
diagnosed according to CPIS criteria. Patients who had a score
6 and the presence of 104 colony-forming units/mL of a target
potential respiratory bacterial pathogen (PRP) in mini-BAL were
diagnosed VAP.
A further six studies (Bellissimo-Rodrigues 2009; DeRiso 1996;
Fields 2008; Jacomo 2011; Panchabhai 2009; Sebastian 2012)
used the CDC criteria as described in Horan 2008.
Four studies (Chen 2008; Feng 2012; Xu 2007; Xu 2008) used the
criteria of the Chinese Society of Respiratory Diseases: presence
of new infiltrates on chest radiographs developed after 48 hours
of mechanical ventilation with any two of the following items: (a)
temperature greater than 38 C, (b) change in characteristics of
bronchial secretions from mucoid to mucopurulent or purulent,
(c) white cell count greater than 10,000/mm3 , (d) positive culture
of tracheal aspirate or positive culture of bronchoalveolar lavage
fluid or both, or (e) arterial oxygen tension/inspiratory fraction
of oxygen PaO2 /FiO2 decreased over 30% within the period of
ventilation.
The study by Hu 2009 reported the outcome of VAP based on
clinical examination plus three criteria: chest radiograph, white
cell count and culture of the aspirate from lower respiratory tract
(but no precise parameters were specified). In Lorente 2012 the
diagnosis of VAP was made by an expert panel blinded to the allocated intervention but the diagnostic criteria were not specified.
The study by Prendergast 2012 had a single diagnostic criteria of a
new or worsening pulmonary infiltrate on chest radiograph. Two
studies used positive culture from the lower respiratory tract as
criteria for diagnosis of VAP (Long 2012; Zhao 2012).
In the remaining two studies with the outcome of VAP, diagnostic
criteria were not reported (Bopp 2006; Roca Biosca 2011) and the
study by Needleman 2011 did not report the outcome of VAP.
Mortality
Twenty included studies reported the outcome of mortality either as ICU mortality or 30-day mortality (Bellissimo-Rodrigues
2009; Berry 2011; Cabov 2010; Caruso 2009; Fourrier 2000;
Fourrier 2005; Jacomo 2011; Kusahara 2012; Long 2012; Lorente
2012; Munro 2009; Ozcaka 2012; Panchabhai 2009; Pobo 2009;
Prendergast 2012; Scannapieco 2009; Sebastian 2012; Seguin
2006; Tantipong 2008; Yao 2011). Where ICU mortality was reported we used these data, and where ICU mortality was not reported we used 30-day mortality.
Measures of secondary outcomes
16
There were 15 studies which reported this outcome (BellissimoRodrigues 2009; Caruso 2009; Fourrier 2000; Fourrier 2005; Hu
2009; Koeman 2006; Long 2012; Lorente 2012; Ozcaka 2012;
Pobo 2009; Prendergast 2012; Scannapieco 2009; Seguin 2006;
Xu 2008; Zhao 2012). The studies by Jacomo 2011 and Sebastian
2012 reported the median duration of ventilation and the range
for each group, but these data could not be combined in a metaanalysis.

There were 14 studies reporting this outcome (BellissimoRodrigues 2009; Bopp 2006; Caruso 2009; Fourrier 2000;
Fourrier 2005; Koeman 2006; Kusahara 2012; Lorente 2012;
Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012;
Seguin 2006; Zhao 2012). The studies by Jacomo 2011 and
Sebastian 2012 reported the median ICU stay and the range for
each group, but these data could not be combined in a meta-analysis.
Systemic antibiotic therapy

There were three studies which reported some measure of systemic antibiotic use. DeRiso 1996 reported the number of patients in each group who required treatment of an infection with
systemic antibiotics during their ICU stay, and Fourrier 2005 and
Scannapieco 2009 both reported the mean number of days of systemic antibiotic use in the intervention and control groups.
Microbial colonisation
Oropharyngeal colonisation is considered to be an important
source in the pathogenesis of VAP and reducing bacterial colonisation may be a step towards prevention of VAP. Unfortunately only
six studies (Cabov 2010; Feng 2012; Grap 2004; Kusahara 2012;
Needleman 2011; Zhao 2012) reported data for the outcome of
numbers of participants with microbial colonisation of plaque in
each treatment group, and each study used a slightly different measure. Additionally, Fourrier 2005 reported the bacteria cultured
from dental plaque only for the subgroup of participants who developed a nosocomial infection, and Scannapieco 2009 reported
a graph of mean log of potential plaque respiratory pathogens in
each group, but we were unable to use these measures in our metaanalysis.
by the corresponding author in one study (Yao 2011), one study

(Scannapieco 2009) reported this outcome in graphs only and the
other study (Roca Biosca 2011) did not report any estimate of
variance so these data could not be used in this review.
Adverse effects
Only two of the included studies (Bellissimo-Rodrigues 2009;
Tantipong 2008) reported adverse effects of the interventions, four
studies reported that there were no adverse effects (Berry 2011;
Jacomo 2011; Ozcaka 2012; Sebastian 2012) and the remaining
studies did not mention adverse effects in the reports.
Excluded studies
There were 25 excluded studies. Reasons are summarised below.
Nine studies were excluded because the methods used to
allocate participants to interventions were not truly random
(Abusibeih 2010; Chao 2009; Genuit 2001; Li 2011; Liwu
1990; McCoy 2012; Pawlak 2005; Santos 2008; Wang 2006).
In six studies the participants were not receiving mechanical
ventilation (Houston 2002; Lai 1997; Liang 2007; Ogata 2004;
Segers 2006; Yin 2004).
In three studies the patients were not critically ill (Epstein
1994; Ferozali 2007; Ueda 2004).
Two studies were reported as abstracts only and our
attempts to find a full publication or obtain sufficient data to
enable inclusion in this review were unsuccessful (MacNaughton
2004; Zouka 2010).
Guo 2007 was excluded because the patients had suffered
lung trauma.
Fan 2012 was excluded because the mouthrinse ingredients
were not listed and may have contained antibiotic, and in Li
2012 the mouthrinse did contain antibiotic.
In Wang 2012 the target intervention was bed elevation
and endotracheal suctioning.
Bordenave 2011 was excluded because communication
from the investigators revealed that this study, listed on
clinicaltrials.gov website as ongoing, was not undertaken due to
funding issues.
For further information see Characteristics of excluded studies.
Risk of bias in included studies
Allocation
Oral health indices
Plaque indices were mentioned as outcomes in five studies
(Needleman 2011; Ozcaka 2012; Roca Biosca 2011; Scannapieco
2009; Yao 2011). Complete data for plaque indices were available
in two studies (Needleman 2011; Ozcaka 2012), were supplied
Sequence generation
Twenty-six of the included studies described clearly a random

method of sequence generation and were assessed at low risk of bias
17
for this domain. The remaining nine studies (Caruso 2009; Feng
2012; Fields 2008; Long 2012; Panchabhai 2009; Roca Biosca
2011; Xu 2007; Xu 2008; Zhao 2012) stated that allocation was
random but provided no further details and were therefore assessed
at unclear risk of bias for this domain.
Allocation concealment
Allocation concealment was clearly described in 19 of the included

studies and they were assessed at low risk of bias for this domain.
In 13 studies (Cabov 2010; Caruso 2009; Chen 2008; Feng 2012;
Fourrier 2000; Grap 2011; Long 2012; Lorente 2012; McCartt
2010; Panchabhai 2009; Xu 2007; Yao 2011; Zhao 2012) allocation concealment was not described in sufficient detail to determine risk of bias and these studies were assessed at unclear risk of
bias. The remaining three studies (Bopp 2006; Tantipong 2008;
Xu 2008) were assessed at high risk of bias because the allocation
was not concealed from the researchers.
The risk of selection bias based on combined assessment of these
two domains was high in three studies (Bopp 2006; Tantipong
2008; Xu 2008), unclear in 15 studies (Cabov 2010; Caruso 2009;
Chen 2008; Feng 2012; Fields 2008; Fourrier 2000; Grap 2011;
Long 2012; Lorente 2012; McCartt 2010; Panchabhai 2009; Roca
Biosca 2011; Xu 2007; Yao 2011; Zhao 2012) and low in the
remaining 17 studies.
Incomplete outcome data

In the studies included in this review loss of participants during
the course of the study is to be expected as these critically ill people
leave the intensive care unit either because they recover and no
longer require mechanical ventilation, or because they die from
their illness. In 20 of the included studies (Bellissimo-Rodrigues
2009; Bopp 2006; Cabov 2010; Caruso 2009; Chen 2008; Feng
2012; Fourrier 2005; Jacomo 2011; Koeman 2006; Kusahara
2012; Long 2012; Lorente 2012; Ozcaka 2012; Pobo 2009;
Sebastian 2012; Seguin 2006; Xu 2007; Xu 2008; Yao 2011; Zhao
2012) either all the randomised participants were included in the
outcome, or the number of losses/withdrawals and the reasons
given were similar in both arms of the study, and these studies
were assessed at low risk of attrition bias.
Eleven of the included studies were assessed at high risk of attrition
bias because the numbers and reasons for withdrawal/exclusion
were different in each arm of the study, or because the number of
participants withdrawn or excluded from the outcomes evaluation
were high and insufficient information was provided (Berry 2011;
Fields 2008; Grap 2004; Grap 2011; Hu 2009; McCartt 2010;
Munro 2009; Needleman 2011; Prendergast 2012; Roca Biosca
2011; Scannapieco 2009). In the remaining four studies there was
insufficient information available to determine the risk of attrition
bias.
Selective reporting
Blinding
Ten studies (Bellissimo-Rodrigues 2009; Cabov 2010; DeRiso
1996; Fourrier 2005; Jacomo 2011; Koeman 2006; Kusahara
2012; Ozcaka 2012; Scannapieco 2009; Sebastian 2012) were described as double blind and were assessed at low risk of performance bias. In the remaining 25 studies blinding of the patients
and their caregivers to the allocated treatment was not possible
because the active and control treatments were so different, and
no placebos were used. These studies were assessed at unclear risk
of performance bias.
Blinding of outcome assessment was possible in all of the included
studies and was described in 22 studies (Bellissimo-Rodrigues
2009; Berry 2011; Cabov 2010; Caruso 2009; DeRiso 1996;
Fourrier 2000; Fourrier 2005; Grap 2004; Hu 2009; Jacomo
2011; Koeman 2006; Kusahara 2012; Lorente 2012; Needleman
2011; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast
2012; Scannapieco 2009; Sebastian 2012; Tantipong 2008; Yao
2011) which were assessed as being at low risk of detection bias.
Seven of the included studies (Bopp 2006; Grap 2011; McCartt
2010; Munro 2009; Seguin 2006; Xu 2007; Xu 2008) reported no
blinding of outcome assessment and were assessed at high risk of
detection bias. In the remaining six studies there was insufficient
information provided and the risk of detection bias was assessed
as unclear.
Twenty-three of the included studies (Bellissimo-Rodrigues 2009;

Berry 2011; Cabov 2010; Caruso 2009; DeRiso 1996; Feng
2012; Fourrier 2000; Fourrier 2005; Koeman 2006; Kusahara
2012; Long 2012; Lorente 2012; Needleman 2011; Ozcaka 2012;
Panchabhai 2009; Pobo 2009; Prendergast 2012; Scannapieco
2009; Seguin 2006; Xu 2007; Xu 2008; Yao 2011; Zhao 2012)
reported the outcomes specified in their methods section in full,
or this information was supplied by trial authors, and these studies
were assessed at low risk of reporting bias.
Four studies did not report all the outcomes specified in their
methods sections (Grap 2004; Grap 2011; McCartt 2010; Roca
Biosca 2011), one study reported outcomes as percentages, and
the denominators for each arm were unclear (Hu 2009), and one
study did not report the number of participants evaluated (Fields
2008). These six trials were assessed at high risk of reporting bias.
The remaining six trials (Bopp 2006; Chen 2008; Jacomo 2011;
Munro 2009; Sebastian 2012; Tantipong 2008) were assessed at
unclear risk of reporting bias because there was insufficient information reported to make a clear judgement.
Other potential sources of bias

Four studies were assessed at high risk of other bias. The study
by Berry 2011 was stopped early due to withdrawal of one of the
investigational products by a regulatory authority, and the study by
18
Pobo 2009 was stopped after 37% of the planned 400 patients had
been recruited because there appeared to be no difference between
the study arms in the outcome of VAP. Grap 2011 did not report
baseline data for each randomised treatment group but the trial
report noted that there was a statistically significant difference
in gender and CPIS score between groups at baseline, and we
considered that this difference was likely to have biased the results.
In the study by Scannapieco 2009 the imputations used for the
missing data were unclear and the pre-study exposure to systemic
antibiotics was greater in the control group, so this study was
assessed at high risk of other bias.
In nine studies (Chen 2008; Fields 2008; Kusahara 2012; Long
2012; Panchabhai 2009; Roca Biosca 2011; Tantipong 2008; Yao
2011; Zhao 2012) the risk of other bias was assessed as unclear.
The reasons for this are as follows. The participants in the treatment group in the study by Chen 2008 received a co-intervention
that was not given to the control group, and in both Fields 2008
and Roca Biosca 2011 the study reports contained insufficient
information for us to be confident that study methodology was
robust. In the study by Kusahara 2012, there was a statistically
significant difference in the age of the children in each arm of the
study and we are unclear whether this is associated with potential
bias. Panchabhai 2009 reported baseline characteristics only for
those participants completing the study, Tantipong 2008 included
participants treated in different units of the hospital where care
and co-interventions are likely to have been different, and in Yao
2011 there is no information as to how the edentulous participants
in each arm were treated. Long 2012 and Zhao 2012 reported
the criteria for VAP diagnosis as being positive culture of lower
respiratory tract secretions, with no other criteria and it is unclear
if this would have introduced a bias in these unblinded studies.
The remaining 22 studies were assessed at low risk of other bias.
Overall risk of bias

Overall just five of the included studies (14%) were assessed at low
risk of bias (Bellissimo-Rodrigues 2009; Fourrier 2005; Koeman
2006; Ozcaka 2012; Sebastian 2012) for all domains and 13 studies (37%) were at unclear risk of bias for at least one domain.
Nearly half of the included studies (17 studies, 49%) were at high
risk of bias in at least one domain (Figure 1; Figure 2).
Effects of interventions
See: Summary of findings for the main comparison
Chlorhexidine (mouthrinse or gel) versus placebo/usual care for
critically ill patients to prevent ventilator-associated pneumonia;
Summary of findings 2 Toothbrushing ( chlorhexidine) versus
no toothbrushing ( chlorhexidine) for critically ill patients to
prevent ventilator-associated pneumonia
Comparison 1: Chlorhexidine versus placebo/usual

care (with or without toothbrushing)
Chlorhexidine antiseptic was evaluated in a total of 20 studies included in this review, but only 17 studies could be included in
meta-analysis for VAP. One study was a very small pilot study
(Bopp 2006, n = 5) and no usable outcome data could be extracted, another study (McCartt 2010) did not report outcome
data in a form that could be used in a meta-analysis. The study
by Scannapieco 2009 reported data in a graph only and stated
that there was no difference between the two chlorhexidine groups
and the control group in the outcome of VAP. Available data from
these studies are recorded in Additional Table 1.
Five of the 20 studies were assessed at high risk of bias (Bopp 2006;
Grap 2004; Grap 2011; McCartt 2010; Munro 2009), four studies
were at low risk of bias (Bellissimo-Rodrigues 2009; Fourrier 2005;
Koeman 2006; Ozcaka 2012) and the remaining 11 studies were
at unclear risk of bias.
These studies have been subgrouped according to whether
chlorhexidine was administered as a liquid mouthrinse or a gel,
and whether chlorhexidine was used in conjunction with toothbrushing or not.
Incidence of VAP
Overall the combined meta-analysis of 17 studies (two at high

risk of bias, 11 at unclear risk of bias and four at low risk of bias)
showed a reduction in VAP with use of chlorhexidine odds ratio
(OR) 0.60, 95% confidence interval (CI) 0.47 to 0.77, P < 0.001,
I2 = 21%) (Analysis 1.1). The statistical heterogeneity observed in
this estimate is not likely to be important.
Seven studies (with a total of 1037 participants) compared
chlorhexidine solution (0.12% or 0.2%) with either placebo (six
studies) or usual care (Grap 2011) without toothbrushing. However, six studies report the use of a swab to either clean the mouth
prior to chlorhexidine application, or to ensure that the chlorhexidine solution was applied to all oral surfaces. (In the study by
Chen 2008 the mode of application is unclear.)
The meta-analysis showed a reduction in VAP in the chlorhexidine
group (OR 0.60, 95% CI 0.38 to 0.94, P = 0.03, I2 = 41%)
(Analysis 1.1, Subgroup 1.1.1). This equates to a number needed
to treat (NNT) of 15 (95% CI 10 to 34).
A further five studies (669 participants) compared chlorhexidine
gel (0.2% or 2%) with placebo (no toothbrushing in either group)
and the meta-analysis showed a similar reduction in VAP associated with chlorhexidine gel (OR 0.57, 95% CI 0.31 to 1.06, P =
0.08, I2 = 45%) (Analysis 1.1, Subgroup 1.1.2).
Three studies (total 408 participants) compared chlorhexidine solution (2%, 0.12% or 0.2%) with placebo (with toothbrushing
in both groups). The meta-analysis showed a reduction in VAP
in the chlorhexidine group (OR 0.44, 95% CI 0.23 to 0.85, P =
0.01, I2 = 0%) (Analysis 1.1, Subgroup 1.1.3).
19
A further study (Kusahara 2012, including 96 children) at unclear

risk of bias compared chlorhexidine gel (0.12%) with placebo
(with toothbrushing in both groups) and found no difference in
the incidence of VAP (Analysis 1.1, Subgroup 1.1.4).
Munro 2009 reported the results from some of the patients randomised into a study with a factorial design. This study showed a
reduction in VAP which did not attain statistical significance (P =
0.06) associated with the use of chlorhexidine, where exposure to
toothbrushing was equal in both groups (Analysis 1.1, Subgroup
1.1.5).
The pilot study by Bopp 2006 also showed a reduction in VAP associated with chlorhexidine. McCartt 2010 did not report VAP as
an outcome, but instead reported mean CPIS scores. While CPIS
> 6 may generally be considered to indicate VAP, this study did
not dichotomise the outcome data. Mean CPIS score showed no
evidence of a difference between chlorhexidine alone, chlorhexidine + toothbrushing and usual care, perhaps because mean CPIS
lacks sensitivity as an outcome measure (Additional Table 1).
Mortality
The outcome of mortality was reported in 15 studies and overall the meta-analysis showed no evidence of a difference between
chlorhexidine and placebo/usual care with minimal heterogeneity
(OR 1.10, 95% CI 0.87 to 1.38, P = 0.44, I2 = 2%) (Analysis
1.2).
Likewise there was no evidence of a difference in mortality in
all of the subgroups (chlorhexidine mouthrinse with or without
toothbrushing).
Chlorhexidine mouthrinse (no toothbrushing) compared to
placebo/usual care (OR 1.16, 95% CI 0.72 to 1.88, P = 0.54, I2
= 36% (Analysis 1.2, Subgroup 1.2.1).
Chlorhexidine gel (no toothbrushing) compared to
placebo/usual care (OR 0.89, 95% CI 0.45 to 1.76, P = 0.73, I2
= 43%) (Analysis 1.2, Subgroup 1.2.2).
Chlorhexidine mouthrinse plus toothbrushing versus
toothbrushing alone (OR 1.09, 95% CI 0.72 to 1.64, P = 0.69, I
2 = 0%) (Analysis 1.2, Subgroup 1.2.3).
The single study (Kusahara 2012) of children receiving
chlorhexidine gel + toothbrushing versus usual care (including
toothbrushing) also showed no difference in the outcome of
mortality (Analysis 1.2, Subgroup 1.2.4).
Koeman 2006 comparing chlorhexidine gel with placebo
showed no difference in mortality (Additional Table 1).
There was no evidence of a difference in duration of ventilation

in any of the subgroups.
Likewise there was no evidence of a difference between the group

receiving chlorhexidine rinse solution compared to placebo/usual
care in the outcome of duration of ICU stay (six RCTs, MD 0.21
days, 95% CI -1.48 to 1.89, P = 0.81, I2 = 9%) and similarly there
was no evidence of a difference in two subgroups (Analysis 1.4,
Subgroup 1.4.1; Analysis 1.4, Subgroup 1.4.2) and insufficient
evidence to determine whether or not there was a difference in
Analysis 1.4, Subgroup 1.4.3.
Duration of systemic antibiotic therapy
Two trials (total of 374 participants) reported this outcome and

there was insufficient evidence to determine whether or not there
is a difference in duration of use of systemic antibiotics between
the chlorhexidine and control groups (MD 0.23 days, 95% CI 0.85 to 1.30, P = 0.68, I2 = 50%) with moderate heterogeneity
probably due to the differences between the two studies in the
mode of chlorhexidine used (Analysis 1.5).
There was also insufficient evidence to determine whether there

is a difference between chlorhexidine and control groups in the
outcome of positive microbiological cultures (three studies, OR
0.69, 95% CI 0.35 to 1.33, P = 0.26, I2 = 70%) (Analysis 1.6). We
combined the two chlorhexidine groups in the Grap 2004 study
for the meta-analysis and the raw data are recorded in Additional
Table 1. Two studies of adults (Cabov 2010; Grap 2004) reported
cultures from the mouth, and trachea respectively and the third
study (Kusahara 2012) of children, reported oropharyngeal culture
results. The clinical differences between these studies may explain
some of the heterogeneity in the meta-analysis.
Another study (Berry 2011) where the data could not be incorporated into the meta-analysis showed no difference in positive cultures between the interventions compared (Additional Table 1).
Oral health indices: plaque index
From the six studies which reported this outcome there is no evidence of a difference in the duration of ventilation between the
groups receiving chlorhexidine solution compared to those receiving placebo/usual care (mean difference (MD) 0.09, 95% CI 0.84 to 1.01 days, P = 0.85, I2 = 24%) (Analysis 1.3).
Two of the studies in this group (Ozcaka 2012; Scannapieco

2009) reported the outcome of plaque index but only Ozcaka
2012 reported numerical data. Neither study found a difference
in plaque indices between the chlorhexidine and control groups
(Analysis 1.7, Additional Table 1).
20
Adverse effects
Three studies in this group reported adverse effects. BellissimoRodrigues 2009 reported that three patients in the chlorhexidine
group and five in the placebo group found the taste unpleasant
and Tantipong 2008 found mild reversible irritation of the oral
mucosa in 10% of the chlorhexidine patients compared to 1% of
the control group patients (Analysis 1.8). Berry 2011 stated that
there were no adverse effects in either group.
Adverse effects were not mentioned in the other studies in this
group.
The outcomes of caregivers preferences and cost were not reported.
Heterogeneity
There is moderate heterogeneity in two of the subgroups (Analysis 1.1, Subgroups 1.1.1 and 1.1.2) which is likely to be due
to clinical differences between these studies, due to variability in
the frequency, application method, volume and concentration of
chlorhexidine solution. In Subgroup 1.1.1, six of the seven studies
used a placebo control and the volume of chlorhexidine (either
0.12% or 0.2%) used varied between 10 and 50 ml administered
either two, three or four times daily. One study (Grap 2011) used
a single application by swab of a very small volume of chlorhexidine pre-operatively. One of the seven studies was on children aged
from birth to 14 years (Jacomo 2011) and the others recruited
adults. In Subgroup 1.1.2, there is also moderate heterogeneity
which may be due to variations in the way the intervention was
delivered. Three of the five studies in this subgroup (Cabov 2010;
Fourrier 2000; Fourrier 2005) administered 0.2% chlorhexidine
gel three times daily following rinsing of the mouth and aspiration
of rinse. The other two studies (Koeman 2006; Sebastian 2012)
used a gel with higher chlorhexidine concentration (2% and 1%
respectively) and applied the gel using a swab.
Sensitivity analysis
For the primary outcome of VAP we conducted a sensitivity analysis excluding the studies at high risk of bias. The estimate remained very similar (OR 0.61, 95% CI 0.49 to 0.78, P < 0.001,
I2 = 29%).
However a meta-analysis of the three studies of children (Jacomo
2011; Kusahara 2012; Sebastian 2012) (342 participants, aged
from 3 months to 15 years) provided no evidence that chlorhexidine compared to placebo showed a difference in the outcomes
of VAP (OR 1.07, 95% CI 0.65 to 1.77, P = 0.79, I2 = 0%) or
mortality (OR 0.73, 95% CI 0.41 to 1.30, P = 0.28, I2 = 0%)
(Analyses not shown).
Publication bias
Each of the subgroups in this comparison contained a small number of studies and therefore it was not appropriate to produce a
funnel plot to investigate possible publication bias.
Comparison 2: Toothbrushing versus no

toothbrushing
The eight studies included in this comparison (Bopp 2006; Fields
2008; Lorente 2012; Munro 2009; Needleman 2011; Pobo 2009;
Roca Biosca 2011; Yao 2011) all had toothbrushing as part of the
intervention, versus no toothbrushing in the control group. Six
of these studies were at high risk of bias and two studies (Lorente
2012; Yao 2011) had an unclear risk of bias. Three studies used
a powered toothbrush (Pobo 2009; Roca Biosca 2011; Yao 2011
) and five used a manual toothbrush. One study (Bopp 2006)
was a very small pilot study (n = 5) and the data from this study
are recorded in Additional Table 1, and the study by Fields 2008
reported no numerical data at all. The study by Roca Biosca 2011
did not report data for each arm of the study and we were not
able to obtain these data from the authors. Available data from
this study are recorded in Additional Table 1.
Incidence of VAP
One small study (Yao 2011, 53 participants), at high risk of bias,

compared usual care plus the addition of twice daily toothbrushing with a powered toothbrush, to usual care alone, and found a
reduction in VAP. The usual care intervention comprised patients
bed being elevated 30 to 45 degrees, hypopharyngeal suctioning,
lips moistened with toothette swab and water, then further hypopharyngeal suctioning. A second study with 147 participants,
also assessed at high risk of bias (Pobo 2009), compared powered
toothbrushing plus usual care including chlorhexidine , with usual
care alone and found no difference in the outcome of VAP. The
combined estimate from these studies showed no difference in the
incidence of VAP (OR 0.35, 95% CI 0.06 to 1.97, P = 0.23, I2 =
81%) (Analysis 2.1, Subgroup 2.1.1) with the heterogeneity likely
due to the additional exposure to chlorhexidine in both groups of
only one of the studies.
In Lorente 2012 where the intervention group received toothbrushing with a manual toothbrush as well as chlorhexidine, compared to chlorhexidine alone in the control group, there was no
evidence of a difference in the incidence of VAP between the intervention and control groups.
A study with a factorial design (Munro 2009) compared toothbrushing with no toothbrushing (equal exposure to chlorhexidine
in both arms), and reported no difference in the development of
VAP (Analysis 2.1, Subgroup 2.1.3).
Bopp 2006 was a very small pilot study (n = 5) of toothbrushing
versus none, and the data are reported in Additional Table 1. There
were no numerical outcome data in the study by Fields 2008;
the report makes the statement that the VAP rate dropped to
21
zero within a week of beginning the every 8 hours toothbrushing

regimen in the intervention group. This rate of zero incidence
of VAP was reportedly sustained for 6 months. Roca Biosca 2011
recruited 117 participants and reported a summary estimate for
the outcome of VAP and found no difference between powered
toothbrushing and no toothbrushing (Additional Table 1).
The combined meta-analysis of four studies (Lorente 2012; Munro
2009; Pobo 2009; Yao 2011) shows no evidence of a difference
in the incidence of VAP due to toothbrushing (OR 0.69, 95%
CI 0.36 to 1.29, P = 0.24 , I2 = 64%) with substantial statistical
heterogeneity likely to be explained by the differences in exposure
to chlorhexidine between the studies (Analysis 2.1).
Oral health indices: plaque score
Two studies (Needleman 2011; Yao 2011) also reported the outcome of plaque score in each group after 5 days or 7-8 days respectively. Each study used a different scale so these data were
combined for meta-analysis using standardised mean difference
(SMD) and showed evidence of reduced plaque in the toothbrushing group (SMD -1.20, 95% CI -1.70 to -0.70, P < 0.001, I2 =
0%) (Analysis 2.6).
Roca Biosca 2011 reported plaque scores, without any estimates
of variance. The trial report also stated that there was no difference
between the groups (Additional Table 1).
Adverse effects
Mortality
Four studies (Lorente 2012; Munro 2009; Pobo 2009; Yao 2011)
evaluated the effect of toothbrushing as an addition to oral care,
on the outcome of mortality. The comparisons were slightly different in each trial but the overall meta-analysis found no evidence
of a difference between intervention and control groups without
heterogeneity (OR 0.85, 95% CI 0.62 to 1.16, P = 0.31, I2 = 0%)
(Analysis 2.2).
Meta-analysis of two trials (total 583 participants) reported the

outcome of mean duration of mechanical ventilation, and showed
no difference associated with toothbrushing (MD -0.85 days, 95%
CI -2.43 to 0.73 days, P = 0.29, I2 = 0%) (Analysis 2.3).
The data from Bopp 2006 are reported in Additional Table 1.
Meta-analysis of two trials (total 583 participants) which reported

the outcome of mean duration of ICU stay found no evidence of a
difference between the groups (MD -1.82, 95%CI -3.95 to 0.32,
P = 0.10, I2 = 0%, Analysis 2.4). The data from Bopp 2006 are
reported in Additional Table 1.
Duration of systemic antibiotic therapy
This outcome was not reported by any of the studies in this group.
Pobo 2009 reported that there were no adverse effects reported

in either arm of the study and none of the other studies in this
comparison mentioned adverse effects.
The outcomes of caregivers preferences and cost were not reported.
Comparison 3: Powered toothbrushing versus manual

toothbrushing
One small study of 78 participants (Prendergast 2012), assessed
at high risk of bias, compared the use of a powered toothbrush
as a component of comprehensive oral care with a control group
receiving manual toothbrushing and standard oral care.
In this study there was no difference between the intervention and
control groups with regard to the outcomes of incidence of VAP,
mortality or mean duration of ventilation or ICU stay (Analysis
3.1; Analysis 3.2; Analysis 3.3; Analysis 3.4). There were no adverse effects mentioned in this study. The outcomes of oral health
indices, microbiological cultures, systemic antibiotic therapy, caregivers preferences for oral hygiene care or cost were not reported
in the study.
Comparison 4: Other oral care solutions

Nine studies (Berry 2011; Caruso 2009; Feng 2012; Hu 2009;
Long 2012; Seguin 2006; Xu 2007; Xu 2008; Zhao 2012) with
a combined total of 1457 participants randomised to treatments,
and all at high risk of bias, evaluated the effects of other solutions
with a potential antiseptic effect on the outcomes of VAP, mortality
and duration of ventilation.
One small study (Needleman 2011, n = 28) reported the number of

patients per group with colonisation of plaque by VAP-associated
pathogens and found no difference between the intervention and
control groups (Analysis 2.5).
Incidence of VAP
Two studies (Feng 2012; Seguin 2006) compared povidone iodine

rinse with a saline rinse and showed evidence of a reduction in
VAP (OR 0.35, 95% CI 0.19 to 0.65, P < 0.001, I2 = 53%).
22
The heterogeneity in this estimate could be due to the additional

intervention of toothbrushing in both groups in Feng 2012.
Seguin 2006 also compared povidone iodine rinse with usual care
(suction alone with no rinse) and found a reduction in VAP. The
result of this study has not been replicated so should be interpreted
with caution.
Long 2012 compared povidone iodine rinse plus toothbrushing
with povidone iodine rinse alone and found a reduction in VAP.
The result of this study has not been replicated so should be interpreted with caution.
Two small studies with a total of 83 participants (Xu 2007; Xu
2008), both at high risk of bias, which compared a saline rinse
with a saline soaked swab found no difference in incidence of VAP
(OR 0.65, 95% CI 0.37 to 1.14, P = 0.13, I2 = 41%).
The studies by Hu 2009 and Xu 2007, both at high risk of bias,
compared both saline rinse plus swab, with a saline soaked swab
alone (usual care) and found some very weak evidence (from total
of 40 participants) that the combined rinse plus swab reduced the
incidence of VAP (OR 0.30, 95% CI 0.14 to 0.63, P = 0.002, I2
= 0%).
Two studies (Caruso 2009; Seguin 2006), both at high risk of bias,
compared a saline rinse with usual care (no rinse) and found a
reduction in VAP (OR 0.50, 95% CI 0.29 to 0.88, P = 0.02, I2
= 39%). While this result should be interpreted cautiously due to
the high risk of bias, there appears to be some evidence that the
use of a saline rinse prior to aspiration of secretions was associated
with reduction of ventilator-associated pneumonia.
A single study (Berry 2011), at high risk of bias, compared bicarbonate rinse plus toothbrushing with a water rinse plus toothbrushing and found no difference in the incidence of VAP.
Another single study (Zhao 2012) compared triclosan rinse with
saline rinse and found no difference in the outcome of VAP over the
duration of the study (Analysis 4.1, Subgroup 4.1.8). The results
of this study have not been replicated so should be interpreted
with caution.
A single 3-arm study compared povidone iodine, furacilin and
usual care (Feng 2012) and found both antiseptics combined with
toothbrushing were more effective than usual care (Analysis 4.1,

Subgroup 4.1.1 and Analysis 4.1, Subgroup 4.1.10) with little difference between the two antiseptic solutions (Analysis 4.1, Subgroup 4.1.9).
Mortality
There was only a single study at high risk of bias in each of five subgroups reporting mortality (Analysis 4.2, Subgroups 4.2.1, 4.2.2,
4.2.3, 4.2.4 and 4.2.6), providing insufficient evidence to determine whether or not there is a difference in mortality. Two studies comparing saline rinse with usual care with no rinse (Caruso
2009; Seguin 2006) showed no difference in mortality (OR 1.20,
95% CI 0.77 to 1.87, P = 0.43, I2 = 0%) (Analysis 4.2, Subgroup
4.2.5). There is no evidence of a difference in mortality for any of
the comparisons reported.
Duration of ventilation and duration of ICU stay
These outcomes were evaluated by single studies within each subgroup, providing insufficient evidence to determine whether or
not there is a difference between the various interventions and
controls.
Saline rinse versus usual care (with no rinse) was evaluated by two
studies (Caruso 2009; Seguin 2006) and there was no evidence
of a difference in either duration of ventilation (MD -0.40 days,
95% CI -2.55 to 1.75, P = 0.72, I2 = 0%) or duration of ICU stay
(MD -1.17 days, 95% CI -3.95 to 1.60, P = 0.41, I2 = 32%).
One study (Feng 2012) reported a reduction in positive cultures

in the povidone iodine group but the results of this study have not
been replicated so should be interpreted with caution.
None of these nine studies reported the outcomes of duration of
systemic antibiotic therapy, adverse effects, caregivers preferences
for oral hygiene care or cost.
23
A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Toothbrushing ( chlorhexidine) versus no toothbrushing ( chlorhexidine) for critically ill patients to prevent ventilator-associated pneumonia (VAP)
Patient or population: Critically ill patients to prevent ventilator-associated pneumonia
Settings: Intensive care units (ICUs)
Intervention: Toothbrushing ( chlorhexidine)
Comparison: No toothbrushing ( chlorhexidine)
Outcomes
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
No toothbrushing
Toothbrushing
Relative effect
(95% CI)
No of participants
(studies)

(GRADE)
Comments
Incidence of VAP
245 per 1000 1
183 per 1000

(105 to 295)
OR 0.69
(0.36 to 1.29)
828
(4 studies)2

low,3,4
Mortality
277 per 1000 1
245 per 1000

(192 to 307)
OR 0.85
(0.62 to 1.16)
828
(4 studies)

moderate2
The mean duration of
Follow-up: mean 1 month ventilation in the control
groups ranged from 9.8
to 10 days
The mean duration of ventilation in the intervention

groups was
0.85 lower
(2.43 lower to 0.73
higher)
583
(2 studies)

moderate 6

Follow-up: mean 1 month stay in the control groups
ranged from 13 to 15
days

stay in the intervention
groups was
1.82 lower
(3.95 lower to 0.32
higher)
583
(2 studies)

moderate6
24
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate
1
Assumed risk is based on the outcomes in the control groups of the included studies
3 studies compared toothbrushing + chlorhexidine with chlorhexidine alone and the fourth study compared toothbrushing with no
toothbrushing (no chlorhexidine in either group)
3 2 studies at high risk of bias and 2 studies at unclear risk of bias
4 Substantial heterogeneity (I2 = 64%). Meta-analysis of 3 studies with chlorhexidine in both groups shows no heterogeneity (I2 = 0%)
5
A fifth study, which randomised 117 participants showed no difference between toothbrushing + chlorhexidine and chlorhexidine alone
(OR 0.78, 95% CI 0.36 to 1.68, P = 0.56). This study was at high risk of bias, and there was insufficient information to include data
from this study in the meta-analysis
6 1 study at high risk of bias and 1 study at unclear risk of bias
2
25
DISCUSSION
Summary of main results

Thirty-five randomised controlled trials are included in this review
and these studies evaluate four main groups of interventions, in
the oral hygiene care of critically ill patients receiving mechanical
ventilation in intensive care units.
Chlorhexidine antiseptic versus placebo/usual care (with or
without toothbrushing)
There is moderate quality evidence from 17 RCTs that the use of
chlorhexidine (either as a mouthrinse or a gel) reduces the odds
of developing VAP (OR 0.60, 95% CI 0.47 to 0.77, P < 0.001, I
2 = 21%) (Summary of findings for the main comparison), with
an NNT of 15 (95% CI 10 to 34). There is no evidence that use
of chlorhexidine is associated with a difference in mortality (15
studies), duration of mechanical ventilation (six studies) or duration of ICU stay (six studies) (moderate quality evidence). There
is insufficient evidence to determine the effect of chlorhexidine on
the other secondary outcomes of this review.
From the three studies of children there was no evidence of a
difference between chlorhexidine and placebo for the outcomes of
VAP and mortality (moderate quality evidence).
Toothbrushing versus no toothbrushing (with or without
chlorhexidine)
Based on four RCTs (low quality evidence) we found no evidence
of a difference between oral care with chlorhexidine plus toothbrushing and oral care with chlorhexidine alone with regard to the
outcome of VAP (OR 0.69, 95% CI 0.36 to 1.29, P = 0.24 , I2 =
64%). There is no evidence of a difference between toothbrushing or no toothbrushing for the outcomes of mortality (OR 0.85,
95% CI 0.62 to 1.16, P = 0.31, I2 = 0%), duration of ventilation
(MD -0.85 days, 95% CI -2.43 to 0.73, P = 0.29, I2 = 0%) or
duration of ICU stay (MD -1.82 days, 95% CI -3.95 to 0.32 days,
P = 0.10, I2 = 0%) (moderate quality evidence).
Oral care with powered toothbrush versus oral care with
manual toothbrush
From the single study in this comparison there is insufficient evidence to determine the effects of powered versus manual toothbrushing on the outcomes of VAP, mortality, duration of mechanical ventilation or duration of ICU stay.
Oral care with other solutions
The studies in this comparison were at high overall risk of bias
and made different comparisons. There is some weak evidence
that povidone iodine rinse is more effective than saline in reducing
VAP (OR 0.35, 95% CI 0.19 to 0.65, P = 0.0009, I2 = 53%)
(two studies, 206 participants, high risk of bias). We found no
evidence of a difference between a saline swab and a saline rinse
with regard to the reduction of VAP (OR 0.65, 95% CI 0.37 to
1.14, P = 0.13, I2 = 41%) (two studies, 83 participants, high risk
of bias), and very weak evidence that use of both a saline swab and
a saline rinse may be more effective than a saline swab alone (OR
0.30, 95% CI 0.14 to 0.63, P = 0.002, I2 = 0%) (two studies, 40
participants, high risk of bias). There is insufficient evidence to
clearly determine the effectiveness of any of the oral care solutions
for any of the outcomes evaluated.
Overall completeness and applicability of

evidence
In this review we have included studies which compared active oral
hygiene care interventions with either placebo or usual care. We
recognise that the use of a placebo is a better control comparison
in research studies because it enables the masking of caregivers as
to which patients are in the active or control group, thus eliminating some possible performance bias. However, we chose to include
pragmatic studies where usual care was the control comparator,
despite recognising that in many instances usual care was not
specified and may have varied between patients and between individual caregivers. Likewise in some of the included studies, the
precise details of what was involved in the oral hygiene care intervention were poorly described making it difficult to determine
the similarity in oral hygiene care practices between studies.
We also recognise that participation in a research study is likely to
have a positive effect on the performance of usual care improving
both the quality of care and compliance with routine practice - a
Hawthorne effect (McCarney 2007). The combination of a usual
care control group, the absence of caregiver blinding in most cases,
and the Hawthorne effect of being part of a study may have reduced
the observed difference in effect between the active and control
interventions in these studies. Two of the studies noted that care
was recorded in patient notes but none of the studies included in
this review reported compliance with oral hygiene care protocols.
Another area of variability between the studies (and possibly also
between studies and usual practice) is the diagnosis of VAP, which
is at least partly subjective and may be made based on variable
diagnostic criteria. Most studies (26/35) stated the criteria used
to diagnose VAP, and the two most common were some version
of the clinical pulmonary infection score (CPIS) based on Pugins
criteria (Cook 1998; Pugin 1991) (16 studies) and Centers for
Disease Control (CDC) criteria as described in Horan 2008 (six
studies). Four studies conducted in China (Chen 2008; Feng
2012; Xu 2007; Xu 2008) used Chinese Society of Respiratory
Diseases (CSRD) criteria for diagnosis of VAP. In two studies some
of the study participants had pneumonia at baseline (Munro 2009;
Sebastian 2012).
Although this review found evidence that the use of chlorhexidine
as part of oral care reduces the incidence of VAP, there was no
evidence of a reduction in mortality. There is some debate in the
literature about the attributable mortality of VAP, but a recent
survival analysis of nearly 4500 patients found that ICU mortality
26
attributable to VAP was about 1% on day 30 (Bekaert 2011),

which might explain our findings.
This review has not found evidence that oral care including both
toothbrushing and chlorhexidine is different from oral care with
chlorhexidine alone in reducing VAP. Only one of the trials of
toothbrushing which reported the outcome of VAP also reported
plaque levels as an indicator of the effectiveness of the toothbrushing carried out in this trial (Yao 2011). This small trial (53 participants), which was assessed at high risk of bias, did not use chlorhexidine in either group, and found a reduction in both plaque and
VAP in the powered toothbrushing group compared to the no
toothbrushing group. Three other trials of toothbrushing in our
meta-analysis (Lorente 2012 (manual), Munro 2009 (manual),
Pobo 2009 (powered toothbrush)), with a combined total of 775
participants included exposure to chlorhexidine in both intervention and control groups. Assessed at unclear, high and high risk of
bias respectively, meta-analysis of these three trials showed no evidence of a difference in the outcome of VAP. A further study (Roca
Biosca 2011), included in this review and also at high risk of bias,
was not able to be included in the meta-analysis, but also found no
difference between oral care with chlorhexidine and toothbrushing and oral care with chlorhexidine alone. All five of these studies
describe the toothbrushing intervention in detail, and note that
nurses delivering the intervention received specific training. While
the presence of ventilator tubes in the mouths of trial participants
makes effective toothbrushing difficult, despite this, it seems likely
that the toothbrushing intervention was carried out thoroughly
within these trials.
Earlier cohort studies noted that patients in ICU who developed
VAP were likely to have increased length of stay in the ICU
(Apostolopoulou 2003; Cook 1998). However, this Cochrane review has not evaluated duration of ICU stay in patients who develop VAP. The studies in this review report mean length of ICU
stay and the standard deviation for each arm of the study. These
are combined in meta-analysis based on an assumption the duration of ICU stay in each arm of each trial follows an approximately
normal distribution. In fact the distribution of duration of stay in
ICU is likely to be skewed and the means are likely to be a poor
indicator of the effect of oral hygiene care on duration of ICU
stay.
This systematic review has not looked at the outcome of cost
of interventions. However, it is likely that the additional cost of
using an antiseptic mouthrinse or gel is low in comparison with
the cost of the antibiotics used to treat VAP. One study (Jacomo
2011) reported the cost of the chlorhexidine gluconate solution
per patient was USD 3.15. Reducing the incidence of VAP using
relatively inexpensive additions to usual care is likely to be a cost
effective, as well as avoiding additional morbidity for the patient.
It is interesting that only mild adverse reactions of chlorhexidine
were reported in three of the 20 studies which evaluated chlorhexidine. In over 2000 participants included in these studies there
was no report of hypersensitivity to chlorhexidine.
Three of the included studies evaluated chlorhexidine in children

aged from a few months to 15 years. These studies found no evidence of a difference in VAP associated with including chlorhexidine in oral hygiene care. The reason(s) for this are unclear.

All the included studies were prospective, randomised controlled
trials but only five of the included studies (14%) were assessed
at low risk of bias (Bellissimo-Rodrigues 2009; Fourrier 2005;
Koeman 2006; Ozcaka 2012; Sebastian 2012) for all domains, 13
studies (37%) were at unclear risk of bias for at least one domain.
Nearly half of the included studies (17 studies, 49%) were at high
risk of bias in at least one domain.
Potential biases in the review process

In order to reduce the risk of publication bias we conducted a
broad search, for both published and unpublished studies, and
there were no restrictions on language. We searched the reference
lists of included studies and contacted many of the authors of
the included studies in order to obtain information that was not
included in the published reports. We also searched the reference
lists of other published reviews of oral hygiene care for critically
ill patients.
We have made a number of changes to the methods of this review since the publication of the protocol (see Differences between
protocol and review). Some of these changes were clarifications,
and some were to take account of other Cochrane reviews published or in preparation, to avoid unnecessary duplication of effort. We acknowledge that post hoc changes to the review methods
may introduce a risk of bias into this review.
Agreements and disagreements with other

studies or reviews
A recent meta-analysis by Pineda 2006 found that the use of
chlorhexidine for oral decontamination did not reduce the incidence of nosocomial pneumonia. However this meta-analysis included only four studies and the outcome was nosocomial pneumonia rather than VAP. A recent review by Labeau 2011 included
14 studies of either chlorhexidine or povidone iodine antiseptics
and found that the use of antiseptics as part of oral hygiene care
reduced the incidence of VAP by approximately one third. Our
review confirmed these findings.
Two published meta-analyses (Alhazzani 2013; Gu 2012) of toothbrushing to reduce VAP included four trials and found no evidence of a difference in incidence of VAP, again possibly due to
low statistical power. Our review has similar conclusions.
27
AUTHORS CONCLUSIONS
Implications for practice
3. Full reporting of methods used to diagnose ventilatorassociated pneumonia.

4. Reporting of adverse effects of interventions.
Effective oral hygiene care is important for ventilated patients in

intensive care to reduce ventilator-associated pneumonia. There
is evidence from this review that oral hygiene care incorporating
chlorhexidine mouthrinse or gel, is effective in reducing the development of ventilator-associated pneumonia in adult patients in
intensive care. The definition of oral hygiene care varied among
the studies included in this review but common elements include
cleaning of the teeth and gums with a swab or gauze, removing
secretions using suction and rinsing the mouth.
Implications for research

Although the included studies provided some evidence of the benefits of oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia, incomplete reporting of studies is a
major limitation. More consistent use of the CONSORT statement for reporting of randomised controlled clinical trials would
increase the value of research.
1. Detailed reporting of methods, such as generation of
allocation sequence, allocation concealment, and numbers and
reasons for withdrawals and exclusions.
2. Use of a placebo where possible to enable blinding.
Further trials of oral hygiene care (including use of manual or

powered toothbrushes, or swabs) should report both measures of
effectiveness of plaque removal and prevention of ventilator-associated pneumonia.
ACKNOWLEDGEMENTS
Thanks to Anne Littlewood, Trials Search Co-ordinator of
Cochrane Oral Health Group for refining search strategies, providing searching results from the databases of CINAHL via EBSCO,
LILACS and OpenSIGLE; to Luisa Fernandez-Mauleffinch,
Philip Riley, and Anne-Marie Glenny for kind help in developing
and refining this review. Our thanks to Ruth Floate for preparing the plain language summary. Our thanks to Luisa FernandezMauleffinch for translation of Santos 2008 from Portuguese and
Roca Biosca 2011 from Spanish, and to Phil Riley for assisting
with the data extraction and risk of bias assessment. Our thanks
to Mervyn Singer for his assistance in clarifying the details of the
criteria for including studies in this review. Our thanks to Tina
Poklepovic for her help in obtaining additional data for one of the
included studies (Cabov 2010).
REFERENCES
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Jacomo 2011 {published data only}
Jacomo AD, Carmona F, Matsuno AK, Manso PH, Carlotti
AP. Effect of oral hygiene with 0.12% chlorhexidine
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children undergoing cardiac surgery. Infection Control &
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Koeman 2006 {published data only}
Koeman M, van der Ven AJ, Hak E, Joore HC,

Kaasjager K, de Smet AG, et al.Oral decontamination with
chlorhexidine reduces the incidence of ventilator-associated
pneumonia. American Journal of Respiratory & Critical Care
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Koeman M, van der Ven AJ, Hak E, Joore JC, Kaasjager
HA, de Smet AM, et al.Less ventilator-associated
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Kusahara 2012 {published data only}
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with 0.12% chlorhexidine for the prevention of ventilatorassociated pneumonia in critically ill children: Randomised,
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Long 2012 {published data only}
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Lorente 2012 {published data only}
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Lafuente N, et al.Ventilator-associated pneumonia with
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McCartt 2010 {published data only}
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Mechanical Toothbrushing and Chlorhexindine Rinse in
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Adults [PhD thesis]. Gainesville, Florida, USA: University of
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Munro 2009 {published data only}
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Ozcaka 2012 {published data only}
Ozcaka O, Basoglu OK, Buduneli N, Tasbakan MS,
Bacakoglu F, Kinane DF. Chlorhexidine decreases the risk
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Abusibeih 2010 {published data only}
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36:S329.
Scannapieco 2009 {published data only}

Scannapieco FA, Yu J, Raghavendran K, Vacanti A, Owens
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Bordenave 2011 {published data only}

Bordenave C. Evaluation of the effectiveness of a protocol
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chlorhexidine 0.12%) on the colonisation of tracheal
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Sebastian 2012 {published data only}

Sebastian MR, Lodha R, Kapil A, Kabra SK. Oral mucosal
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Seguin P, Tanguy M, Laviolle B, Tirel O, Malledant Y.
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30
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Zouka M, Soultati I, Hari H, Pourzitaki C, Paroutsidou G,
Thomaidou E, et al.Oral dental hygiene and ventilatorassociated pneumonia prevention in an ICU setting:
Comparison between two methods (preliminary data of a
randomised prospective study). Intensive Care Medicine
2010;36:S103.
References to studies awaiting assessment

Anon 2012 {published data only}
Anon. EB57 Development of an oral care-based programme
for prevention of ventilator-associated pneumonia. Critical
Care Nurse 2012;32(2):e34.
Baradari 2012 {published data only}
Baradari AG, Khezri HD, Arabi S. Comparison of
antibacterial effects of oral rinses chlorhexidine and herbal
mouth wash in patients admitted to intensive care unit.
Bratislavske Lekarske Listy 2012;113(9):55660.
Seo 2011 {published data only}
Seo H-K, Choi E-H, Kim J-H. The effect of oral hygiene for
ventilator-associated pneumonia (VAP) incidence. Journal
of Korean Critical Care Nursing 2011;4(2):1.
Yun 2011 {published data only}
Yun H-Y, Lee E-S, Kim J-Y, Kim H-S, Kim K-A, Kim E-S,
et al.Effect of tooth-brushing on oral health and ventilator-
31
associated pneumonia of critically ill patients. Journal of

Korean Critical Care Nursing 2011;4(2):1.
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NCT 01657396 {unpublished data only}
Implementation and evaluation of revised protocols for oral
hygiene for mechanically ventilated patients. Ongoing
study July 2012 (currently recruiting).
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Alhazzani W, Smith O, Muscedere J, Medd J, Cook D.
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Apostolopoulou E, Bakakos P, Katostaras T, Gregorakos
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ATS Guideline 2005
American Thoracic Society, Infectious Diseases Society of
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Azarpazhooh 2006
Azarpazhooh A, Leake JL. Systematic review of the
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Azoulay 2006
Azoulay E, Timsit JF, Tafflet M, de Lassence A, Darmon
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Bekaert 2011
Bekaert M, Timsit JF, Vansteelandt S, Depuydt P, Vsin
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El-Solh 2004
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Pugin J, Auckenthaler R, Mili N, Janssens JP, Lew
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Scannapieco FA, Stewart EM, Mylotte JM. Colonization of
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Schulz KF, Grimes DA. Generation of allocation sequences
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Tablan OC, Anderson L, Besser R, Bridges C, Hajjeh R.
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Terpenning M. Geriatric oral health and pneumonia risk.
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Treloar DM, Stechmiller JK. Use of a clinical assessment
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Whittaker CJ, Lier CM, Kolenbrander PE. Mechanisms of
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Indicates the major publication for the study
33
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Bellissimo-Rodrigues 2009
Methods
Study design: RCT, 2 parallel groups

Location: Sao Paulo, Brazil
Number of centres: 1
Study period: March 2006 to February 2008
Funding source: Not stated
Participants
Setting: ICU in tertiary care hospital

Inclusion criteria: All patients admitted to ICU with expected stay > 48 hours. Not all
participants received mechanical ventilation
Exclusion criteria: Previous chlorhexidine sensitivity, pregnancy, formal indication for
chlorhexidine use, prescription of another oral topical medication
Number randomised: 200 (only 133 on ventilators)
Number evaluated: 194
Baseline characteristics:
-Intervention group: Age: median 62.5 (17-89) M/F: 47/51; APACHEII Score: median
17 (5-35)
-Control group: Age: median 54.0 (15-85) M/F: 51/45; APACHEII Score: median 19
(5-41)
Interventions
Comparison: 0.12% chlorhexidine solution versus placebo

Experimental group (n = 64 on vent): 0.12% chlorhexidine solution applied orally 3
times daily. Oral hygiene was conducted by nurses specially trained in the protocol. 3
times daily after mechanical cleaning of the mouth by a nurse, 15 ml of study solution
was applied and attempts made to distribute solution over all oral surfaces
Control group (n = 69 on vent): The same protocol was conducted with the placebo
solution, which was identical in colour consistency smell and taste
Outcomes
1. Respiratory tract infections (VAP for those on ventilators)

2. Respiratory tract infection-free survival time
3. Time from ICU admission to first RTI
4. Duration of mechanical ventilation
5. Length of ICU stay
6. Total mortality
7. Mortality due to RTI
8. Antibiotic use
9. Microbiological culture of endotracheal secretions
10. Adverse effects
Notes
Sample size calculation: to have sufficient power to detect a 69% difference in incidence
of VAP with = 5% and = 20% it was estimated that 96 patients per group were
required
Only 133/194 of patients evaluated received mechanical ventilation
Email sent 3 September 2012. Reply received
34
(Continued)
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Low risk

bias)
randomised Method of sequence generation not described but undertaken by pharmacy
Allocation concealment (selection bias)
only the pharmacist knew which code

numbers corresponded to which type of solution
Low risk
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Double blind
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
Double blind
Incomplete outcome data (attrition bias)

All outcomes
Low risk
6/200 patients were excluded from the

analysis. 1 control patient needed to receive
chlorhexidine treatment, and further 3 in
control group and 2 in experimental group
were excluded due to protocol violation.
Unlikely to have introduced a bias
Selective reporting (reporting bias)
Low risk
All planned outcomes reported
Other bias
Low risk
No other sources of bias identified
Berry 2011
Methods
Study design: Feasibility study - single blind parallel group RCT with 3 groups
Location: Australia
Study period:
Funding source: Hospital
Participants
Setting: A 20-bed adult intensive care unit in a university hospital

Inclusion criteria: All intubated patients admitted to the unit were considered for inclusion in the study provided they met the following criteria: able to be randomised within
12 hours of intubation, aged over 15 years and next of kin able to give informed consent
Exclusion criteria: Patients were ineligible for study participation if they: required specific
oral hygiene procedures in relation to maxillofacial trauma or dental trauma/surgery;
had been in the ICU previously during the current period of hospitalisation; received
irradiation or chemotherapy on admission to the ICU or in the preceding 6 weeks; or
suffered an autoimmune disease. Informed consent was obtained for all subjects and
35
Berry 2011
(Continued)
agreement to participate could be withdrawn at any time

Number randomised: 225 (71, 76, 78 in Groups 1, 2, 3)
Number evaluated: 109 (33, 33, 43 in Groups 1, 2, 3)
Group 1 (chlorhexidine 0.2% aqueous) group: Age: 58.219.4; M/F: 35/36; APACHEII
Score: 22.87.8
Group 2 (sodium bicarbonate mouthwash rinsed 2 hourly): Age: 60.417.5; M/F: 42/
24; APACHEII Score: 22.07.5
Group 3 (sterile water rinsed 2 hourly): Age: 59.118.1; M/F: 44/34; APACHEII Score:
21.67.8
Interventions
Comparison: Chlorhexidine 0.2% versus water versus sodium bicarbonate

Group 1: Twice daily irrigation with chlorhexidine 0.2% aqueous oral rinse with 2 hourly
irrigation with sterile water
Group 2: Sodium bicarbonate mouthwash rinsed 2 hourly
Group 3: sterile water rinsed 2 hourly (used as the control in this review)
All treatment options included a comprehensive cleaning of the mouth using a soft,
pediatric toothbrush 3 times a day
Outcomes
3 outcome variables were reported:

1. Microbial colonisation of dental plaque (or gums in edentulous patients)
2. Incidence of VAP
3. Adverse events
Notes
Sample size calculation: Feasibility study to inform sample size calculation for main study
Risk of bias
Bias
Authors judgement

bias)
...randomisation into one of three groups

according to a balanced randomisation table prepared by biostatistician
Study packs were identical in outward appearance and allocation remained blinded
until study pack opened by attending nurse
Low risk
Blinding of participants and personnel Unclear risk

(performance bias)
All outcomes
Participants: Blinding not possible, but

non-blinding of carers may have introduced a risk of bias

bias)
All outcomes
Microbiologist and radiologists who assessed outcomes were blinded to allocated

treatment

All outcomes
102/225 participants evaluated. High rate

of attrition and reasons varied in each
group. Death rate higher in Group B,
breach of inclusion criteria more likely in
High risk
36
Berry 2011
(Continued)
Groups B &C
Low risk
Planned outcomes reported
Other bias
High risk
Study stopped early due to withdrawal of

investigational product by regulator
Bopp 2006
Methods
Study design: Pilot study, 2-arm RCT

Location: USA
Study period: February to August 2002
Funding source: Grant from American Dental Hygienists Associations Institute for Oral
Health
Participants
Setting: Critical care unit

Inclusion criteria: Orally and nasally intubated patients entering critical care unit
Exclusion criteria: Taking metronidazole, history of allergy to chlorhexidine, sensitive
to alcohol, risk for endocarditis, history of other serious illness (specified), those with
pneumonia
Number randomised: 5
Number evaluated: 5
-Intervention group: Age: 40, range 28-52; M/F: 0/2
-Control group: Age: 73.7, range 62-81; M/F: 2/1
Interventions
Comparison: 0.12% chlorhexidine + suction toothbrush versus suction swab +

hydrogen peroxide
Experimental group (n = 2): Twice daily oral hygiene care with 0.12% chlorhexidine
gluconate during intubation period plus oral cleaning with PlaqVac suction toothbrush
Control group (n = 3): Standard oral care 6 times daily using a suctioning soft foam swab
and half strength hydrogen peroxide, plus oral lubricant
Outcomes
Microbial colonisation VAP, mortality
Notes
Sample size calculation: This was a pilot study. Data were not used in meta-analysis on
advice of statistician
Email sent to contact author 14 November 2012, reply received 19 November 2012
Risk of bias
Bias
Authors judgement

bias)

...randomly assigned to either control or
experimental treatment by the flip of a
coin
37
Bopp 2006
(Continued)
High risk
Coin toss was undertaken by researcher. No

allocation concealment

(performance bias)
All outcomes
Blinding not possible. Reply from contact

author they were not blinded
Blinding of outcome assessment (detection High risk

bias)
All outcomes
Reply from contact author they were not

blinded

All outcomes
Low risk
All randomised patients included in outcome evaluation
Unclear risk
VAP planned and reported in this pilot

study. Microbial culture data not reported
per person, and mortality is also reported
Other bias
Low risk
No other sources of bias detected
Cabov 2010
Methods
Study design: 2-parallel arm RCT

Location: Croatia
Study period: March to December 2008
Funding source: Supported by Croatian Ministry of Science Education and Sports Grant
number 065-1080057-0429
Participants
Setting: Surgical ICU in university hospital

Inclusion criteria: Aged > 18 years, medical condition suggesting hospitalisation in ICU >
3 days, eventual requirement for mechanical ventilation by oro or nasotracheal ventilation
Exclusion criteria:
Number randomised: 60. 40 of the 60 participants (17 and 23 in each group) were on
mechanical ventilation
-Intervention group: Age: 5716; M/F: 19/11
-Control group: Age: 5219; M/F: 20/10
Interventions
Comparison: Chlorhexidine gel versus placebo

Experimental group (n = 17): 3 times daily, following standard oral care comprising
rinsing mouth with bicarbonate isotonic serum, followed by gently oropharyngeal sterile
aspiration, patients received application of 0.2% chlorhexidine gel applied by nurses to
dental gingival and oral surfaces using a sterile gloved finger
Control group (n = 23): Standard oral care, 3 times daily as above followed by administration of placebo gel
In both groups gel was left in place and oral cavity was not rinsed
38
Cabov 2010
(Continued)
Outcomes
Simplified acute physiological score (SAPS), dental status, dental plaque, plaque culture,
nosocomial infections, mortality
Notes
Sample size calculation: Not reported
Risk of bias
Bias
Authors judgement

bias)
...randomized into two groups using a

computer-generated balanced randomization table
Unclear who conducted the allocation and

whether it was concealed from the investigators
Unclear risk

(performance bias)
All outcomes
Double blind

bias)
All outcomes
Double blind

All outcomes
Low risk
All randomised participants included in

outcome evaluations
Low risk
Other bias
Low risk
Caruso 2009
Methods
Study design: 2-arm RCT

Location: Brazil
Study period: August 2001 to December 2004
Participants
Setting: Closed medical surgical ICU unit in oncologic hospital

Inclusion criteria: Patients aged > 18 years expected to need mechanical ventilation for
> 72 hours through orotracheal or tracheotomy tube
Exclusion criteria: Previous mechanical ventilation within past month, mechanical ventilation for > 6 hours prior to study enrolment, contraindication to bronchoscopy and
expected to die or stop treatment within 48 hours
39
Caruso 2009
(Continued)
-Intervention group: Age: 6514 years; M/F: 66/64
-Control group: Age: 636 years; M/F: 70/62
Interventions
Comparison: Saline rinse versus usual care

Experimental group (n = 130): Instillation of 8 ml of isotonic saline prior to tracheal
suctioning, which was conducted by respiratory therapists
Control group (n = 132): Tracheal suction alone with no saline instillation
Aspirations were carried out when 1 of the following occurred: visible airway secretion
into endotracheal tube, discomfort or patient asynchrony, noisy breathing, increased
peak expiratory pressures, or decreased tidal volume during ventilation attributed to
airway secretion
Outcomes
1. Incidence of VAP
2. Duration of ventilation in ICU
3. Length of stay in ICU
4. ICU mortality
5. Tracheal colonisation
6. Suctions per day, chest radiographs
Notes
Sample size calculation: Estimated that 130 patients per group required to give 80%
power with alpha 5% to detect a decrease in VAP from 30% to 15%
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Unclear risk

bias)
randomised No details of method of sequence generation provided in report
Not described
Unclear risk

(performance bias)
All outcomes
Attending physicians and nurses blinded to

study group. Intervention carried out by
respiratory therapists available on ICU 24/
7

bias)
All outcomes
Outcome assessment conducted by physicians and nurses blinded to allocated treatment

All outcomes
Low risk
All randomised patients included in outcome evaluation
Low risk
All planned outcomes reported in full
Other bias
Low risk
40
Chen 2008
Methods
Study design: A single centre RCT with 2 parallel groups

Location: China
Number of centres: 1 surgical ICU in provincial hospital
Study period: Not stated
Funding source: External
Participants
Inclusion criteria: Admission into the ICU, orally intubated, receiving mechanical ventilation 7 days, without oral and lung disease
Exclusion criteria: Using hormone therapy, with diabetes
Intervention group: n = 60; mean age: 42.09.0; M/F: 39/21
Control group: n = 60; mean age: 40.08.0; M/F: 45/15
Baseline characteristics were comparable
Interventions
Comparison: Oral care + chlorhexidine rinse versus saline rinse

Intervention group: Oral cavity irrigated with 50 ml GSE rinse (chlorhexidine + extracts
of grapefruit + FE enzyme) then aspirated off, 4 times a day, and routine oral nursing
care was given once a day after the first irrigation
Control group: Oral irrigation with 50 ml saline, 4 times a day, without the combination
of routine oral care
Outcomes

1. Incidence of VAP after 7 days of mechanical ventilation
2. Incidence of oral inflammation (ulceration and herpes)
3. Change in bacteria colonisation: the throat swab cultures at baseline and after treatment
Notes
GSE rinse: We are advised by reviewers from China that GSE rinse should be treated as
chlorhexidine + 2 potentially active other antiseptics
Diagnosis of VAP was according to Chinese Society of Respiratory Diseases criteria
Information translated from Chinese paper by Shi Zongdao and colleagues
Risk of bias
Bias
Authors judgement

bias)
Patients were randomised into different

groups according to a randomised number
table
Not mentioned
Unclear risk

(performance bias)
All outcomes
Blinding not described and not possible.

Difference between intervention and control means carers would be aware of who
was in each group
Blinding of outcome assessment (detection Unclear risk

bias)
Blinding not described
41
Chen 2008
(Continued)
All outcomes
All outcomes
Low risk
No withdrawals
Unclear risk
Insufficient information on throat swab

culture result (baseline and after treatment)
Other bias
Unclear risk
The treatment group received co-intervention of routine oral nursing care once daily,
but this was not done in the control group
DeRiso 1996
Methods
Study design: Parallel group RCT

Location: Indiana USA
Funding source: The study was supported by a grant from the August Tomusk Foundation
Participants
Setting: Surgical ICU for post-operative cardiac surgery

Inclusion criteria: Patients undergoing cardiac surgery which required cardiopulmonary
bypass
Exclusion criteria: Intra-operative death, pre-operative infection or intubation, pregnancy, heart and lung transplant recipients, known hypersensitivity to chlorhexidine
Number randomised: Unclear
Number evaluated: 353 (173 in chlorhexidine group and 180 in control)
-Intervention group: Age: 64.10.86; M/F: 119/54
-Control group: Age: 63.50.84; M/F: 123/57
Interventions
Comparison: Chlorhexidine oral rinse versus placebo

Experimental group: 0.5 fl ounce (approx 15 ml) of 0.12% chlorhexidine (+ 11.6%
ethanol (Proctor & Gamble)) mouthrinse used as oropharyngeal rinse and rigorously
applied to buccal, pharyngeal, gingival tongue and tooth surfaces for 30 seconds twice
daily
Control group: Placebo mouthrinse identical in appearance containing base solution and
3.2% ethanol (1/3 of concentration of active solution)
All patients also received the standard oral care of the ICU (systemic antibiotics, pressor
agents and nutritional support as deemed necessary
Outcomes

1. Nosocomial infection rates (upper & lower RTI, UTI, fungemias, line sepsis, wound
& blood infection, other infection)
2. Non-prophylactic antibiotic use
3. Length of stay in hospital
4. Duration of intubation
5. Mortality
42
DeRiso 1996
(Continued)
Notes

Unclear duration of mechanical ventilation. Unable to contact author
Risk of bias
Bias
Authors judgement

bias)
..the pharmacy randomised the patients

to either experimental or control group by
means of computer driven random number
generator
Low risk
Allocation was performed in pharmacy and

solutions wit identical appearance were dispensed for use in ICU

(performance bias)
All outcomes
Double blind. Quote: matching

placeboBoth were packaged in 120-mL
brown bottles and labelled Oral Rinse Solution: Peridex/Placebo Trial Solution with
a 1-week expiration date

bias)
All outcomes
Double blind

All outcomes
Unclear risk
Number of patients originally randomised

to treatment or control groups not stated
Low risk
Planned outcomes reported (no data for

length of stays, duration of ventilation)
Other bias
Low risk
Feng 2012
Methods
Study design: A single centre RCT with 3 parallel groups (2 groups included in this
review)
Location: China
Number of centres: 1 ICU in a city hospital
Study period: February 2009 to January 2011
Participants
Inclusion criteria: Entry ICU, with orotracheal intubation and ventilation

Exclusion criteria: Pulmonary infection, stomatitis or oral tumours before intubation,
accompanied with ulcer of the digestive tract, malignant tumours of the body, taking
steroids 3 days, diabetes
43
Feng 2012
(Continued)

Intervention group: 0.05% povidone iodine: n = 71; mean age: 43.78.1 years
Intervention group: 1/5000 furacilin: n = 65; mean age: 38.511.6 years
Control group: Saline n = 68; mean age: 40.38.5 years
Baseline characteristics: Not specified
Interventions
Comparison: Povidone iodine + toothbrushing versus saline + toothbrushing

Group A (n = 71): Toothbrushing along the slits between the teeth with 0.05% povidone
iodine by nurses, then the oropharyngeal cavity was rinsed with 50 ml of the solution
and it was suctioned out completely. This procedure was repeated 4 times a day
Group B: Toothbrushing along the slits between the teeth with 1/5000 furacilin (antibiotic) by nurses. Excluded from this review
Control group (n = 68): Toothbrushing along the slits between the teeth with 0.9%
saline by nurses, then the oropharyngeal cavity was rinsed with 50 ml of the saline and
it was suctioned out completely. This procedure was repeated 4 times a day
Outcomes

1. Incidence of VAP
2. Rates of oral ulcer and/or herpes
3. Oral cleaness - no odour, no foreign bodies and visually clean surfaces of tube and
equipment
4. Throat swab culture
Notes
Risk of bias
Bias
Authors judgement

bias)
Patients were divided into three groups according to randomisation principle
Not specified
Unclear risk

(performance bias)
All outcomes
Blinding not described and not possible for

the carers who would be aware of who was
in each group

bias)
All outcomes
Not specified

All outcomes
Low risk
All randomised participants included in the

outcome evaluation
Low risk
The results were fully reported
Other bias
Low risk
44
Fields 2008
Methods

Location: Akron Ohio, USA
Study period: October 2005 to March 2006
Funding source: Internal hospital funding
Participants
Setting: 24-bed stroke, neurological and medical ICU

Inclusion criteria: Any mechanically ventilated patient on the stroke/medical ICU intubated in the hospital for < 24 hours , no previous diagnosis of pneumonia
Exclusion criteria: Patients with prior tracheotomies, younger than 18 years, AIDS secondary to immunocompromised systems, edentulous patients
Number randomised: Not stated
Number evaluated: Not stated
Baseline characteristics: Not reported
Interventions
Comparison: Toothbrushing 8 hourly versus usual care

Experimental group: Nurse brushed patients teeth, tongue and hard palate for > 1
minute, then used toothette swab to swab patients teeth tongue and hard palate for >
1 minute, then apply moisturiser to lips. Mouth and pharynx were suctioned as needed
using catheter which was replaced every 24 hours. Oral assessment every 12 hours. Oral
care kit #2 provided for each participant, with worksheet #2
Control group: Usual care (unspecified) which could include up to 2 toothbrushings
daily and toothette mouthcare as needed. Nurses used oral care kit #1 and worksheet #1
Outcomes
1. Incidence of VAP
Notes
Sample size calculation: Desired sample size was 200 ventilator dependent patients or
2000 ventilator days
Email sent to authors 3 September 2012 requesting numbers of patients treated. No
reply received. Trial included in text as narrative only
Risk of bias
Bias
Authors judgement

bias)
..a plastic bin labelled 1-350, containing sealed envelopes which each had either
worksheet #1 or #2, plus information about
the trial to give to families. No mention of
whether envelopes were sequentially numbered. Method of sequence generation not
described
Allocation contained in sealed envelopes
Low risk

(performance bias)
All outcomes
Not possible, both nurses and patients

would have known allocated treatment
45
Fields 2008
(Continued)

bias)
All outcomes
Outcome of VAP assessed by infection control nurse. Unclear whether this person was
blinded to allocated treatment

All outcomes
High risk
Comment: The study neither reports the

number of patients randomised nor the
number analysed
High risk
Comment: No numerical data were reported in this paper. VAP incidence was not
reported by treatment group or with any
measure of variance
Other bias
Unclear risk
Insufficient information in the trial report

to produce confidence in the methodology
of this trial
Fourrier 2000
Methods
Study design: Single blind RCT

Location: Lille, France
Study period: June 1997 to July 1998
Participants
Setting: Adult ICU

Inclusion criteria: Patients admitted to ICU aged > 18 years, medical condition likely to
require ICU stay of 5 days, requiring mechanical ventilation by oro or nasopharyngeal
intubation or tracheostomy
Exclusion criteria: Edentulous patients
-Intervention group: Age: 51.215.2; M/F: 19/11; SAPS II Score: 3715
-Control group: Age: 50.415.5; M/F: 19/11; SAPS II Score: 3313
Interventions
Comparison: Rinse + chlorhexidine gel versus rinse alone

Experimental group: After mouthrinsing and oropharyngeal aspiration, 0.2% chlorhexidine gel was applied to dental and gingival surfaces of the patient using glove protected
finger. Intervention 3 times daily
Control group: Mouthrinsing with bicarbonate isotonic serum followed by gentle
oropharyngeal aspiration 4 times daily during ICU stay
Patients were allowed to eat and drink freely
Outcomes
1. Incidence of nosocomial infections

2. Dental status (DMFT/CAO)
3. Amount of dental plaque (Loe & Silness Index)
4. Plaque bacterial culture
46
Fourrier 2000
(Continued)
Notes

Investigators verified antibacterial activity of chlorhexidine gel in vitro prior to study
Unclear numbers on mechanical ventilation developing VAP. Email sent 14 November
2012
Risk of bias
Bias
Authors judgement

bias)
...patients were randomized into two

groups according to a computer-generated
balanced randomization table
Insufficient information was reported to

determine whether or not the allocation of
the sequence was concealed
Unclear risk

(performance bias)
All outcomes
Not possible as no placebo used

bias)
All outcomes
Bacteriologist blinded to randomisation

code, and evaluation of nosocomial infections done by hygienist nurse and physician not aware of the treatment given

All outcomes
Unclear risk
Unclear how many patients are included in

the evaluation of the outcomes
Low risk
Planned outcome of nosocomial infection,

dental plaque, and colonisation reported
Other bias
Low risk
Groups appear similar at baseline. No other

sources of bias identified
Fourrier 2005
Methods
Study design: A multicentre double-blind placebo-controlled study with 2 parallel groups

Location: France
Number of centres: 6 ICUs (3 in university hospitals & 3 in general hospitals)
Study period: January 2001 to September 2002
Funding source: Partial funding from Programme Hospitalier de Recherche Clinique
PHRC (French Ministry of Health)
Participants
Inclusion criteria: Age > 18 years and a medical condition suggesting an ICU stay at
least 5 days and the requirement of mechanical ventilation by orotracheal or nasotracheal
intubation. Only patients hospitalised for 48 hours before admission in the ICU could
be included
47
Fourrier 2005
(Continued)
Exclusion criteria: Patients with a tracheostomy tube at recruitment; completely edentulous; suffering from facial trauma; post-surgical and requiring specific oropharyngeal
care; known allergy to chlorhexidine
Age group: Mean 61.0 SD 14.7, 61.1 years SD 14.9 in each group
Number evaluated: 228 (ITT)
Intervention group: Age: 61.114.9; M/F: 73/41; SAPS II Score: 45.017.5
Control group: Age: 61.014.7; M/F: 83/31; SAPS II Score: 45.217.5
Interventions

Intervention (n = 114): After mouthrinsing and aspiration, plaque antiseptic decontamination of gingival and dental plaque with a 0.2% chlorhexidine gel provided by nurses
at least 3 times a day during the entire ICU stay
Control (n = 114): A placebo gel, same usage as that of plaque antiseptic decontamination
Toothbrushing was not allowed in the protocol
Outcomes
The following variables were reported and compared:

1. Incidence of VAP
2. Incidence of VAP (%) per 1000 days of mechanical ventilation
3. Incidence of VAP (%) per 1000 days of intubation
5. Mortality from day 0 to day 28
6. ICU days (meanSD)
7. Days of intubation (meanSD)
8. Antibiotic days (meanSD)
Notes
Sample size calculation: Calculation provided based on expected incidence of nosocomial

infections of 30% in placebo group and 15% in treatment group. Planned interim
analysis to determine effects of interventions, and study stopped based on pre-planned
stopping rule after this interim analysis
Email sent to author 14 November 2012
Risk of bias
Bias
Authors judgement

bias)
...randomly assigned block randomization stratified by site
Low risk
all randomization lists were held in sealed

envelopes in the pharmacy departments of
the 6 centres

(performance bias)
All outcomes
The placebo gel was undistinguishable by

colour, taste or odour with the tested agent.
The investigators were unaware of patients
assignments
48
Fourrier 2005
(Continued)

bias)
All outcomes
Double blind

All outcomes
Low risk
Only 1 patient in intervention group was

excluded and the reason was clearly explained. ITT analysis
Low risk
All planned outcomes clearly defined and

reported
Other bias
Low risk
No other sources of bias identified. Although this study was stopped early interim
analysis was planned in protocol and carried out appropriately
Grap 2004
Methods
Study design: Multicentre RCT with 3 parallel groups

Location: USA
Funding source: AD Williams Foundation of Virginia Commonwealth University
Participants
Inclusion criteria: 18 years, admitted to the ED, surgical trauma ICU or neuroscience
ICU who required endotracheal intubation and were mechanically ventilated
Exclusion criteria: Edentulous persons
Age group: Mean 50.3 SD 16.0 range 20-87
Number evaluated: Variable
Spray group: n = 11; swab group: n = 12; control group: n = 11. M/F: 24/10; mean
APACHE III Score: 63.123.8
Interventions
Comparison: Chlorhexidine spray versus chlorhexidine swab versus usual care

Spray group (n = 11): At early post-intubation a single oral application of 0.12% chlorhexidine gluconate was given in 20 sprays for about 2 ml of the agent
Swab group (n = 12): At early post-intubation a single oral application of 0.12% chlorhexidine gluconate was given by swabbing for about 2 ml of the agent
Control (n = 11): Usual care method but not described
Outcomes
1. Change of mean CPIS from admission to the time of 48 hours

2. Number of the cases with positive cultures in the study period
Notes
Sample size calculation: Not reported but study was a pilot
Risk of bias
49
Grap 2004
(Continued)
Bias
Authors judgement

bias)
Randomized . using a block randomization scheme
The block size varied so that the research

assistants were not able to predict the next
group assignment
Low risk

(performance bias)
All outcomes
Not possible as no placebos used

bias)
All outcomes
Data collectors and culture evaluators were

blinded

All outcomes
High risk
Only 12/34 participants had complete data

at admission and at 48 hours for evaluation of VAP. Attrition mainly due to endotracheal extubation but numbers greater
in both chlorhexidine groups compared to
control
High risk
Planned outcomes of negative oral cultures

and CPIS (no variance estimates) reported
in minority of participants. Unclear number of VAP, and no mortality data reported
Other bias
Low risk
Grap 2011
Methods
Study design: RCT

Location: Virginia USA
Number of centres: 2 units in same hospital, Level 1 trauma centre
Funding source: Triservice Nursing research program grant TSNRP MDA-905-03-TS02
Participants
Setting: Surgical trauma ICU & neuroscience ICU

Inclusion criteria: Patients intubated within 12 hours of admission to trauma centre
(intubation may have occurred in emergency department, in the field or in pre-hospital
setting)
Exclusion criteria: Previous endotracheal tube placed in 48 hours prior to admission,
clinical diagnosis of pneumonia on admission, burn injuries, edentulous persons
Number randomised: 152, 7 lost, enrolled sample 145 (71/74) (only 75 were still intubated after 48 hours)
Number evaluated: At 48 or 72 hours = 60 (36/24) (for VAP) 39 (21/18)
50
Grap 2011
(Continued)
Baseline characteristics: Not reported for each randomised group in total

Those with 48/72 hour data:
-Experimental group: n = 36, M/F 27/9, APACHE II 70.6930.14
-Control group: n = 24, M/F 11/13, APACHE II 60.4623.45
Interventions
Comparison: Chlorhexidine applied by swab versus usual care

Experimental group: 1 5 ml dose of chlorhexidine 0.12% applied to all areas of oral cavity
by swab within 12 hours prior to intubation. All patients received usual oral comfort
care (details not reported)
Control group: Usual oral comfort care as per usual practice
Outcomes
1. Incidence of VAP
2. CPIS score
3. APACHE III
4. TRISS
5. Oral Health (DMFT)
Notes
Sample size calculation: Not reported (but pilot study published in 2004)
Email sent and reply received to clarify the data
Risk of bias
Bias
Authors judgement

bias)
The subjects were randomised to a treatment group or control group using a block
randomisation scheme
Not described
Unclear risk

(performance bias)
All outcomes
Not possible because no placebo used

bias)
All outcomes
Not mentioned and probably not done as

researchers were nurses and likely to be involved in both delivery of interventions and
assessment of outcomes

All outcomes
High risk
Huge attrition, and reasons for losses not

described for each group. Conclusions
based on 39/152 (26%) of those originally
randomised to treatment or control
High risk
Primary outcome planned was development of VAP but inclusion criteria used in
this study meant that less than half those
randomised were at risk of developing VAP
51
Grap 2011
(Continued)
Other bias
High risk
Study report notes statistically significant

difference in gender and CPIS score between groups at baseline. No baseline
characteristics data reported for each randomised group, and likely that important
prognostic factors e.g. place of intubation,
surgery, may have been different in each
group
Hu 2009
Methods
Study design: RCT

Location: Beijing, China
Study period:
Funding source: No external funding
Participants
Setting: ICU in second affiliated hospital of PLA General Hospital

Inclusion criteria: Patients in ICU receiving mechanical ventilation
Exclusion criteria: Unclear
Number evaluated: Unclear
Baseline characteristics: Not reported for each randomised group in total
Those with 48/72 hour data:
-Experimenal group: n = 25, M/F 16/9, age range 19-68
-Control group: n = 22, M/F 13/9, age range 22-60
Interventions
Comparison: Saline swab + rinse versus saline swab

Experimental group: Lips, teeth, tongue and palate were swabbed with a saline saturated
cotton ball and the oral cavity was rinsed with saline twice daily
Control group: Lips, teeth, tongue and palate were swabbed with saline saturated cotton
ball twice daily
Outcomes
VAP, mortality, days on ventilator, days in hospital, halitosis, ulceration
Notes
Information translated from Chinese paper by Shi Zongdao and colleagues. Unable to
confirm outcome data with trial authors
Risk of bias
Bias
Authors judgement

bias)
Email from author the sequence was generated by using a random number table
Email from author allocation was concealed using opaque envelopes numbered
with inclusion sequence
Low risk
52
Hu 2009
(Continued)

(performance bias)
All outcomes
Patients and carers were not blinded to interventions received

bias)
All outcomes
Email from author the outcome assessors

were are group of nurses not involved with
the interventions. Probably blinded to allocated treatment group

All outcomes
High risk
The number of participants included in the

outcome assessments at each time point is
unclear. VAP reported as percentages only?
High risk
All planned outcomes reported but as percentages only?
Other bias
Low risk
Jacomo 2011
Methods
Study design: Double-blind placebo-controlled RCT (NCT00829842)

Location: Sao Paulo, Brazil
Study period: February 2006 to February 2008
Participants
Setting: Tertiary care hospital paediatric ICU

Inclusion criteria: Children with congenital heart disease undergoing cardiac surgery
with or without cardiopulmonary bypass, admitted to paediatric ICU for post-operative
care
Exclusion criteria: Pre-operative pneumonia, hypersensitivity to chlorhexidine, congenital or acquired immunodeficiency, refusal to participate
Number evaluated: 160 (4 intra-operative deaths)
-Intervention group: Age: median12.2 (0-176 months); M/F: 42/45
-Control group: Age: median 10.8 (0-204 months); M/F: 35/38
Interventions
Comparison: Chlorhexidine (gargle or swab) versus placebo

Experimental group: Oral hygiene with 0.12% chlorhexidine gluconate solution, administered pre-operatively and twice daily post-operatively. 0.3 ml/kg of body weight
were used in children aged > 6 years, who gargled for 30 seconds avoiding ingestion.
In younger children and intubated post-operative patients solution was applied to oral
mucosa, gingival, tongue and tooth surfaces for 30 seconds with a spatula wrapped in
gauze
Control group: Received the same treatment with placebo solution that looked and tasted
the same
53
Jacomo 2011
(Continued)
All patients received orotracheal intubation and prophylactic systemic antibiotics intravenously for 48 hours
Outcomes
1. Incidence of nosocomial pneumonia

2. Incidence of VAP
3. Duration of intubation
4. Need for reintubation
5. Time to development of pneumonia
6. Length of paediatric ICU/hospital stay
7. 28-day mortality
Notes
Sample size calculation: Estimated that 160 participants would detect a reduction in
50% in incidence of nosocomial pneumonia (31% to 15.5%) with = 0.05 & = 0.20
NCT 00829842 at ClinicalTrials.gov
Risk of bias
Bias
Authors judgement

bias)
..randomized to the experimental or control groups by means of a list generated by

a computerized system that uses a random
number generator to produce customized
sets of random numbers
Low risk
The randomisation list was held in the

hospital pharmacy and all investigators
were unaware of patients assignments

(performance bias)
All outcomes
Double blind. Texture, colour, and flavour

of placebo similar to active solution, placed
in similar containers and labelled A or B

bias)
All outcomes
Double blind. ..the diagnosis of nosocomial pneumonia was made independently

by the PICU physicians and an infection
control practitioner blinded to the patients
group

All outcomes
Low risk
2 participants in each group died and were

therefore excluded from pneumonia outcomes
Unclear risk
Planned outcomes clearly reported but unclear how many trial participants were ventilated for at least 48 hours
Other bias
Low risk
54
Koeman 2006
Methods
Study design: A multicentre randomised double-blind placebo-controlled trial with 3

parallel groups
Location: 2 university hospitals and 3 general hospitals in the Netherlands
Number of centres: 5 hospitals (2 surgical and 5 mixed ICUs)
Study period: February 2001 to March 2003
Funding source: ZONMw Netherlands Organization for Health Research and Development (project number 2200.0046)
Participants
Inclusion criteria: Consecutive adult patients (> 18 years of age) needing mechanical
ventilation for at least 48 hours were included within 24 hours after intubation and start
of mechanical ventilation
Exclusion criteria: A pre-admission immunocompromised status, pregnancy, and if the
physical condition did not allow oral application of study medication
Age group:
Group A: Chlorhexidine group: n = 127; mean age: 60.915.3; M/F: 71/57; APACHEII:
22.27.02
Group B: Chlorhexidine/COL group: n = 128; mean age: 62.419.1; M/F: 66/61;
APACHEII: 23.77.38
Group C: Control group: n = 130; mean age: 62.115.9; M/F: 93/37; APACHEII: 21.
87.43
Interventions
Comparison: Chlorhexidine (in petroleum jelly) versus petroleum jelly alone

Group A: Chlorhexidine group (n = 127): Oral decontamination with chlorhexidine
(2%) in Vaseline petroleum jelly
Group B: Chlorhexidine/COL group (n = 128): Oral decontamination with chlorhexidine plus colistin antibiotic chlorhexidine/colistin (CHX/COL 2%/2%) in Vaseline
petroleum jelly
Group C: Control (n = 130): Oral decontamination with Vaseline petroleum jelly
Trial medication was administered 4 times daily, after removing remnants of the previous
dose with a gauze moistened with saline. Approximately 2 cm of paste, approximately
0.5 g was put on a gloved fingertip and administered to each side of the buccal cavity
Outcomes
The following outcome variables were reported for each group:

1. Incidence of VAP
2. Incidence of early onset VAP
3. Days ventilated (meanSD)
4. ICU stay (meanSD)
5. Days in hospital after ICU discharge (meanSD)
6. Changes of endotracheal colonisation through cultures in 3 time windows after ventilation, 1-3 days, 5-8 days and 9-12 days respectively
Notes
Sample size calculation: Reported in paper together with planned sequential analysis
Only Group A and Group C included in this review
Risk of bias
Bias
Authors judgement

55
Koeman 2006
(Continued)

bias)
...randomly assigned to one of three study

groups by computerised randomisation
schedule. Randomization was stratified by
hospital
Trial medication (chlorhexidine 2% in

petroleum jelly (Vaseline) FNA, chlorhexidine 2% with COL 2% in Vaseline FNA,
and Vaseline FNA) was produced and labelled by the Department of Clinical Pharmacy of the University Hospital Maastricht. Experimental and placebo pastes
were tasteless and of comparable smell and
consistency
Low risk

(performance bias)
All outcomes
Double blind, placebo controlled

bias)
All outcomes
Double blind, placebo controlled

All outcomes
Low risk
The study was discontinued in 6 patients, 5

participants withdrew consent, 1 due to adverse event. Intention-to-treat analysis included all participants for primary outcome
Low risk
Other bias
Low risk
Unlikely
Kusahara 2012
Methods
Study design: Double-blind placebo-controlled RCT

Location: Sao Paulo Brazil
Number of centres: 1, tertiary care hospital affiliated with Federal University of Sao Paulo
Brazil
Study period: 36 months dates not stated
Funding source: Funded by a grant from Fundacao de Amparo a Pesquisa do Estado de
Sao Paulo (04-13361-2)
Participants
Setting: PICU
Inclusion criteria: Children admitted to PICU likely to require ventilation within 24
hours of admission
Exclusion criteria: Newborn, confirmed diagnosis of pneumonia at admission, known
hypersensitivity to chlorhexidine, tracheostomy, duration of ventilation less than 48
hours, intubated for more than 24 hours prior to PICU admission
56
Kusahara 2012
(Continued)
Number randomised: 96 (46/50)

Number evaluated: 96, at day 2 (44/45), at day 4 23/23
-Intervention group: Age: 1249.75 months; M/F: 28/18
-Control group: Age: 34.558.8 months; M/F: 32/18
Interventions
Toothbrushing + 0.12% chlorhexidine gel versus toothbrushing + placebo

Experimental group: Oral care with toothbrushing and oral gel containing chlorhexidine
twice daily (08:00 & 20:00 hours). Mouth was divided into 4 quadrants and each
brushed in a defined pattern. With child in lateral position, gel was applied directly to
toothbrush, and all tooth surfaces (vestibular, lingual, occlusal and incisal) were cleaned
and ventral surface of tongue was brushed posterior to anterior. Each quadrant was rinsed
with water and excess fluid and debris was removed with continuous suction. Finally
oral foam applicator was immersed in the gel and applied all over the gingival surfaces
of the patient
Control group: Oral care with toothbrushing and placebo oral gel twice daily. With
child in lateral position, gel was applied directly to toothbrush, and all tooth surfaces
(vestibular, lingual, occlusal and incisal) were cleaned and ventral surface of tongue was
brushed posterior to anterior. Each quadrant was rinsed with water and excess fluid and
debris was removed with continual suction. Finally oral foam applicator was immersed
in the gel and applied all over the gingival surfaces of the patient
Outcomes
1. Incidence of VAP
2. Duration of ventilation in PICU
3. Length of stay in PICU
4. Hospital mortality
5. Tracheal colonisation with Gram +ve & -ve organisms
Notes
Sample size calculation: Reported that this was not done due to the absence of previous
research on this population
Email correspondence with Prof Pedreira confirmed that Pedreira 2009 and Kusuhara
2012 both refer to the same study. NCT 01083407 & NCT0410682 at ClinicalTrials.
gov
Risk of bias
Bias
Authors judgement

bias)
..randomised into two groups using a balanced randomisation table generated by

True Epistat Program
Both chlorhexidine and identical placebo

gels were supplied by pharmacy in identical containers and only the pharmacist was
aware of the gel type for each patient
Low risk
57
Kusahara 2012
(Continued)

(performance bias)
All outcomes
Double blind. Identical placebo used so

that neither participants nor clinical staff
were aware of allocated treatment

bias)
All outcomes
Double blind. Only the pharmacist was

aware of the gel type for each patient

All outcomes
Low risk

outcome evaluation
Low risk
One primary and 4 secondary outcomes

reported in full
Other bias
Unclear risk
Statistically significant difference in mean

age of children in each group. This may
have introduced a bias
Long 2012
Methods

Location: China
Number of centres: 1 ICU in the university hospital
Study period: February 2010 to March 2012
Funding source: Program for masters degree
Participants
Inclusion criteria: Patients admitted to ICU, with oral intubation, receiving mechanical
ventilation 48 hours, age 18 years, patients or their relatives agreed to participate
in the study
Exclusion criteria: Intubated in emergency e.g. after cardiac arrest, operations upon the
oral cavity, trauma of the respiratory tract, with severe bleeding or coagulation disorders
Number evaluated: 61 (the other 9 were death or ventilation < 48 hours)
Intervention group: Mean age: 60.0610.71 years, M/F 20/11, APACHE 17.941.24
Control group: Mean age: 63.6710.02 years, M/F 18/12, APACHE 18.230.57
Interventions
Comparison: Povidone iodine + toothbrushing versus povidone iodine alone

Experimental group (n = 31): Modified oral nursing method: swab with 0.1% povidone
iodine immediately before intubation, then toothbrushing and rinsing with 0.1 povidone
iodine, 3 times a day
Control group (n = 30): Usual oral nursing method: swab with cotton balls soaked with
0.1% povidone iodine
Outcomes
3 outcome variables were available:

1. Incidence of VAP
2. Mortality
3. Ventilation days
58
Long 2012
(Continued)
Notes
Microbial examinations for the aspirate secretions obtained from inferior respiratory
tract every day after intubation were referred for diagnosis of VAP
Risk of bias
Bias
Authors judgement

bias)
...patients were randomly assigned into 2

groups, observing group and control group
with 35 cases in each group
Not specified
Unclear risk

(performance bias)
All outcomes

in each group

bias)
All outcomes
Not specified

All outcomes
Low risk
9 randomised patients were excluded from

analysis, numbers and reasons similar for
each group
Low risk
Other bias
Unclear risk
Only the results of microbial examination

of the aspirate secretions from the inferior
respiratory tract as tool of VAP diagnosis
may not be enough
Lorente 2012
Methods

Location: Tenerife, Spain
Study period: August 2010 to August 2011
Funding source: Hospital funding
Participants
Setting: Medical/surgical ICU

Inclusion criteria: Consecutive patients undergoing invasive mechanical ventilation for
at least 24 hours
Exclusion criteria: Edentulous, aged < 18 years, pregnant, HIV positive, white blood
cells < 1000 cells/mm3 , solid or haematological tumour, immunosuppressive therapy,
mechanical ventilation duration less than 24 hours
59
Lorente 2012
(Continued)

-Intervention group: Age: 61.015.6 years; M/F: 146/71
-Control group: Age: 60.416.6 years; M/F: 145/74
Interventions
Toothbrushing + 0.12% chlorhexidine gel versus chlorhexidine alone

Experimental group (n = 217): Oral cleansing performed with 0.12% chlorhexidine
impregnated gauze, and oral cavity injection, followed by manual brushing of the teeth
with a brush impregnated with 0.12% chlorhexidine (tooth by tooth on the anterior and
posterior surfaces, the gum line and the tongue for a period of 90 seconds)
Control group (n = 219): Oral cleansing performed with 0.12% chlorhexidine impregnated gauze, and oral cavity injection only
In both groups nurse performed oral care every 8 hours. First endotracheal cuff pressure
was tested, oropharyngeal secretions were aspirated, then chlorhexidine impregnated
gauze was used to cleanse the teeth tongue and mucosal surfaces, followed by injection of
10 ml 0.12% of chlorhexidine digluconate into oral cavity, and finally after 30 seconds
the OParea was suctioned
Outcomes
1. Incidence of VAP
2. Duration of ventilation
3. ICU mortality
4. Tracheal colonisation with Gram +ve & -ve organisms
5. Antibiotic exposure
Notes
Sample size calculation: Estimated that 218 patients per group required to give 80%
power and alpha error of 5%, to show a reduction in VAP from 15% to 7.5%
Risk of bias
Bias
Authors judgement

bias)
..a list of random numbers generated with

Excel software (Microsoft, Seattle, WA)
No information about allocation concealment
Unclear risk

(performance bias)
All outcomes
Not possible

bias)
All outcomes
The diagnosis of VAP was made by an expert panel, blinded to group assignment

All outcomes
Low risk
All randomised patients are included in the

outcome evaluations
Low risk
Planned outcomes reported in full
60
Lorente 2012
(Continued)
Other bias
Low risk
McCartt 2010
Methods
Study design: 3-arm quasi experimental RCT

Location: Florida, USA
Funding source: Nursing dissertation
Participants
Setting: Medical/surgical ICU

Inclusion criteria: Patients aged > 18 years, anticipated to be orally intubated for at least
72 hours
Exclusion criteria: Admitting diagnosis of pneumonia, nasally intubated, expected to be
extubated within 24 hours
Number evaluated: Variable (70-80)
-Experimental group A: Age: 63 years; M/F: 11/18
-Experimental group B: Age: 60 years; M/F:16/15
Interventions
Comparison: Toothbrushing + 0.12% chlorhexidine gel versus chlorhexidine alone

Experimental group (n = 29): Chlorhexidine gluconate spray 0.12% twice daily at 12hour intervals
Experimental group (n = 31): Chlorhexidine gluconate spray + toothbrushing twice daily
at 12-hour intervals
Control group (n = 25): Standard hygiene care with toothette swabs
Outcomes
1. Oral pH
2. Oral cultures
3. Clinical Pulmonary Infection score
4. Oral assessment
Notes
Sample size calculation: Reported to have been done but unclear numbers per group
required
Email sent to author 24 January 2013 - no reply received
Risk of bias
Bias
Authors judgement

bias)
..randomly assigned utilizing random

tables generated by the Office of Research
and Development in the Department of
Nursing at the University of Florida
Not described
Unclear risk
61
McCartt 2010
(Continued)

(performance bias)
All outcomes
Not possible

bias)
All outcomes
Not done

All outcomes
High risk
Numbers evaluated at 72 hours appear to

be 69 (5, 7, 4 lost from groups A, B & C
respectively) reasons not stated
High risk
Stated purpose of the study was to determine whether there was a difference in VAP
but this outcome was not reported
Other bias
Low risk
Munro 2009
Methods

Location: 3 ICUs in large urban University Medical Centre, Virginia, USA
Number of centres: 3 (ICUs)
Funding source: Grant NIH R01 NR07652
Participants
Inclusion criteria: Critically ill adults (over 18) in 3 intensive care units were enrolled
within 24 hours of intubation. All patients older than 18 years (n = 10913) in medical,
surgical/trauma, and neuroscience ICUs were screened for inclusion
Exclusion criteria: Clinical diagnosis of pneumonia at the time of intubation, edentulous
patients, patients who had a previous endotracheal intubation during the current hospital
admission
Group 1: 26/18 M/F, age mean 46.1 (18.2)
Group 2: 28/21 M/F, age mean 47.1 (15.7)
Group 3: 28/20 M/F, age mean 47.3 (18.8)
Group 4: 37/14 M/F, age mean 46.8 (16.4)
Number randomised: 547 (but 355 subsequently excluded due to pneumonia at baseline)
Interventions
Comparison: Chlorhexidine swab versus toothbrushing versus both versus usual

care
Group 1: (n = 44) a 0.12% solution of chlorhexidine gluconate (chlorhexidine) 5 mL
by oral swab twice daily (at 10 AM and 10 PM)
Group 2: (n = 49) toothbrushing (manual toothbrush) 3 times a day (at 9 AM, 2 PM,
and 8 PM), detailed toothbrushing protocol followed quadrant by quadrant
Group 3: (n = 48) combination care (toothbrushing 3 times a day and chlorhexidine
every 12 hours)
Group 4: (n = 51) control (usual care)
62
Munro 2009
(Continued)
Outcomes
VAP measured by CPIS score, also dichotomised at day 1, 3, 5, 7

Mortality (died during hospitalisation)
Notes
Median length of stay and stay in ICU were presented
Risk of bias
Bias
Authors judgement

bias)
A randomized controlled 2 2 factorial experimental design was used...Patients were

randomly assigned to 1 of 4 treatments.
Patients were randomized to treatment
within each ICU according to a permuted
block design developed by the biostatistician (D.K.M.) before the start of the study
Not mentioned but probably done as allocation was made by statistician
Low risk

(performance bias)
All outcomes
Not possible

bias)
All outcomes
Not described, and probably not done

All outcomes
High risk
355/547 (65%) of those originally randomised were excluded from the analysis
at day 3 because they were found to have
pneumonia at baseline
Unclear risk
VAP reported as percentages only and denominator unclear
Other bias
Low risk
63
Needleman 2011
Methods

Location: London UK
Study period: March 2007 to May 2009
Funding source: Partially funded by UK Department of Health NIHR Biomedical Research Centres funding scheme
Participants
Setting: Neurocritical care unit

Inclusion criteria: Admitted to hospital < 48 hours prior to neurocritical care unit admission, expected to survive > 48 hours, and expected to require endotracheal intubation
for > 48 hours
Exclusion criteria: Edentulous, known adverse reaction to chlorhexidine, recent history
of chest infection, received antibiotics within 3 months prior to study start
Number evaluated: 44 - 28 (attrition over time)
-Intervention group: Age: 53.012.5; M/F: 14/9
-Control group: Age: 42.712.8; M/F: 13/10
Interventions
Comparison: Chlorhexidine rinse + powered toothbrush versus chlorhexidine swab

alone
Experimental group (n = 23): Oral hygiene using a powered toothbrush (Colgate
Actibrush) plus 20 ml of chlorhexidine solution 4 times daily for 2 minutes per session
Oropharyngeal suction was used to remove excess fluid or debris
Control group (n = 23): Oral hygiene using a sponge toothette plus 20 ml of chlorhexidine
solution 4 times daily for 2 minutes per session. Oropharyngeal suction was used to
remove excess fluid or debris
Outcomes
1. Oral plaque colonisation with VAP-associated bacteria

2. Amount of dental plaque
Outcomes measured on days 1 (pre-oral hygiene), 3 and 5
Notes
Sample size calculation: Estimated that 16 patients per group would be required to detect
a reduction from 63% to 10% in presence of VAP-associated pathogens, which would
be clinically important
Risk of bias
Bias
Authors judgement

bias)
Randomization sequence was computer

generated using SPSS statistical software
Randomisation was concealed from those

recruiting patients in sequentially numbered sealed opaque envelopes, which
were prepared by the statistician
Low risk
64
Needleman 2011
(Continued)

(performance bias)
All outcomes
Not possible because experimental and

control interventions were so different

bias)
All outcomes
..oral hygiene assessment, microbial sampling, microbial assessment and data analysis were masked with regard to experimental group status

All outcomes
High risk
Losses to follow-up were high, due to early

tracheal extubation, death or transfer to another facility. Numbers for each cause not
given and total numbers were high and different in each group (13/23 (57%) control
and 5/23 (22%) experimental participants
at day 5)
Low risk
Other bias
Low risk
Ozcaka 2012
Methods
Study design: Double-blind placebo-controlled RCT

Location: Izmir, Turkey
Study period: November 2007 to November 2009
Funding source: The study was funded solely by the institutions of the authors
Participants
Setting: Respiratory ICU

Inclusion criteria: Patients aged 18 or over, admitted to respiratory ICU expecting to
require ventilation for > 48 hours
Exclusion criteria: Witnessed episode of aspiration, confirmed diagnosis of post-obstructive pneumonia, known hypersensitivity to chlorhexidine, diagnosed thrombocytopenia, pregnancy, oral mucositis, readmission to same ICU, expected survival < 1 week,
edentulism
-Intervention group: Age: 60.514.7 years
-Control group: Age: 56.018.2 years
Interventions
Comparison: Chlorhexidine solution versus saline

Experimental group (n = 32): Oral mucosa was swabbed with 0.2% chlorhexidine on
sponge pellets, 4 times daily. Excess rinse was suctioned from patients mouth after 1
minute
Control group (n = 34): Oral mucosa was swabbed with saline on sponge pellets, 4 times
daily. Excess rinse was suctioned from patients mouth after 1 minute
65
Ozcaka 2012
(Continued)
Deep suctioning was performed in both groups every 6 hours and following position
changes to remove pooled secretions from around the cuff of the endotracheal tube
Outcomes
1. Incidence of VAP
2. Mortality
3. Duration of ventilation in ICU
5. Presence of potential respiratory pathogens in minibronchoalveolar lavage
Notes
Sample size calculation: Estimated that 28 participants per group would be required to
give 81% power with alpha of 5%, to show a reduction in VAP from 70% to 30%
Email sent 22 January 2013 and reply received 29 January 2013
Risk of bias
Bias
Authors judgement

bias)
The randomisation prepared a set of subject identification (SID) numbers which

had assigned treatment
Comment: Description unclear, but involvement of statistician suggests this was
well done
Low risk
Study nurse obtained the SID number

when the patient was enrolled
Comment: Allocation was probably concealed and not able to be anticipated by investigators

(performance bias)
All outcomes
Assignment of treatment was blinded to

patients and to all investigators, including periodontist, .... respiratory ICU physicians and outcome statisticians

bias)
All outcomes

patients and to all investigators, including periodontist, .... respiratory ICU physicians and outcome statisticians

All outcomes
Low risk
66 patients randomised, 1 secondary exclusion from each group, and 2 and1 early
deaths in chlorhexidine and control groups,
respectively
Comment: Unlikely to have introduced a
bias
Low risk
66
Ozcaka 2012
(Continued)
Other bias
Low risk
Panchabhai 2009
Methods
Study design: Open-label RCT

Location: Mumbai India
Study period: 8 months - dates not stated
Participants
Setting: ICU (mixed medical and surgical), tertiary care hospital

Inclusion criteria: All patients admitted to ICU during study period who signed consent
Exclusion criteria: Pregnant women, those with pneumonia at baseline, those for whom
oral care was contraindicated, those with allergy to chlorhexidine
Number evaluated: 471 (only 88/83 = 171 on mechanical ventilation)
Baseline characteristics (given for 471 who completed the trial only):
-Intervention group: Age: 35.215.9; M/F: 136/88; APACHEII Score: 12(9-17)
-Control group: Age: 36.916.2; M/F: 171/76; APACHEII Score: 14(9-19)
Interventions
Comparison: Chlorhexidine versus potassium permanganate

Experimental group (n = 250): Oral and pharyngeal suction of pooled secretions followed
by swabbing of the oral cavity, teeth, palate, buccal spaces, posterior pharyngeal wall,
and hypopharynx with normal saline.Then oropharyngeal cleansing, following the same
procedure, twice daily with 0.2% chlorhexidine solution
Control group (n = 262): Oral and pharyngeal suction of pooled secretions followed by
swabbing of the oral cavity, teeth, palate, buccal spaces, posterior pharyngeal wall, and
hypopharynx with normal saline.Then oropharyngeal cleansing twice daily, following
the same procedure, with 0.01% potassium permanganate solution
Non-intubated patients, rinsed with water, then rinsed and gargled with 10 ml of study
solution. No eating/drinking for 1 hour post-intervention
Outcomes
1. Incidence of nosocomial pneumonia

2. Day of development of pneumonia
3. Mortality (hospital)
4. Duration of ICU stay
Notes
Sample size calculation: This study had a statistical power of 75% to detect a 50%
reduction in the incidence of nosocomial pneumonia in the study group with 95% level
of confidence. Assuming the incidence of pneumonia in the control group was 16%,
506 subjects were required
Email sent to author 14 November 2012
Risk of bias
Bias
Authors judgement
67
Panchabhai 2009
(Continued)

bias)
..randomly assigned to treatment .... by

concealed simple random sampling
Comment: No details of sequence generation provided
..concealed simple randomisation

Comment: Unclear whether allocation was
concealed from researchers
Unclear risk

(performance bias)
All outcomes
Open-label RCT

bias)
All outcomes
Open-label RCT but two independent,

blinded reviewers made the diagnosis of
nosocomial pneumonia

All outcomes
Unclear risk
26/250 (10%) and 15/262 (5.7%) were excluded from the analysis in the chlorhexidine and control groups respectively. Reasons given were ICU stay < 48 hours, 14/
250 versus 6/262, and protocol violation
12/250 and 9/262 respectively
Low risk
All planned outcomes reported in full
Other bias
Unclear risk
Baseline parameters only reported for those

who completed the study
Pobo 2009
Methods
Study design: Prospective, single blind, randomised trial with parallel groups
Location: Spain
Number of centres: 1 ICU at a hospital
Funding source: This work was supported by Fondo de Investigaciones Sanitarias (FISS
06/060), Centro de Investigacin Biomdica en Red Enfermedades Respiratorias (06/
06/36), and the Agency for the Administration of University and Research Grants (2005/
SGR/920)
Participants
Inclusion criteria: Intubated adults without evidence of pulmonary infection, expected to

remain ventilated for longer than 48 hours. Randomised within 12 hours of intubation
Exclusion criteria: Edentulous, suspicion of pneumonia at time of intubation or evidence
of massive aspiration during intubation, tracheostomy (or expected within 48 hours),
recent enrolment in other trials, pregnancy, and chlorhexidine allergy
Age group: Adults
Intervention group: n = 74; age: 55.317.9; M/F: 49/25; mean APACHEII Score: 18.
87.1
68
Pobo 2009
(Continued)
Control group: n = 73; age: 52.617.2; M/F: 46/27; mean APACHEII Score: 18.77.3
Number randomised: 147 (74 in toothbrush group and 73 in standard care group)
Interventions
Comparison: Powered toothbrush + standard oral care versus standard oral care
alone
Group 1 (n = 74): Standard oral care plus toothbrush group: besides the standard oral
care, toothbrushing was performed tooth by tooth, on anterior and posterior surfaces,
and along the gumline, the tongue was also brushed. A powered toothbrush was used
(Braun Oral B AdvancePower 450 TX, Braun GmbH). This procedure was repeated
once every 8 hours
Group 2 (n = 73): Standard oral care: maintaining head elevation at 30 degrees. After
aspiration of oropharyngeal secretions and adjustment of endotracheal cuff pressure,
a gauze containing 20 ml of 0.12% chlorhexidine digluconate was applied to all the
oral surfaces including tongue and mucosal surface, and 10 ml of 0.12% chlorhexidine
digluconate was injected into oral cavity, being aspirated after 30 seconds, repeated every
8 hours
Outcomes

1. Incidence of VAP
2. Incidence of suspected VAP per 1000 days of mechanical ventilation
3. Mean days of mechanical ventilation (meanSD)
4. ICU length of stay (meanSD)
5. Mortality
Notes
In the review, the standard oral care group was viewed as intervention with chlorhexidine
and the other group was viewed as control with toothbrushing
Sample size calculation: Estimated that 200 patients per group would be required to
show a 50% reduction in VAP with 80% power and alpha error of 5%. After 147 of
planned 400 patients were randomised the study was stopped by the steering committee
due to no difference in VAP between the groups
Risk of bias
Bias
Authors judgement

bias)
Randomisation by means of a computer

generated list, stratified for antibiotic use at
admission
The list was concealed in opaque sealed

envelopes opened by the nurse within 12
hours of intubation
Low risk

(performance bias)
All outcomes
Blinding not possible. Participants unlikely

to be aware of treatment, but carers were
aware
69
Pobo 2009
(Continued)

bias)
All outcomes
Investigators and attending physicians were

blinded to assigned groups

All outcomes
Low risk
No withdrawals. All randomised participants included in the analysis
Low risk
Expected outcomes reported including adverse events
Other bias
High risk
Study stopped early after recruitment of

147 of planned 400 patients because no
differences between groups were found and
revised estimates indicated that 1500 patients would need to be recruited to show
a difference. Numbers not feasible in this
centre
Prendergast 2012
Methods
Study design: Prospective, randomised trial with 2 parallel groups. NCT 00518752
Location: USA
Number of centres: 1 neuroscience ICU at a tertiary medical centre
Study period: August 2007 to August 2009
Participants
Inclusion criteria: All patients aged at least 18 years admitted to neuroscience ICU,
intubated within 24 hours of admission
Exclusion criteria: Pregnancy, edentulous, aged < 18 years, facial fractures or trauma
affecting oral cavity, unstable cervical fractures, anticipated extubation within 24 hours,
grim prognosis
Intervention group: n = 38; age: 5417.8; M/F: 19/19
Control group: n = 40; age: 5118.4; M/F: 23/17
Number randomised: 78 (38 in comprehensive group and 40 in standard care group)
Number evaluated: Variable (less than 11 patients/group)
Interventions
Comparison: Powered toothbrush + comprehensive oral care versus manual toothbrush + standard oral care
Group 1 (n = 38): Tongue scraping using a low profile tongue scraper with posterior to
anterior sweeping motion across the dorsal surface of the tongue. Then toothbrushing
with Oral B vitality powered toothbrush + Biotene (non-foaming) toothpaste for 2
minutes, then a liberal application or Oral Balance gel. Care performed twice daily
Group 2 (n = 40): Standard oral care: using manual paediatric toothbrush, toothpaste
with 1000 ppm fluoride with SLS and water-based inert lubricant (KY jelly). Care
performed twice daily
70
Prendergast 2012
(Continued)
Outcomes

1. Oral and sputum cultures every 48 hours
2. Incidence of suspected VAP (day 2-6)
3. ICU length of stay (meanSD)
4. Mortality
Notes

Risk of bias
Bias
Authors judgement

bias)
..randomized ... using a computer generated list maintained in a separate locked

cabinet
..list was maintained in a separate locked

cabinet from enrolment forms to prevent
manipulation of eligibility judgements
Low risk

(performance bias)
All outcomes
Not possible

bias)
All outcomes
Diagnosis of VAP by examination of chest

radiographs, by physicians blinded to allocated treatment (information in Prendergast dissertation)

All outcomes
High risk
Unclear how many were assessed at each

time point but paper states that less than
11 patients in each group at each time
point
Low risk
Other bias
Low risk
71
Roca Biosca 2011

Methods
Study design: Single blind RCT

Location: Tarragona, Spain
Study period: June 2006 to May 2009
Funding source: Grant from Health Investigation Fund (FISS 06/060)
Participants
Setting: ICU (14-bed)

Inclusion criteria: Adults aged > 18 years, requiring mechanical ventilation for at least
48 hours, no pneumonia at baseline, at least 2 premolars and 1 incisor, consenting to
take part
Exclusion criteria: Edentulous, suspected pneumonia < 18 years, requiring < 48 mechanical ventilation, tracheotomy, moribund (death expected within 72 hours) allergic
to chlorhexidine
Number evaluated:
Baseline characteristics: Report states that there were no differences in gender, age, diagnosis, APACHE scores between the groups at baseline. No supporting data reported
Interventions
Comparison: Powered toothbrush + standard oral care versus standard oral care
alone
Experimental group: RASPALL - Standard oral hygiene protocol + powered toothbrush.
Patient was elevated to 35 degrees, oropharyngeal secretions were aspirated, intubation
cuff pressure checked, then teeth, tongue and oral cavity cleaned with swab soaked in
10 ml 0.12% chlorhexidine digluconate. Solution left for 30 seconds then excess was
aspirated. All tooth surfaces then brushed using a powered toothbrush
Control group: Standard oral hygiene protocol alone as described for treatment group
Outcomes
4 outcome variables planned:

1. Plaque index (Loe & Silness) days 1, 5 and 10
2. Plaque cultures
3. VAP (reported as NAV)
4. Halitosis
Notes

Translated from Portuguese by Luisa Fernandez-Mauleffinch
Email to authors sent 14 November 2012
Risk of bias
Bias
Authors judgement

bias)
Group assignment was done randomly by

sealed envelope
Method of sequence generation not described
Group assignment was done randomly by

sealed envelope
Low risk
72
Roca Biosca 2011
(Continued)

(performance bias)
All outcomes
Not possible to blind patients or personnel

bias)
All outcomes
Study described as single blind but unclear

who was blinded. Microbiologist?

All outcomes
High risk
Numbers of patients included in outcome

of plaque index were 74 and 73 at day 0, 60
and 57, at day 5 and 29 and 32 at day 10
for toothbrush and control groups respectively. Reasons for missing outcome data
are extubation, need for tracheotomy, VAP,
death or intubation for total of 28 days. No
information as to numbers per group missing for each reason
High risk
Planned outcomes of plaque index and microbiological culture reported but data for
VAP and halitosis in each group not reported
Other bias
Unclear risk
Insufficient information in trial report to

be clear about potential for other bias
Scannapieco 2009
Methods
Study design: A randomised, double-blind, placebo-controlled clinical trial

Location: USA
Number of centres: 1 18-bed trauma ICU
Study period: March 2004 until November 2007
Funding source: USPH grant R01DE-14685 from the National Institute of Dental and
Craniofacial Research
Participants
Inclusion criteria: Those admitted to the ICU who were expected to be intubated and
mechanically ventilated within 48 hours of admission
Exclusion criteria: A witnessed aspiration suspected with chemical pneumonitis; a confirmed diagnosis of post-obstructive pneumonia e.g. advanced lung cancer; a known
hypersensitivity to chlorhexidine; absence of consent; a diagnosed thrombocytopenia
(platelet count less than 40 and/or a INR above 2, or other coagulopathy); a do not
intubate order; children under the age of 18 years; pregnant women; legal incarceration;
transfer from another ICU; oral mucositis; immunosuppression either-HIV or druginduced e.g. organ transplant patients or those on long term steroid therapy; and readmission to the ICU
Intervention group (chlorhexidine 1): n = 47; mean age: 44.819.9; M/F: 43/15; mean
73
Scannapieco 2009
(Continued)
APACHEII Score: 18.54.1

Intervention group (chlorhexidine 2): n = 50; mean age: 47.619.1; M/F: 44/14; mean
APACHEII Score: 19.76.1
Control group: n = 49; mean age: 50.022.5; M/F: 36/23; mean APACHEII Score: 19.
16.1
Interventions
Comparison: Chlorhexidine twice per day + toothbrush versus chlorhexidine once

per day + toothbrush versus placebo + toothbrush
Intervention group: Chlorhexidine (0.12% CHX gluconate) was applied using a rinsesaturated oral foam applicator (Sage Products, Cary, IL, USA) once a day (placebo at
other time)
Intervention group: Chlorhexidine (0.12% CHX gluconate) was applied using a rinsesaturated oral foam applicator (Sage Products, Cary, IL, USA) twice a day (in the morning
at about 8 AM and in the evening at about 8 PM)
Control group: Placebo was applied using a rinse-saturated oral foam applicator twice
per day
All groups had routine oral care using a suction toothbrush (Sage Products, Cary, IL,
USA) twice a day and as needed to brush teeth and the surface of the tongue or approximately 1 to 2 minutes, and applying suction at completion and as needed during the
brushing
Outcomes
1. Incidence of VAP (diagnosed as the presence of more than 104 CFU of pathogen/ml
of bqBAL fluid)
2. Death
3. Days ventilated
4. Days in hospital
5. Antibiotic use
Notes
Sample size calculation: Estimated that 53 patients per arm would give 90% power to
detect a 505 decrease in colonisation. For outcomes 2 to 5, the P values were for 3 group
comparisons
NCT00123123 at ClinicalTrials.gov
Risk of bias
Bias
Authors judgement

bias)
A web-based subject enrolment system

which allocated randomised subject identification numbers
The oral topical treatment for each box was

formulated and prepared by the hospital
pharmacy. Sealed envelopes containing a
random number were generated in blocks
of 6 to provide concealment of patient assignment from the investigators
Low risk
74
Scannapieco 2009
(Continued)

(performance bias)
All outcomes

patients and all investigators including
outcome assessors, statisticians and care
providers

bias)
All outcomes

patients and all investigators including
outcome assessors, statisticians and care
providers

All outcomes
High risk
175 subjects were randomised, microbiological baseline data were available for 146
subjects, 115 had full data at 48 hours.
Greater than 20% drop-outs in all groups.
ITT analysis used for 175 patients but unclear what imputation was used to account
for losses
Unclear risk
Planned microbiological outcomes were reported only in graphs with no data presented
Other bias
High risk
Problems with data analysis due to unclear

denominator and imputations. Pre-study
antibiotic exposure higher in control group
Sebastian 2012
Methods
Study design: Double-blind stratified placebo-controlled RCT

Location: New Delhi, India
Study period: November 2007 to April 2009
Funding source: Indian Council of Medical Research Grant. Chlorhexidine gel and
placebo supplied by ICPA Health Products Limited
Participants
Setting: Paediatric ICU (6 beds)

Inclusion criteria: Patients aged 3 months to 15 years who required orotracheal or nasotracheal intubation and mechanical ventilation. Patients with pneumonia at baseline
were also included as these made up 66% of patient population
Exclusion criteria: Patients mechanically ventilated for > 48 hours prior to paediatric
ICU admission, those with tracheostomies, with inaccessible oral cavities, or with known
hypersensitivity to chlorhexidine
-Intervention group: Age: 13/41, 3-12 months; 28/41, 1 year to 15 years; M/F: 23/18
-Control group: Age: 15/45, 3-12 months; 30/45, 1 year to 15 years; M/F: 27/18
75
Sebastian 2012
(Continued)
Interventions

Experimental group (n = 41): Oral cavity was suctioned to remove secretions then mucosal surfaces were cleaned with saline soaked gauze. Then 0.75 cm 1% chlorhexidine
gel was applied to each side of the mouth using a standardised disposable applicator
Control group (n = 45): Oral cavity was suctioned to remove secretions then mucosal
surfaces were cleaned with saline soaked gauze. Then 0.75 cm placebo gel was applied
to each side of the mouth using a standardised disposable applicator
Care was repeated every 8 hours
Outcomes
1. Incidence of VAP
3. Duration of hospital stay
4. Hospital mortality
5. Type and antibiotic sensitivity of organisms cultured
Notes
Sample size calculation: Estimated that 91 patients per group were required to give 80%
power with alpha 5% to detect a reduction in VAP from 40% to 20%
NCT00597688 at ClinicalTrials.gov
This study included patients with pneumonia at baseline and used age appropriate CDC
criteria to diagnose VAP
Risk of bias
Bias
Authors judgement

bias)
Eligible participants were stratified into 1 of

4 groups based on age group and presence
or pneumonia at baseline. Within each stratum patients were randomised to receive
either chlorhexidine or placebo gel. ..the
random sequence was generated for each
stratum using STATA 9.0 in blocks of 6
No details about how the allocation was

communicated to the researchers, but allocation likely to have been concealed
Low risk

(performance bias)
All outcomes
Double blind

bias)
All outcomes
Double blind

All outcomes

ITT analysis
Low risk
76
Sebastian 2012
(Continued)
Low risk
All planned outcomes reported. Medians

and IQRs (as reported) are the correct
statistic for a skewed distribution but cannot be combined in meta-analysis
Other bias
Low risk
Paper states that the funding agency did

not have any role in the study design, data
collection and analysis, decision to publish
or preparation of the manuscript
Seguin 2006
Methods
Study design: 3-arm parallel RCT

Location: Rennes, France
Study period: August 2001 to January 2003
Participants
Setting: Surgical ICU

Inclusion criteria: Adult patients (> 18 years) with closed head trauma admitted to ICU
and expected to need mechanical ventilation for at least 2 days
Exclusion criteria: Admitted more than 12 hours after initial trauma, those with facial,
thoracic, abdominal or spinal injuries, known history of reaction to iodine or of respiratory disease, chest infiltrates at admission or need for curative antibiotics
Number randomised: 110 (38/36/36)
Number evaluated: 98 (36/31/31)
-Iodine group: Age: 3817 years; M/F: 28/10
-Saline group: Age: 3816 years; M/F: 24/12
Interventions
Comparison: Povidone Iodine versus saline versus usual care (no rinse)
Iodine group (n = 38): Nasopharynx and oropharynx rinsed 4 hourly with 20 ml of 10%
povidone iodine aqueous solution (Betadine oral rinse solution) reconstituted in a 60 ml
solution with sterile water, followed by aspiration of oropharyngeal secretions
Saline group (n = 36): Nasopharynx and oropharynx rinsed 4 hourly with 60 ml saline,
followed by aspiration of oropharyngeal secretions
Control group (n = 36): Standard regimen without any installation but with aspiration
of oropharyngeal secretions
For all patients the suction catheters were inserted as distally as possible. Procedures were
reported on patients chart
Outcomes
1. Incidence of VAP - early and late onset

2. Duration of ventilation in surgical ICU
3. Length of stay in surgical ICU
4. Surgical ICU mortality
77
Seguin 2006
(Continued)
Notes
Sample size calculation: Estimated that 30 patients in each group would provide 80%
power with alpha error 5% to detect a reduction in VAP from 50% to 20%
Risk of bias
Bias
Authors judgement

bias)
Patients were randomly assigned to received one of three regimens according

to computer-generated random number
codes kept in sealed envelopes
Patients were randomly assigned to received one of three regimens according

to computer-generated random number
codes kept in sealed envelopes
Low risk

(performance bias)
All outcomes
Not possible

bias)
All outcomes
Outcome assessors not blinded. Attempts

were made to make the diagnosis of VAP
as objective as possible using a clear set of
criteria and VAP diagnosis was confirmed
by positive bronchoalveolar lavage culture.
However risk of detection bias remains

All outcomes
Low risk
12 randomised patients (11%) excluded

from analysis. 6 patients (1/3/2 in each
group) were withdrawn because unexpected recovery meant that they were not
on mechanical ventilation for 48 hours and
a further 6 patients (1/2/3) died. Unlikely
to have introduced a bias
Low risk
Other bias
Low risk
78
Tantipong 2008
Methods

Location: Thailand
Number of centres: 1 tertiary care university hospital
Study period: January 2006 through March 2007
Funding source: Thailand Research Fund and Faculty of Medicine Siriraj Hospital
Participants
Inclusion criteria: Eligible patients were adults aged = 18 years who were hospitalised in
intensive care units (a total of 36 beds) or general medical wards (a total of 240 beds) at
Siriraj Hospital and who received mechanical ventilation
Exclusion criteria: Patients who had pneumonia at enrolment or who had a chlorhexidine
allergy
Number evaluated: 207 (110 patients received mechanical ventilation for > 48 hours)
Experimental group: n = 102; age: 56.520.1; M/F: 50/52; mean APACHEII Score: 16.
77.9
Control group: n = 105; age: 60.319.1; M/F: 51/54; mean APACHEII Score: 18.2
8.1
Patients demographic characteristics between groups did not differ significantly
Interventions
Comparison: Toothbrush + chlorhexidine versus toothbrush + placebo

Experimental group (n = 102): Received oral care 4 times per day with brushing the
teeth, suctioning any oral secretions, and rubbing the oropharyngeal mucosa with 15 ml
of a 2% chlorhexidine solution, until their endotracheal tubes were removed
Control group (n = 105): Underwent the same oral care procedure with normal saline
solution
Outcomes

1. Incidence of VAP
2. Number of cases of VAP per 1000 ventilator-days
3. Incidence of VAP for patients who received mechanical ventilation for more than 2
days
4. Overall mortality
5. Mean days of mechanical ventilation (meanSD)
6. Rate of irritation of oral mucosa
Notes
Sample size calculation: Estimated that 108 patient per group required to give 80%
power to detect a 50% decrease in VAP with 5% Type 1 error
>
Risk of bias
Bias
Authors judgement

bias)
..randomized..... by stratified randomization according to sex and hospital location

of eligible patient
Not mentioned and probably not done
High risk
79
Tantipong 2008
(Continued)

(performance bias)
All outcomes
Not blinded as chlorhexidine solution had

different odour and taste from saline

bias)
All outcomes
The assessors who determined whether a

patient developed pneumonia were unaware of the patients study group assignment

All outcomes
Unclear risk

outcome evaluation but only 53% of participants on ventilators for > 2 days and
therefore at risk of VAP
Unclear risk
Planned outcome VAP but not all participants at risk and information unclear. Mortality reported
Other bias
Unclear risk
Only 60% of study participants received

ventilation in ICU and only 53% of participants received mechanical ventilation
for more than 48 hours. Likely that nursing care protocols were different in general
medical wards compared to ICUs
Xu 2007
Methods

Location: Nanjing, China
Study period: December 2004 to June 2006
Participants
Setting: ICU in drum tower hospital of Nanjing University

Inclusion criteria: Critically ill adult patients in ICU receiving mechanical ventilation
Exclusion criteria: Participants with severe oral diseases, mechanical ventilation for more
than 24 hours prior to study entry, those who refused oral care protocol
Baseline characteristics: Not reported for each randomised group
Interventions
Comparison: Saline swab versus saline rinse versus both

Experimental group A (n = 58): Rinsing the oropharyngeal cavity with saline for 5-10
seconds, followed by suction aspiration, repeated 5-10 times twice daily for 7 days
Experimental group B (n = 62): Both wipe and rinse as above, twice daily for 7 days
Control group (n = 44): Usual care - wiping the oropharyngeal cavity with saline-soaked
cotton ball twice daily for 7 days
80
Xu 2007
(Continued)
Outcomes
VAP, stomatitis, fungal infection
Notes

Risk of bias
Bias
Authors judgement

bias)
randomly allocated but no details of sequence generation described
Not described
Unclear risk

(performance bias)
All outcomes
Not described, and probably not possible

bias)
All outcomes
Not described and probably not done

All outcomes
Low risk

outcome evaluation
Low risk
Other bias
Low risk
Xu 2008
Methods

Location: Shandong, China
Study period: No stated
Participants
Setting: ICU of the second hospital of Shandong University

Inclusion criteria: Adult patients entering ICU receiving mechanical ventilation expected
to last > 48 hours
Exclusion criteria: Patients with pulmonary infections
Baseline characteristics: Not reported for each randomised group
Interventions
Comparison: Saline rinse versus saline swab

Experimental group (n = 64): Rinse of the oropharyngeal cavity with saline for 5-10
seconds, followed by suction aspiration and repeated 5-10 times, twice daily
81
Xu 2008
(Continued)
Control group (n = 52): Standard oral care comprising scrubbing with a cotton ball
soaked in saline, twice daily
Outcomes
VAP, duration of ventilation (days)
Notes

Risk of bias
Bias
Authors judgement

bias)
randomly allocated Method of sequence

generation not described
High risk

(performance bias)
All outcomes
Not mentioned and probably not possible

bias)
All outcomes

All outcomes
Low risk

outcome evaluation
Low risk
Both outcomes listed in methods are reported in the results section
Other bias
Low risk
Yao 2011
Methods
Study design: Single blind pilot RCT (NCT 00604916)

Location: Taiwan
Study period: March to November 2007
Funding source: Grants from Taiwan National Science Council and career development
grant from National Health Research Institutes
Participants
Setting: Surgical ICU

Inclusion criteria: Intubated and ventilated post-operative patients expected to be in ICU
> 48 hours and expected to require mechanical ventilation for 48-72 hours with nasal
or endotracheal intubation
Exclusion criteria: Patients with pneumonia at baseline
82
Yao 2011
(Continued)
Number evaluated: 53 (VAP), day 3-4 50, day 7-8 42

-Intervention group: Age: 60.716.0; M/F: 17/11; APACHEII Score: 19.6 5.2
-Control group: Age: 60.516.5; M/F: 17/8; APACHEII Score: 19.4 4.4
Interventions
Comparison: Oral care + toothbrushing twice per day versus usual oral care
Experimental group: Standardised oral care protocol twice daily for 15-20 minutes for
7 days from trained intervention nurse. Bed elevated 30 to 45 degrees, hypopharyngeal suctioning, mouth moistened with 5-10 ml purified water, buccal surfaces of teeth
cleaned with powered toothbrush and lingual tooth surfaces and tongue, gums and mucosa massaged with soft paediatric toothbrush. Oral cavity then cleaned with toothette
swab connected to a suction tube and rinsed with 50 ml water + hypopharyngeal suctioning
Control group: Received oral care protocol, twice daily for 10-15 minutes provided
by same trained intervention nurse. Patients elevated, hypopharyngeal suctioning, lips
moistened with toothette swab and water, then further hypopharyngeal suctioning
Outcomes
1. Oral Assessment Guide (OAG Eilers et al 1988) score

2. Plaque score (Turesky-Gilmore-Glickman modification of Quigley-Hein plaque index
with disclosing dye. Recorded 1 tooth from each quadrant (prioritising premolars and
incisors) scores summed)
3. Duration of ventilation
4. Length of ICU stay
5. Incidence of VAP (defined as CPIS > 6)
4. Mortality (ICU)
Notes
Sample size calculation: Pilot study

Email sent to author 14 November 2012. Reply received 12 December 2012
Risk of bias
Bias
Authors judgement

bias)
...randomized using a computer generated

randomization table
Unclear risk
Not mentioned in trial report

Comment: Unclear whether allocation was
concealed from researchers prior to assignment

(performance bias)
All outcomes
Experimental group received toothbrushing (both powered and manual) and control group did not, so blinding of participants and personnel not possible
83
Yao 2011
(Continued)

bias)
All outcomes
Outcomes assessed by 2 hygienists blinded

to allocated treatment. VAP assessed by
CPIS score

All outcomes
Low risk
VAP outcome assessed in all randomised

participants. For oral health and plaque
outcomes 8/28 (experimental) and 7/25
(control) patients lost (transferred to ward)
and 2/28 patients in experimental group
died
Low risk
Planned outcomes reported, but denominators unclear for VAP and mortality.
However this information was supplied by
email from the authors
Other bias
Unclear risk
3/28 (11%) and 1/25 (4%) patients in experimental and control groups were edentulous. Unclear how the intervention and
outcomes were applied in these participants
Zhao 2012
Methods

Location: China
Number of centres: 1 surgical ICU in city hospital
Study period: May 2010 to April 2011
Participants
Inclusion criteria: Admission into the ICU, orally intubated, receiving mechanical ventilation
Exclusion criteria: Not specified
Number randomised: 324 (162 per group)
Age group: Mean 66.2515.28
Baseline characteristics were comparable
Interventions
Comparison: Yikou (triclosan) rinse versus saline

Experimental group: Oral cavity swab with 15 ml of Yikou gargle (triclosan is main
ingredient), 4 times a day
Control group: Oral cavity swab with normal saline, 4 times a day
Secretions were aspirated using suction once daily and sent to lab for culture
Outcomes
3 outcome variables were available:

1. Incidence of VAP in less than 4 days of ventilation and within 4 to 10 days of ventilation
2. Mechanical ventilation days
3. ICU stay days
4. Culture of the samples taking from oropharyngeal cavity and inferior respiratory tract
84
Zhao 2012
(Continued)
(Table 3, detection rates of microbial pathogens before and after oral nursing care were
listed)
Notes
Diagnosis of VAP was mainly determined by microbial examination of the aspirate

secretions from the inferior respiratory tract, which was performed every day
Risk of bias
Bias
Authors judgement

bias)
randomly divided into 2 groups
Not specified
Unclear risk

(performance bias)
All outcomes

in each group

bias)
All outcomes
Not specified

All outcomes
Low risk
The main results were all reported
Low risk
The results were fully reported
Other bias
Unclear risk
Only the results of microbial examination

of the aspirate secretions from the inferior
respiratory tract as tool of VAP diagnosis
was mentioned and its diagnostic efficacy
may not be enough
APACHE II = Acute Physiology and Chronic Health Evaluation II; CAO = caries/absent/occluded; CDC = Centers for Disease
Control; CHX = chlorhexidine; CPIS = Clinical Pulmonary Infection Score; DMFT = decayed/missing/filled teeth; ED = emergency
department; ICU = intensive care unit; INR = international normalised ratio; IQRs = interquartile ranges; ITT = intention-to-treat;
M/F = male/female; PICU = paediatric intensive care unit; ppm = parts per million; RCT = randomised controlled trial; RTI =
respiratory tract infection; SAPS = Simplified Acute Physiologic Score; SD = standard deviation; SLS = sodium lauryl sulfate; TRISS
= Trauma Injury Severity Score; UTI = urinary tract infection; VAP = ventilator-associated pneumonia
85
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Abusibeih 2010
Quasi-randomised trial
Bordenave 2011
Identified from ClinicalTrials.gov website as ongoing study but email from contact author on 8 November
2012 confirmed that this study did not proceed due to lack of funding
Chao 2009
Not RCT
Epstein 1994
The participants involved in the study were not critically ill
Fan 2012
The ingredients of the mouthwash used in the trial were not reported, so we could not judge the mouthwash
containing antibiotics or not
Ferozali 2007
The target population was long term care residents, not critically ill patients in hospitals
Genuit 2001
Not RCT
Guo 2007
RCT, but patients had lung trauma (injury before receiving the oral nursing intervention)
Houston 2002
Likely that less than 10% of study participants had mechanical ventilation for a minimum of 48 hours
Lai 1997
RCT of critically ill patients, unclear how many were on mechanical ventilation, outcome candidiasis
Li 2011
Participants allocated to groups by alternation (not RCT)
Li 2012
The mouthwash Kouitai used in the trial contains both chlorhexidine and metronidazole, and the later is an
antibiotic
Liang 2007
The participants involved in the study did not use mechanical ventilation
Liwu 1990
Clinical controlled trial, not an RCT
MacNaughton 2004
Published as abstract only with interim analysis. Insufficient information in abstract to include this study in
the systematic review and attempts to locate full publication or to contact the author unsuccessful
McCoy 2012
Not RCT
Ogata 2004
The target population was patients about to receive orotracheal intubation, they were not on mechanical
ventilation. Study about gargling with povidone iodine before oral intubation to reduce the transport of
bacteria into the trachea, not oral care intervention in critically ill patients to reduce VAP
Pawlak 2005
Not RCT
Santos 2008
Email reply from Dr Santos stated that The nurse put the first admission on biotene and the second admission
on cetylpyridium, the third admission on biotene and so on. Alternation as an allocation method is not truly
random and therefore this study was excluded
86
(Continued)
Segers 2006
The participants involved in the study did not use mechanical ventilation
Ueda 2004
The target population was patients at nursing homes, not critically ill patients in hospitals
Wang 2006
Quasi-randomised controlled trial
Wang 2012
The interventions being tested in the experimental group includes elevation of the head of the bed, closed
endotracheal suctioning in addition to oral nursing care, which is outside the scope of the review
Yin 2004
RCT aiming to improve oral cleanliness. Unlikely that participants received mechanical ventilation
Zouka 2010
Abstract only, insufficient information to include in review. Emailed contact author 6 November 2012 without
response
RCT = randomised controlled trial
Characteristics of studies awaiting assessment [ordered by study ID]

Anon 2012
Methods
Participants
Interventions
EB57 oral care-based programme for reducing VAP
Outcomes
Notes
Full-text copy requested from library
Baradari 2012
Methods
Double-blind RCT
Participants
60 ICU patients divided into 2 equal groups. Seems unlikely that they are receiving mechanical ventilation
Interventions
Chlorhexidine versus herbal mouthrinse
Outcomes
Notes
Language: Iranian - will require translation. Full-text copy requested from library
87
Seo 2011
Methods
Participants
Interventions
Oral hygiene
Outcomes
Notes
Language: Korean - will require translation. Full-text copy requested from library
Yun 2011
Methods
Participants
Interventions
Toothbrushing
Outcomes
Notes
Language: Korean - will require translation. Full-text copy requested from library
ICU = intensive care unit; RCT = randomised controlled trial; VAP = ventilator-associated pneumonia
Characteristics of ongoing studies [ordered by study ID]

NCT 01657396
Trial name or title
Implementation and evaluation of revised protocols for oral hygiene for mechanically ventilated patients
Methods
RCT - 3-arm parallel group study
Participants
Adults in intensive care units in Alberta, Canada
Interventions
SAGE Q care (commercial package) versus SAGE Q care plus chlorhexidine versus standard oral hygiene care
Outcomes
VAP, frequency of oral care procedures, OA score, duration of ICU and hospital stay, ICU and hospital
mortality, antimicrobial utilisation, acquisition of antimicrobial resistant organisms
Starting date
July 2012 (currently recruiting)
Contact information
Dr Dan Zuege (dan.zuege@albertahealthservices.ca )
Notes
88
ICU = intensive care unit; OA = oral assessment; RCT = randomised controlled trial; VAP = ventilator-associated pneumonia
89
DATA AND ANALYSES
Comparison 1. Chlorhexidine versus placebo/usual care
Outcome or subgroup title

1 Incidence of VAP
1.1 Chlorhexidine solution
versus placebo (no tbrushing
in either group)
1.2 Chlorhexidine gel versus
placebo (no tbrushing in either
group)
versus placebo (tbrushing both
groups)
placebo (tbrushing both
groups)
versus usual care (some
tbrushing in each group)
2 Mortality
in either group)
group)
groups)
groups)
3 Duration of ventilation
in either group)
group)
groups)
4 Duration of ICU stay
in either group)
No. of
studies
No. of
participants
17
7
2402
1037
Odds Ratio (M-H, Random, 95% CI)

0.60 [0.47, 0.77]

0.60 [0.38, 0.94]
669
0.57 [0.31, 1.06]
408
0.44 [0.23, 0.85]
96
1.03 [0.44, 2.42]
192
0.58 [0.32, 1.02]
14
6
2111
973

1.10 [0.87, 1.38]

1.16 [0.72, 1.88]
414
0.89 [0.45, 1.76]
628
1.09 [0.72, 1.64]
96
0.67 [0.24, 1.81]
6
3
933
316
Mean Difference (IV, Random, 95% CI)

0.09 [-0.84, 1.01]

-2.74 [-0.63, 0.63]
543
1.26 [-0.78, 3.30]
74
-1.30 [-4.20, 1.60]
6
2
833
194

0.21 [-1.48, 1.89]

-1.22 [-4.07, 1.62]
Statistical method
Effect size
90

group)
groups)
5 Duration of systemic antibiotic
therapy
group)
groups)
6 Positive cultures
in either group)
group)
groups)
7 Plaque index
8 Adverse effects
8.1 Unpleasant taste
8.2 Reversible mild irritation
of oral mucosa
543
0.53 [-1.56, 2.61]
96
5.0 [-2.20, 12.20]
374
Mean Difference (IV, Fixed, 95% CI)
0.23 [-0.85, 1.30]
228
-1.18 [-3.41, 1.05]
146
0.65 [-0.58, 1.88]
3
1
170
34
Odds Ratio (M-H, Fixed, 95% CI)

0.69 [0.35, 1.33]

0.62 [0.13, 2.88]
40
0.15 [0.03, 0.63]
96
1.40 [0.55, 3.53]
1
2
1
1
401
194
207

Totals not selected

2.22 [0.84, 5.90]
0.57 [0.13, 2.47]
11.30 [1.42, 90.01]
Comparison 2. Toothbrushing versus no toothbrushing

1 Incidence of VAP
1.1 Powered toothbrush +
usual care ( CHX) versus
usual care ( CHX)
1.2 Toothbrush + CHX versus
CHX alone
1.3 Toothbrush (+some CHX)
versus no toothbrush (+some
CHX)
2 Mortality
2.1 Powered toothbrush+
usual care versus usual care
CHX alone
No. of
studies
No. of
participants
4
2
828
200

0.69 [0.36, 1.29]

0.35 [0.06, 1.97]
436
0.87 [0.47, 1.62]
192
1.09 [0.62, 1.92]
4
2
828
200

0.85 [0.62, 1.16]

1.32 [0.14, 12.90]
528
0.86 [0.59, 1.25]
Statistical method
Effect size
91
2.3 Toothbrush alone versus

no treatment
CHX alone
CHX alone
5 Colonisation with VAP
associated organisms (Day 5)
5.1 versus CHX alone
6 Plaque score
6.1 Powered toothbrush
versus usual care
100
1.20 [0.44, 3.25]
2
2
583

Subtotals only
-0.85 [-2.43, 0.73]
2
2
583

Subtotals only
-1.82 [-3.95, 0.32]
Risk Ratio (M-H, Fixed, 95% CI)
Subtotals only
Risk Ratio (M-H, Fixed, 95% CI)

Std. Mean Difference (IV, Fixed, 95% CI)
Std. Mean Difference (IV, Fixed, 95% CI)
0.82 [0.40, 1.68]

-1.20 [-1.70, -0.70]
-1.20 [-1.70, -0.70]
1
1
2
2
28
76
76
Comparison 3. Powered toothbrush versus manual toothbrush

1 Incidence of VAP
1.1 Powered tbrush + comp
oral care versus manual tbrush
+ std oral care
2 Mortality
+ std oral care
+ std oral care
+ std oral care
No. of
studies
1
1
No. of
participants
Statistical method
Effect size
78

Subtotals only
0.8 [0.28, 2.31]
1
1
78

Subtotals only
1.06 [0.14, 7.90]
1
1
78

Subtotals only
0.0 [-1.78, 1.78]
1
1
78

Subtotals only
-2.0 [-5.93, 1.93]
Comparison 4. Other oral care solutions

1 Incidence of VAP
1.1 Povidone iodine versus
saline
usual care
No. of
studies
No. of
participants
9
2
206

Subtotals only
0.35 [0.19, 0.65]
67
0.13 [0.03, 0.50]
Statistical method
Effect size
92
1.3 Povidone iodine (+

tbrush) versus povidone iodine
alone
1.4 Saline rinse versus saline
swab
1.5 Saline rinse + swab versus
saline swab (usual care)
1.6 Saline rinse versus usual
care
1.7 Bicarbonate rinse versus
water
1.8 Triclosan rinse versus
saline
1.9 Furacilin versus povidone
iodine
1.10 Furacilin versus saline
2 Mortality
saline
usual care
alone
saline swab (usual care)
2.5 Saline rinse versus usual
care
2.6 Bicarbonate rinse versus
water
saline
usual care
alone
3.4 Saline versus usual care
saline swab
3.6 Saline rinse versus saline
swab
saline
saline
usual care
4.3 Saline versus usual care
61
0.26 [0.07, 0.93]
218
0.65 [0.37, 1.14]
153
0.30 [0.14, 0.63]
324
0.50 [0.29, 0.88]
154
1.03 [0.25, 4.27]
324
0.80 [0.52, 1.24]
136
0.41 [0.17, 1.03]
1
5
1
133
67

0.19 [0.08, 0.46]

Subtotals only
0.42 [0.13, 1.33]
67
0.83 [0.24, 2.91]
61
0.54 [0.12, 2.47]
47
0.29 [0.06, 1.31]
324
1.20 [0.77, 1.87]
154
3.82 [1.18, 12.30]
6
1
67

Subtotals only
-1.0 [-4.36, 2.36]
67
-3.0 [-7.67, 1.67]
61
0.13 [-0.78, 1.04]
2
1
324
47

-0.40 [-2.55, 1.75]

-3.91 [-5.85, -1.97]
116
324
-10.80 [-15.88, -5.

72]
-5.24 [-5.64, -4.84]
3
1
67

Subtotals only
1.0 [-5.23, 7.23]
67
-4.0 [-10.99, 2.99]
324
-1.17 [-3.95, 1.60]
93

saline
5 Positive cultures
saline
324
-4.97 [-5.55, -4.39]
1
1
139

Subtotals only
0.45 [0.21, 0.97]
Analysis 1.1. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 1 Incidence of VAP.
Review:
Comparison: 1 Chlorhexidine versus placebo/usual care

Outcome: 1 Incidence of VAP
Study or subgroup
Chlorhexidine
Placebo/Usual care
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
1 Chlorhexidine solution versus placebo (no tbrushing in either group)

DeRiso 1996
5/173
17/180
5.1 %
0.29 [ 0.10, 0.79 ]
Chen 2008 (1)
16/60
28/60
7.9 %
0.42 [ 0.19, 0.89 ]
Panchabhai 2009
14/88
15/83
7.4 %
0.86 [ 0.39, 1.91 ]
16/64
17/69
7.6 %
1.02 [ 0.46, 2.24 ]
7/21
10/18
3.3 %
0.40 [ 0.11, 1.47 ]
Jacomo 2011 (3)
16/87
11/73
6.9 %
1.27 [ 0.55, 2.94 ]
Ozcaka 2012
12/29
22/32
4.8 %
0.32 [ 0.11, 0.92 ]
522
515
43.1 %
0.60 [ 0.38, 0.94 ]
Grap 2011 (2)
Subtotal (95% CI)
Total events: 86 (Chlorhexidine), 120 (Placebo/Usual care)

Heterogeneity: Tau2 = 0.15; Chi2 = 10.19, df = 6 (P = 0.12); I2 =41%
Test for overall effect: Z = 2.24 (P = 0.025)
2 Chlorhexidine gel versus placebo (no tbrushing in either group)
Fourrier 2000
5/30
14/28
3.8 %
0.20 [ 0.06, 0.67 ]
Fourrier 2005
13/114
12/114
7.0 %
1.09 [ 0.48, 2.51 ]
Koeman 2006
13/127
23/130
8.5 %
0.53 [ 0.26, 1.10 ]
1/17
6/23
1.2 %
0.18 [ 0.02, 1.64 ]
Sebastian 2012 (4)
12/41
14/45
6.0 %
0.92 [ 0.36, 2.30 ]
Subtotal (95% CI)
329
340
26.5 %
0.57 [ 0.31, 1.06 ]
Cabov 2010

3 Chlorhexidine solution versus placebo (tbrushing both groups)
0.01
0.1
Favours chlorhexidine
10
100
Favours placebo/u care
(Continued . . . )
94
(. . .
Study or subgroup
Chlorhexidine
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI
n/N
n/N
5/58
10/52
4.2 %
0.40 [ 0.13, 1.25 ]
14/100
12/49
6.6 %
0.50 [ 0.21, 1.19 ]
1/71
4/78
1.2 %
0.26 [ 0.03, 2.42 ]
229
179
12.0 %
0.44 [ 0.23, 0.85 ]
15/46
16/50
6.7 %
1.03 [ 0.44, 2.42 ]
46
50
6.7 %
1.03 [ 0.44, 2.42 ]
Tantipong 2008
Scannapieco 2009 (5)
Placebo/Usual care
Berry 2011
Subtotal (95% CI)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.33, df = 2 (P = 0.85); I2 =0.0%
4 Chlorhexidine gel versus placebo (tbrushing both groups)
Kusahara 2012 (6)
Subtotal (95% CI)

Heterogeneity: not applicable
5 Chlorhexidine solution versus usual care (some tbrushing in each group)
Munro 2009 (7)
38/92
55/100
11.7 %
0.58 [ 0.32, 1.02 ]
92
100
11.7 %
0.58 [ 0.32, 1.02 ]
1184
100.0 %
0.60 [ 0.47, 0.77 ]
Subtotal (95% CI)

Total (95% CI)
1218

Test for subgroup differences: Chi2 = 2.42, df = 4 (P = 0.66), I2 =0.0%
0.01
0.1
10
100
(1) CHX active ingredient in GSE rinse

(2) Single pre-operative CHX rinse, no placebo
(3) Children
(4) Children
(5) 50 patients treated 1x/day % 50 2x/day
(6) Children
(7) Study with factorial design and equal exposure to toothbrushing in both groups
95
Analysis 1.2. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 2 Mortality.

Review:

Outcome: 2 Mortality
Study or subgroup
Chlorhexidine
Placebo/Usual care
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI

DeRiso 1996
2/173
10/180
2.3 %
0.20 [ 0.04, 0.92 ]
Panchabhai 2009
64/88
51/83
12.5 %
1.67 [ 0.88, 3.19 ]
Munro 2009
13/44
9/51
5.7 %
1.96 [ 0.74, 5.15 ]
34/64
32/69
11.2 %
1.31 [ 0.66, 2.59 ]
5/87
5/73
3.3 %
0.83 [ 0.23, 2.98 ]
17/29
19/32
5.1 %
0.97 [ 0.35, 2.69 ]
485
488
40.1 %
1.16 [ 0.72, 1.88 ]
Jacomo 2011 (1)

Ozcaka 2012
Subtotal (95% CI)

Fourrier 2000
3/30
7/30
2.5 %
0.37 [ 0.08, 1.58 ]
Fourrier 2005
31/114
24/114
13.9 %
1.40 [ 0.76, 2.58 ]
0/17
0/23
Sebastian 2012 (2)
16/41
21/45
7.2 %
0.73 [ 0.31, 1.73 ]
Subtotal (95% CI)
202
212
23.6 %
0.89 [ 0.45, 1.76 ]
36/102
37/105
15.8 %
1.00 [ 0.57, 1.77 ]
12/48
10/49
5.8 %
1.30 [ 0.50, 3.37 ]
16/116
8/59
6.4 %
1.02 [ 0.41, 2.54 ]
5/71
4/78
2.9 %
1.40 [ 0.36, 5.44 ]
337
291
31.0 %
1.09 [ 0.72, 1.64 ]
Cabov 2010
Not estimable

Tantipong 2008
Munro 2009
Scannapieco 2009
Berry 2011
Subtotal (95% CI)

0.01
0.1
10
100
(Continued . . . )
96
(. . .
Study or subgroup
Chlorhexidine
Placebo/Usual care
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI

Kusahara 2012 (3)
8/46
12/50
5.3 %
0.67 [ 0.24, 1.81 ]
Subtotal (95% CI)
46
50
5.3 %
0.67 [ 0.24, 1.81 ]
1041
100.0 %
1.10 [ 0.87, 1.38 ]

Total (95% CI)
1070

0.01
0.1
10
100
(1) Children
(2) Children
(3) Children
97
Analysis 1.3. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 3 Duration of ventilation.
Review:

Outcome: 3 Duration of ventilation
Study or subgroup
Chlorhexidine
N
Mean
Difference
Placebo/Usual care
Mean(SD)
Mean(SD)
Weight
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI

64
11.1 (1.1)
69
11 (1.1)
53.1 %
0.10 [ -0.27, 0.47 ]
Ozcaka 2012
29
9 (8.3)
32
12.3 (11.9)
3.1 %
-3.30 [ -8.41, 1.81 ]
Scannapieco 2009
97
8.9 (5.1)
25
9.7 (6.3)
10.0 %
-0.80 [ -3.47, 1.87 ]
Subtotal (95% CI)
190
126
66.1 % 0.00 [ -0.63, 0.63 ]

Fourrier 2000
30
13 (12)
28
18 (20)
1.1 %
-5.00 [ -13.56, 3.56 ]
Fourrier 2005
114
11.7 (8.7)
114
10.6 (8.7)
13.0 %
1.10 [ -1.16, 3.36 ]
Koeman 2006
127
9.16 (12)
130
6.95 (8.1)
11.0 %
2.21 [ -0.30, 4.72 ]
Subtotal (95% CI)
271
25.2 % 1.26 [ -0.78, 3.30 ]
272

Scannapieco 2009
50
Subtotal (95% CI)
50
8.4 (5.2)
24
9.7 (6.3)
8.7 %
-1.30 [ -4.20, 1.60 ]
24
8.7 % -1.30 [ -4.20, 1.60 ]
422
100.0 % 0.09 [ -0.84, 1.01 ]

Total (95% CI)
511

Test for subgroup differences: Chi2 = 2.20, df = 2 (P = 0.33), I2 =9%
-10
-5
10
98
Analysis 1.4. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 4 Duration of ICU stay.
Review:

Outcome: 4 Duration of ICU stay
Study or subgroup
Chlorhexidine
N
Mean
Difference
Placebo/Usual care
Mean(SD)
Mean(SD)
Weight
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI

64
9.7 (9.4)
69
10.4 (9.4)
23.9 %
-0.70 [ -3.90, 2.50 ]
Ozcaka 2012
29
12.2 (11.3)
32
15.4 (13.5)
7.0 %
-3.20 [ -9.43, 3.03 ]
Subtotal (95% CI)
93
101
30.9 % -1.22 [ -4.07, 1.62 ]

Fourrier 2000
30
18 (16)
28
24 (19)
3.4 %
-6.00 [ -15.07, 3.07 ]
Fourrier 2005
114
14 (8.5)
114
13.3 (8.8)
42.4 %
0.70 [ -1.55, 2.95 ]
Koeman 2006
127 13.77 (17.4)
130 12.45 (12.9)
18.0 %
1.32 [ -2.43, 5.07 ]
Subtotal (95% CI)
271
63.8 % 0.53 [ -1.56, 2.61 ]
272

Kusahara 2012
Subtotal (95% CI)
46
15.8 (23.6)
46
50
10.8 (8.32)
5.3 %
5.00 [ -2.20, 12.20 ]
50
5.3 % 5.00 [ -2.20, 12.20 ]
423
100.0 % 0.21 [ -1.48, 1.89 ]

Total (95% CI)
410

-50
-25
25
50
99
Analysis 1.5. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 5 Duration of systemic
antibiotic therapy.
Review:

Outcome: 5 Duration of systemic antibiotic therapy
Study or subgroup
Chlorhexidine
N
Mean
Difference
Placebo/Usual care
Mean(SD)
Mean(SD)
114
10.6 (8.8)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Fourrier 2005
Subtotal (95% CI)
114
9.42 (8.4)
114
23.2 %
114
-1.18 [ -3.41, 1.05 ]
23.2 % -1.18 [ -3.41, 1.05 ]

Scannapieco 2009
97
Subtotal (95% CI)
97
3.75 (3.7)
49
3.1 (3.5)
76.8 %
0.65 [ -0.58, 1.88 ]
49
76.8 % 0.65 [ -0.58, 1.88 ]
163
100.0 % 0.23 [ -0.85, 1.30 ]

Total (95% CI)
211
Heterogeneity: Chi2 = 1.98, df = 1 (P = 0.16); I2 =50%

-10
-5
10
100
Analysis 1.6. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 6 Positive cultures.
Review:

Outcome: 6 Positive cultures
Study or subgroup
Chlorhexidine
Placebo/Usual care
n/N
n/N
Odds Ratio
Weight
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI

6/23
4/11
19.0 %
0.62 [ 0.13, 2.88 ]
23
11
19.0 %
0.62 [ 0.13, 2.88 ]
7/17
19/23
45.1 %
0.15 [ 0.03, 0.63 ]
17
23
45.1 %
0.15 [ 0.03, 0.63 ]
13/46
11/50
35.9 %
1.40 [ 0.55, 3.53 ]
46
50
35.9 %
1.40 [ 0.55, 3.53 ]
84
100.0 %
0.69 [ 0.35, 1.33 ]
Grap 2004 (1)
Subtotal (95% CI)

Cabov 2010 (2)
Subtotal (95% CI)

Kusahara 2012 (3)
Subtotal (95% CI)

Total (95% CI)
86

0.01
0.1
10
100
(1) Oral culture

(2) Tracheal culture
(3) Children
101
Analysis 1.7. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 7 Plaque index.
Review:

Outcome: 7 Plaque index
Study or subgroup
Chlorhexidine
Ozcaka 2012
Mean
Difference
Placebo/Usual care
Mean(SD)
Mean(SD)
29
86.6 (21.6)
32
84.7 (19.3)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
1.90 [ -8.42, 12.22 ]
-100
-50
50
100
Analysis 1.8. Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 8 Adverse effects.
Review:

Outcome: 8 Adverse effects
Study or subgroup
Placebo/Usual care
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
3/98
5/96
84.6 %
0.57 [ 0.13, 2.47 ]
98
96
84.6 %
0.57 [ 0.13, 2.47 ]
10/102
1/105
15.4 %
11.30 [ 1.42, 90.01 ]
102
105
15.4 %
11.30 [ 1.42, 90.01 ]
201
100.0 %
2.22 [ 0.84, 5.90 ]
M-H,Fixed,95% CI
1 Unpleasant taste
Subtotal (95% CI)
Total events: 3 (Favours chlorhexidine), 5 (Placebo/Usual care)

2 Reversible mild irritation of oral mucosa
Tantipong 2008
Subtotal (95% CI)

Total (95% CI)
200
0.01
0.1
10
100
(Continued . . . )
102
(. . .
Study or subgroup
Placebo/Usual care
Odds Ratio
Weight
n/N
n/N
M-H,Fixed,95% CI
Continued)
Odds Ratio
M-H,Fixed,95% CI

0.01
0.1
10
100
Analysis 2.1. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 1 Incidence of VAP.

Review:
Comparison: 2 Toothbrushing versus no toothbrushing

Study or subgroup
Toothbrushing
No toothbrushing
n/N
n/N
1 Powered toothbrush + usual care (
CHX) versus usual care (
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
CHX)
Pobo 2009 (1)
15/74
18/73
25.2 %
0.78 [ 0.36, 1.69 ]
Yao 2011 (2)
4/28
14/25
14.7 %
0.13 [ 0.03, 0.49 ]
102
98
40.0 %
0.35 [ 0.06, 1.97 ]
21/217
24/219
29.3 %
0.87 [ 0.47, 1.62 ]
217
219
29.3 %
0.87 [ 0.47, 1.62 ]
48/97
45/95
30.7 %
1.09 [ 0.62, 1.92 ]
97
95
30.7 %
1.09 [ 0.62, 1.92 ]
Subtotal (95% CI)
Total events: 19 (Toothbrushing), 32 (No toothbrushing)

2 Toothbrush + CHX versus CHX alone
Lorente 2012
Subtotal (95% CI)

3 Toothbrush (+some CHX) versus no toothbrush (+some CHX)
Munro 2009 (3)
Subtotal (95% CI)
0.01
0.1
Toothbrushing
10
100
No toothbrushing
(Continued . . . )
103
(. . .
Study or subgroup
Toothbrushing
No toothbrushing
n/N
n/N
416
412
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI

Total (95% CI)
100.0 %
0.69 [ 0.36, 1.29 ]

0.01
0.1
Toothbrushing
10
100
No toothbrushing
(1) CHX in both groups

(2) No CHX in either group
(3) Study with factorial design and equal exposure to CHX in both groups
Analysis 2.2. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 2 Mortality.

Review:

Study or subgroup
Toothbrushing
No toothbrushing
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
1 Powered toothbrush+ usual care versus usual care

Pobo 2009 (1)
16/74
23/73
18.1 %
0.60 [ 0.29, 1.26 ]
3/28
0/25
1.1 %
7.00 [ 0.34, 142.52 ]
102
98
19.2 %
1.32 [ 0.14, 12.90 ]
13/44
11.7 %
0.79 [ 0.32, 1.99 ]
Yao 2011
Subtotal (95% CI)

Munro 2009
12/48
0.01
0.1
Toothbrushing
10
100
No toothbrushing
(Continued . . . )
104
(. . .
Study or subgroup
Lorente 2012
Toothbrushing
No toothbrushing
Odds Ratio
MH,Random,95%
CI
Weight
Continued)
Odds Ratio
MH,Random,95%
CI
n/N
n/N
62/217
69/219
59.2 %
0.87 [ 0.58, 1.31 ]
265
263
70.9 %
0.86 [ 0.59, 1.25 ]
10/49
9/51
9.9 %
1.20 [ 0.44, 3.25 ]
49
51
9.9 %
1.20 [ 0.44, 3.25 ]
412
100.0 %
0.85 [ 0.62, 1.16 ]
Subtotal (95% CI)

3 Toothbrush alone versus no treatment
Munro 2009
Subtotal (95% CI)

Total (95% CI)
416

0.01
0.1
Toothbrushing
10
100
No toothbrushing
105
Analysis 2.3. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 3 Duration of ventilation.

Review:

Study or subgroup
Toothbrushing
Mean
Difference
No toothbrushing
Weight
IV,Fixed,95% CI
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
217
9.18 (14.13)
219
9.93 (15.39)
32.5 %
-0.75 [ -3.52, 2.02 ]
74
8.9 (5.8)
73
9.8 (6.1)
67.5 %
-0.90 [ -2.82, 1.02 ]

Lorente 2012
Pobo 2009
Subtotal (95% CI)
291
100.0 % -0.85 [ -2.43, 0.73 ]
292
Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.93); I2 =0.0%

Test for subgroup differences: Not applicable
-10
-5
Toothbrushing
10
No toothbrushing
Analysis 2.4. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 4 Duration of ICU stay.
Review:

Study or subgroup
Toothbrushing
N
Mean
Difference
No toothbrushing
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Lorente 2012
Pobo 2009
Subtotal (95% CI)
217 12.07 (15.55)

74
12.9 (8.7)
291
219 13.04 (17.27)

73
15.5 (9.6)
48.0 %
-0.97 [ -4.05, 2.11 ]
52.0 %
-2.60 [ -5.56, 0.36 ]
100.0 % -1.82 [ -3.95, 0.32 ]
292

-10
-5
Toothbrushing
10
No toothbrushing
106
Analysis 2.5. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 5 Colonisation with VAP
associated organisms (Day 5).
Review:

Outcome: 5 Colonisation with VAP associated organisms (Day 5)
Study or subgroup
Toothbrushing
No toothbrushing
n/N
n/N
Risk Ratio
Weight
Needleman 2011
5/10
11/18
100.0 %
0.82 [ 0.40, 1.68 ]
Subtotal (95% CI)
10
18
100.0 %
0.82 [ 0.40, 1.68 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 versus CHX alone

0.01
0.1
Toothbrushing
10
100
No toothbrushing
107
Analysis 2.6. Comparison 2 Toothbrushing versus no toothbrushing, Outcome 6 Plaque score.

Review:

Outcome: 6 Plaque score
Study or subgroup
Toothbrushing
Std.
Mean
Difference
No toothbrushing
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI
1 Powered toothbrush versus usual care

Needleman 2011 (1)
18 0.75 (0.5027)
Yao 2011 (2)
25
Total (95% CI)
43
2.51 (0.91)
9 1.35 (0.5074)
24
3.73 (1.06)
33.4 %
-1.15 [ -2.02, -0.29 ]
66.6 %
-1.22 [ -1.83, -0.60 ]
100.0 % -1.20 [ -1.70, -0.70 ]
33

Test for overall effect: Z = 4.68 (P < 0.00001)
-4
-2
Toothbrushing
No toothbrushing

(2) No CHX in either group
108
Analysis 3.1. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 1 Incidence of VAP.
Review:
Comparison: 3 Powered toothbrush versus manual toothbrush

Study or subgroup
Powered toothbrush
Manual toothbrush
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
M-H,Fixed,95% CI
1 Powered tbrush + comp oral care versus manual tbrush + std oral care
Prendergast 2012
8/38
10/40
100.0 %
0.80 [ 0.28, 2.31 ]
Subtotal (95% CI)
38
40
100.0 %
0.80 [ 0.28, 2.31 ]
Total events: 8 (Powered toothbrush), 10 (Manual toothbrush)

0.01
0.1
Powered toothbrush
10
100
Manual toothbrush
Analysis 3.2. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 2 Mortality.
Review:

Study or subgroup
Powered toothbrush
Manual toothbrush
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
M-H,Fixed,95% CI
Prendergast 2012
2/38
2/40
100.0 %
1.06 [ 0.14, 7.90 ]
Subtotal (95% CI)
38
40
100.0 %
1.06 [ 0.14, 7.90 ]
Total events: 2 (Powered toothbrush), 2 (Manual toothbrush)

0.01
0.1
Powered toothbrush
10
100
Manual toothbrush
109
Analysis 3.3. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 3 Duration of
ventilation.
Review:

Study or subgroup
Powered toothbrush
N
Mean
Difference
Manual toothbrush
Mean(SD)
Mean(SD)
40
8 (4)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Prendergast 2012
38
Subtotal (95% CI)
38
8 (4)
100.0 %
40
0.0 [ -1.78, 1.78 ]
100.0 % 0.0 [ -1.78, 1.78 ]

-10
-5
Powered toothbrush
10
Manual toothbrush
Analysis 3.4. Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 4 Duration of ICU
stay.
Review:

Study or subgroup
Powered toothbrush
N
Mean
Difference
Manual toothbrush
Mean(SD)
Mean(SD)
40
18 (9.4)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Prendergast 2012
38
Subtotal (95% CI)
38
16 (8.3)
100.0 %
-2.00 [ -5.93, 1.93 ]
100.0 % -2.00 [ -5.93, 1.93 ]
40

-100
-50
Powered toothbrush
50
100
Manual toothbrush
110
Analysis 4.1. Comparison 4 Other oral care solutions, Outcome 1 Incidence of VAP.
Review:
Comparison: 4 Other oral care solutions

Study or subgroup
Experimental
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
18/71
29/68
65.2 %
0.46 [ 0.22, 0.94 ]
3/36
12/31
34.8 %
0.14 [ 0.04, 0.58 ]
107
99
100.0 %
0.35 [ 0.19, 0.65 ]
3/36
13/31
100.0 %
0.13 [ 0.03, 0.50 ]
36
31
100.0 %
0.13 [ 0.03, 0.50 ]
4/31
11/30
100.0 %
0.26 [ 0.07, 0.93 ]
31
30
100.0 %
0.26 [ 0.07, 0.93 ]
Xu 2007
11/58
16/44
49.2 %
0.41 [ 0.17, 1.01 ]
Xu 2008
30/64
26/52
50.8 %
0.88 [ 0.42, 1.84 ]
122
96
100.0 %
0.65 [ 0.37, 1.14 ]
M-H,Fixed,95% CI
1 Povidone iodine versus saline

Feng 2012 (1)
Seguin 2006
Subtotal (95% CI)
Total events: 21 (Experimental), 41 (Control)

2 Povidone iodine versus usual care
Seguin 2006
Subtotal (95% CI)

3 Povidone iodine (+ tbrush) versus povidone iodine alone

Long 2012
Subtotal (95% CI)

4 Saline rinse versus saline swab
Subtotal (95% CI)

5 Saline rinse + swab versus saline swab (usual care)
Hu 2009
4/25
10/22
36.3 %
0.23 [ 0.06, 0.89 ]
Xu 2007
10/62
16/44
63.7 %
0.34 [ 0.13, 0.84 ]
0.01
0.1
Favours experimental
10
100
Favours control
(Continued . . . )
111
(. . .
Study or subgroup
Experimental
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
87
Subtotal (95% CI)
Continued)
Weight
Odds Ratio
66
100.0 %
0.30 [ 0.14, 0.63 ]
M-H,Fixed,95% CI

6 Saline rinse versus usual care
Caruso 2009
14/130
31/132
77.5 %
0.39 [ 0.20, 0.78 ]
Seguin 2006
12/31
13/31
22.5 %
0.87 [ 0.32, 2.41 ]
161
163
100.0 %
0.50 [ 0.29, 0.88 ]
4/76
4/78
100.0 %
1.03 [ 0.25, 4.27 ]
76
78
100.0 %
1.03 [ 0.25, 4.27 ]
73/162
82/162
100.0 %
0.80 [ 0.52, 1.24 ]
162
162
100.0 %
0.80 [ 0.52, 1.24 ]
8/65
18/71
100.0 %
0.41 [ 0.17, 1.03 ]
65
71
100.0 %
0.41 [ 0.17, 1.03 ]
8/65
29/68
100.0 %
0.19 [ 0.08, 0.46 ]
65
68
100.0 %
0.19 [ 0.08, 0.46 ]
Subtotal (95% CI)

7 Bicarbonate rinse versus water
Berry 2011
Subtotal (95% CI)

8 Triclosan rinse versus saline
Zhao 2012
Subtotal (95% CI)

9 Furacilin versus povidone iodine
Feng 2012 (2)
Subtotal (95% CI)

10 Furacilin versus saline
Feng 2012 (3)
Subtotal (95% CI)

0.01
0.1
10
100
Favours control
(1) Toothbrushing in both groups

112
Analysis 4.2. Comparison 4 Other oral care solutions, Outcome 2 Mortality.

Review:

Study or subgroup
Experimental
Control
n/N
n/N
Odds Ratio
Weight
6/36
10/31
100.0 %
0.42 [ 0.13, 1.33 ]
36
31
100.0 %
0.42 [ 0.13, 1.33 ]
6/36
6/31
100.0 %
0.83 [ 0.24, 2.91 ]
36
31
100.0 %
0.83 [ 0.24, 2.91 ]
3/31
5/30
100.0 %
0.54 [ 0.12, 2.47 ]
31
30
100.0 %
0.54 [ 0.12, 2.47 ]
3/25
7/22
100.0 %
0.29 [ 0.06, 1.31 ]
25
22
100.0 %
0.29 [ 0.06, 1.31 ]
Seguin 2006
10/31
6/31
11.5 %
1.98 [ 0.62, 6.37 ]
Caruso 2009
67/130
65/132
88.5 %
1.10 [ 0.68, 1.78 ]
161
163
100.0 %
1.20 [ 0.77, 1.87 ]
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI

Seguin 2006
Subtotal (95% CI)

Seguin 2006
Subtotal (95% CI)


Long 2012
Subtotal (95% CI)

4 Saline rinse + swab versus saline swab (usual care)

Hu 2009
Subtotal (95% CI)

5 Saline rinse versus usual care
Subtotal (95% CI)

6 Bicarbonate rinse versus water
0.01
0.1
10
100
Favours control
(Continued . . . )
113
(. . .
Study or subgroup
Experimental
Berry 2011
Control
Odds Ratio
Continued)
Odds Ratio
Weight
n/N
n/N
13/76
4/78
100.0 %
3.82 [ 1.18, 12.30 ]
76
78
100.0 %
3.82 [ 1.18, 12.30 ]
Subtotal (95% CI)
M-H,Fixed,95% CI
M-H,Fixed,95% CI

0.01
0.1
10
100
Favours control
Analysis 4.3. Comparison 4 Other oral care solutions, Outcome 3 Duration of ventilation.
Review:

Study or subgroup
Experimental
Mean
Difference
Control
Mean(SD)
Mean(SD)
36
9 (8)
31
10 (6)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Seguin 2006
Subtotal (95% CI)
36
31
100.0 %
-1.00 [ -4.36, 2.36 ]
100.0 %
-1.00 [ -4.36, 2.36 ]
100.0 %
-3.00 [ -7.67, 1.67 ]
100.0 %
-3.00 [ -7.67, 1.67 ]
100.0 %
0.13 [ -0.78, 1.04 ]
100.0 %
0.13 [ -0.78, 1.04 ]

Seguin 2006
Subtotal (95% CI)
36
9 (8)
36
31
12 (11)
31

Long 2012
Subtotal (95% CI)
31
31
10.29 (1.93)
30
10.16 (1.7)
30
-10
-5
10
Favours control
(Continued . . . )
114
(. . .
Study or subgroup
Experimental
N
Mean
Difference
Control
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Continued)
Mean
Difference
IV,Fixed,95% CI

4 Saline versus usual care
Caruso 2009
130
11.2 (11.2)
132
11.1 (9)
76.2 %
0.10 [ -2.36, 2.56 ]
Seguin 2006
31
10 (6)
31
12 (11)
23.8 %
-2.00 [ -6.41, 2.41 ]
100.0 %
-0.40 [ -2.55, 1.75 ]
100.0 %
-3.91 [ -5.85, -1.97 ]
100.0 %
-3.91 [ -5.85, -1.97 ]
100.0 %
-10.80 [ -15.88, -5.72 ]
Subtotal (95% CI)
161
163

5 Saline rinse + swab versus saline swab
Hu 2009
Subtotal (95% CI)
25
12.45 (1.17)
25
22
16.36 (4.52)
22

6 Saline rinse versus saline swab
Xu 2008
Subtotal (95% CI)
64
22.5 (11.1)
64
52
33.3 (15.8)
52
100.0 % -10.80 [ -15.88, -5.72 ]

Zhao 2012
Subtotal (95% CI)
162
8.96 (1.09)
162
162
14.2 (2.37)
162
100.0 %
-5.24 [ -5.64, -4.84 ]
100.0 %
-5.24 [ -5.64, -4.84 ]

-10
-5
10
Favours control
115
Analysis 4.4. Comparison 4 Other oral care solutions, Outcome 4 Duration of ICU stay.
Review:

Study or subgroup
Experimental
Mean
Difference
Control
Mean(SD)
Mean(SD)
36
15 (14)
31
14 (12)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Seguin 2006
Subtotal (95% CI)
36
31
100.0 %
1.00 [ -5.23, 7.23 ]
100.0 %
1.00 [ -5.23, 7.23 ]
100.0 %
-4.00 [ -10.99, 2.99 ]
100.0 %
-4.00 [ -10.99, 2.99 ]

Seguin 2006
Subtotal (95% CI)
36
15 (14)
36
31
19 (15)
31

3 Saline versus usual care
Caruso 2009
130
17.2 (12.3)
132
17.6 (12.8)
83.2 %
-0.40 [ -3.44, 2.64 ]
Seguin 2006
31
14 (12)
31
19 (15)
16.8 %
-5.00 [ -11.76, 1.76 ]
100.0 %
-1.17 [ -3.95, 1.60 ]
100.0 %
-4.97 [ -5.55, -4.39 ]
100.0 %
-4.97 [ -5.55, -4.39 ]
Subtotal (95% CI)
161
163

Zhao 2012
Subtotal (95% CI)
162
10.65 (2.21)
162
162
15.62 (3.06)
162

-100
-50
50
100
Favours control
116
Analysis 4.5. Comparison 4 Other oral care solutions, Outcome 5 Positive cultures.
Review:

Outcome: 5 Positive cultures
Study or subgroup
Experimental
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
14/71
24/68
100.0 %
0.45 [ 0.21, 0.97 ]
71
68
100.0 %
0.45 [ 0.21, 0.97 ]
M-H,Fixed,95% CI

Feng 2012
Subtotal (95% CI)

0.01
0.1
10
100
Favours control
ADDITIONAL TABLES
Table 1. Other outcome data from included studies
Comparison
Outcome
Data
CHX versus placebo/control ( Microbial colonisation

Berry 2011)
There was no significant difference in comparison of change in

microbial growth from day 1 to
day 4 between CHX and control groups
Toothbrushing versus none ( Incidence of VAP

Bopp 2006)
0/2 cases in toothbrushing

group and 1/3 case in control
group
Mean 5.5 days (SD 0.3896) n

= 2 in toothbrushing group and
mean 5 days (SD 0.8051) n = 3
Mean 18 days (SD 1.6695) n =

2 in toothbrushing group and
mean 10.3 days (SD 2.6971) n
=3
Effect estimate (95% CI)
117
Table 1. Other outcome data from included studies
(Continued)
CHX versus placebo/control ( Microbial colonisation

Grap 2004)
Positive cultures in 3/11 patients in CHX spray group, 3/

12 patients in CHX swab group
and 4/11 patients in control
group over the study period
CHX versus placebo (Koeman Mortality

2006)
Hazard ratio
HR 1.12 (0.72 to 1.17)
Hazard ratio, Gram positive organisms

Hazard ratio, Gram negative organisms
HR 0.695 (0.606 to 0.796)

(Gram positive)
HR 0.826 (0.719 to 0.950)
(Gram negative)
CHX spray versus CHX spray Mean CPIS at 72 hours com- CHX spray: CPIS score at 72
+ toothbrush versus usual care pared to baseline
hours mean 4.88 (SD 2.14) n =
(McCartt 2010)
24
CHX spray + toothbrush: CPIS
score at 72 hours mean 5.00
(SD 1.84) n = 24
Usual care: CPIS score at 72
hours mean 5.19 (SD 1.56) n =
21
CHX spray versus usual care P

= 0.58
CHX + toothbrushing versus
usual care P = 0.71
Experimental groups combined
versus usual care P = 0.57
Oral microbial colonisation
Powered toothbrush + CHX Plaque index

versus CHX alone (Roca Biosca
2011)
Incidence of VAP
CHX (once daily or twice daily) Plaque index

versus placebo (Scannapieco
2009)
Mean in toothbrush group 1.68

(n = 29) and mean in control
group 1.91 (n = 32)
No estimates of variance but reported that P = 0.7 (no difference)
Odds ratio 0.78 (95% CI 0.36
to 1.68, P = 0.56)
No difference between the 3
groups (data presented graphically)
CHX = chlorhexidine; CI = confidence interval; CPIS = Clinical Pulmonary Infection Score; HR = hazard ratio; ICU = intensive care
unit; SD = standard deviation; VAP = ventilator-associated pneumonia
118
APPENDICES
Appendix 1. Cochrane Oral Health Groups Trials Register search strategy
#1 ((critical* AND ill*):ti,ab) AND (INREGISTER)
#2 ((depend* and patient*):ti,ab) AND (INREGISTER)
#3 ((critical care or intensive care or ICU or CCU):ti,ab) AND (INREGISTER)
#4 ((intubat* or ventilat*):ti,ab) AND (INREGISTER)
#5 ((#1 or #2 or #3 or #4)) AND (INREGISTER)
#6 ((pneumonia or nosocomial infect* or VAP):ti,ab) AND (INREGISTER)
#7 (#5 and #6) AND (INREGISTER)
Appendix 2. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1
MeSH descriptor Critical illness this term only
#2
(critical* in All Text near/6 ill* in All Text)
#3
(depend* in All Text near/6 patient* in All Text)
#4
MeSH descriptor Critical care this term only
#5
(intensive-care in All Text or intensive care in All Text or critical-care in All Text or critical care in All Text)
#6
ICU in Title, Abstract or Keywords
#7
((intubat* in All Text near/5 patient* in All Text) or (ventilat* in All Text near/5 patient* in All Text))
#8
(#1 or #2 or #3 or #4 or #5 or #6 or #7)
#9
(VAP in Title, Abstract or Keywords or VAP in Title, Abstract or Keywords)
#10
nosocomial infection* in Title, Abstract or Keywords
#11
MeSH descriptor Pneumonia, Ventilator-Associated this term only
#12
pneumonia in All Text
#13
(#9 or #10 or #11 or #12)
#14
MeSH descriptor Oral health this term only
#15
MeSH descriptor Oral hygiene explode all trees
#16
MeSH descriptor Dentifrices explode all trees
#17
MeSH descriptor Mouthwashes explode all trees
#18
MeSH descriptor Periodontal diseases explode all trees
#19
periodont* in All Text
#20
(oral care in All Text or oral health in All Text or oral-health in All Text or mouth care in All Text or oral hygien* in
All Text or oral-hygien* in All Text or dental hygien* in All Text or decontaminat* in All Text)
#21 (mouthwash* in All Text or mouth-wash* in All Text or mouth-rins* in All Text or mouthrins* in All Text or oral rins* in All
Text or oral-rins* in All Text or artificial saliva in All Text or saliva substitut* in All Text or ( (denture* in All Text near/6 clean* in
All Text) or toothpaste* in All Text) or dentifrice* in All Text)
#22
(#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
#23
(#8 and #13)
#24
(#22 and #23)
119
Appendix 3. MEDLINE via OVID search strategy

1. CRITICAL ILLNESS/
2. (critical$ adj5 ill$).mp.
3. (depend$ adj5 patient$).mp.
4. INTENSIVE CARE/
5. (intensive care or intensive-care or critical care or critical-care).mp.
6. ICU.mp. or CCU.ti,ab.
7. ((intubat$ or ventilat$) adj5 patient$).mp.
8. or/1-7
9. PNEUMONIA, VENTILATOR-ASSOCIATED/
10. pneumonia.ti,ab.
11. VAP.ti,ab.
12. nosocomial infection.mp.
13. or/9-12
14. exp ORAL HYGIENE/
15. exp DENTIFRICES/
16. MOUTHWASHES/
17. ANTI-INFECTIVE AGENTS, LOCAL/
18. Cetylpyridinium/
19. Chlorhexidine/
20. Povidone-Iodine/
21. (oral care or mouth care or oral hygien$ or oral-hygien$ or dental hygien$).ti,ab.
22. (mouthwash$ or mouth-wash$ or mouth-rins$ or mouthrins$ or oral rins$ or oral-rins$ or toothpaste$ or dentifrice$ or
toothbrush$ or chlorhexidine$ or betadine$ or triclosan$ or cepacol or Corsodyl or Peridex or Hibident or Prexidine or Parodex
or Chlorexil or Peridont or Eludril or Perioxidin or Chlorohex or Savacol or Periogard or Chlorhexamed or Nolvasan or Sebidin or
Tubulicid or hibitane).mp.
23. (antiseptic$ or antiinfect$ or local microbicide$ or topical microbicide$).mp.
24. or/14-23
25. 8 and 13 and 24
Appendix 4. EMBASE via OVID search strategy

1. CRITICAL ILLNESS/
2. (critical$ adj5 ill$).mp.
3. (depend$ adj5 patient$).mp.
4. INTENSIVE CARE/
5. (intensive care or intensive-care or critical care or critical-care).mp.
6. (ICU or CCU).ti,ab.
7. ((intubat$ or ventilat$) adj5 patient$).mp.
8. or/1-7
9. PNEUMONIA, VENTILATOR-ASSOCIATED/
10. pneumonia.ti,ab.
11. VAP.ti,ab.
12. nosocomial infection.mp.
13. or/9-12
14. exp ORAL HYGIENE/
15. exp DENTIFRICES/
16. MOUTHWASHES/
17. ANTI-INFECTIVE AGENTS, LOCAL/
18. Cetylpyridinium/
19. Chlorhexidine/
20. Povidone-Iodine/
120
21. (oral care or mouth care or oral hygien$ or oral-hygien$ or dental hygien$).ti,ab.
22. (mouthwash$ or mouth-wash$ or mouth-rins$ or mouthrins$ or oral rins$ or oral-rins$ or toothpaste$ or dentifrice$ or
toothbrush$ or chlorhexidine$ or betadine$ or triclosan$ or cepacol or Corsodyl or Peridex or Hibident or Prexidine or Parodex
or Chlorexil or Peridont or Eludril or Perioxidin or Chlorohex or Savacol or Periogard or Chlorhexamed or Nolvasan or Sebidin or
Tubulicid or hibitane).mp.
23. (antiseptic$ or antiinfect$ or local microbicide$ or topical microbicide$).mp.
24. or/14-23
25. 8 and 13 and 24
The above subject search was linked to the Cochrane Oral Health Group filter for EMBASE via OVID:
1. random$.ti,ab.
2. factorial$.ti,ab.
3. (crossover$ or cross over$ or cross-over$).ti,ab.
4. placebo$.ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
7. assign$.ti,ab.
8. allocat$.ti,ab.
9. volunteer$.ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
14. or/1-13
15. ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/
16. HUMAN/
17. 16 and 15
18. 15 not 17
19. 14 not 18
Appendix 5. CINAHL via EBSCO search strategy

S25
S14 and S24
S24
S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23
S23
(antiseptic* or antiinfect* or local microbicide* or topical microbicide*)
S22
(mouthwash* or mouth-wash* or mouth-rins* or mouthrins* or oral rins* or oral-rins* or toothpaste* or dentifrice* or
toothbrush* or chlorhexidine* or betadine* or triclosan* or cepacol or Corsodyl or Peridex or Hibident or Prexidine or Parodex or
Chlorexil or Peridont or Eludril or Perioxidin or Chlorohex or Savacol or Periogard or Chlorhexamed or Nolvasan or Sebidin or
Tubulicid or hibitane)
S21
(oral care or mouth care or oral hygien* or oral-hygien* or dental hygien*)
S20
(MH Povidone-Iodine)
S19
(MH Chlorhexidine)
S18
(MH Antiinfective Agents, Local)
S17
MH MOUTHWASHES
S16
(MH DENTIFRICES+)
S15
(MH Oral Hygiene+)
S14
S8 AND S13
S13
S9 or S10 or S11 or S12
S12
TI pneumonia or AB pneumonia
S11
MH PNEUMONIA, VENTILATOR-ASSOCIATED
S10
TI nosocomial infection and AB nosocomial infection
S9
TI VAP or AB VAP
S8
S1 or S2 or S3 or S4 or S5 or S6 or S7
121
S7
S6
S5
S4
S3
S2
S1
((intubat* N5 patient*) or (ventilat* N5 patient*))

TI ICU or AB ICU or TI CCU or AB CCU
(intensive-care or intensive care or critical-care or critical care)
MH CRITICAL CARE
(depend* N6 patient*)
(critical* N6 ill*)
MH CRITICAL ILLNESS
Appendix 6. LILACS via BIREME Virtual Health Library search strategy

(Mh Critical illness or Enfermedad Crtica or Estado Terminal or critical illness$ or Mh Intensive care or Cuidados Intensivos or
Terapia Intensiva or critical care or intensive care or ICU or CCU or intubate$ or ventilate$) [Words] and (Mh Pneumonia,
Ventilator-Associated or Neumonia Asociada al Ventilador or Pneumonia Associada Ventilao Mecnica or (ventilator AND
pneumonia)) [Words] and (Mh Oral hygiene or oral hygiene or Higiene Bucal or oral care or mouth care or mouthwash$ or
mouthrins$ or toothpaste$ or dentifrice$ or chlorhexidine or betadine or triclosan or Clorhexidina or Clorexidina or Antispticos
Bucales or Antisspticos Bucais or Cepillado Dental or Escovao Dentria or antiseptic$ or antiinfective$)
Appendix 7. Chinese Biomedical Literature Database search strategy

#1
]:
:1978-2012
#2
:ICU -
:1978-2012
#3
:VAP -
:1978-2012
#4
:
:1978-2012
#5 #4 or #3 or #2 or #1
#6
#7
#8
]:
#9
[
]:
#10 #9 or #8 or #7 or #6
#11 #10 and #5
[
#12
]:
#13
:
#14 #13 or #12
#15 #14 and #11
Appendix 8. China National Knowledge Infrastructure search strategy

#1
((
(
)(
);2003-2012;
=VAP)
#2
=
)(
);
#3
(
)(
);
(
(
=ICU)
))
(
(
=
(
)
)
122
Appendix 9. Wan Fang Database search strategy

((
=(
) ) )
1.
2.
((
=(
) ICU) )
3.
((
=(
) VAP) )
4.
((
=(
) ) )
5.
((
=(
) ) )
6.
((
=(
)
) )
7.
((
=(
)
) )
8.
((
=(
)
) )
9.
((
=(
) ) ) ((
=(
) ICU) ) ((
=(
) VAP) )
10. ((
=(
) ) ) ((
=(
) ) ) ((
=(
)
) ) ((
=(
)
) ) ((
=(
)
) )
11.
( ((
=(
) ) ) ((
=(
) ) ) ((
=(
)
) ) ((
=(
)
) )
((
=(
)
) ) ) ( ((
=(
) ) ) ((
=(
) ) ) ((
=(
)
) ) ((
=(
)
) ) ((
=(
)
) ) ((
=(
) ) ) ((
=(
) ICU) ) ((
=(
)
VAP) ) )
Appendix 10. OpenGrey search strategy

oral health or oral hygiene or oral care or mouth care or dental hygiene or mouthwash* or mouth-wash or mouthrinse* or
mouth-rinse* or artificial saliva or saliva substitute* or toothpaste* or dentifrice* or periodontic* or periodontal
AND
critical care or intensive care or ICU or critical illness or intubated or ventilated
Appendix 11. ClinicalTrials.gov search strategy

ventilator and pneumonia and oral hygiene
WHATS NEW
Last assessed as up-to-date: 14 January 2013.
Date
Event
Description
27 November 2013
Amended
Minor typographical error.
CONTRIBUTIONS OF AUTHORS
Zongdao Shi and Huixu Xie: As joint first authors, conceiving, designing and co-ordinating the protocol, preparing a draft of the
review.
Sue Furness: Contact author, updating background, revising inclusion criteria, screening search results, extracting data, assessing risk
of bias, conducting meta-analysis and revising the text of the review.
Helen Worthington: Screening search results, extracting data, assessing risk of bias, conducting meta-analysis.
Ian Needleman: Updating background and revising inclusion criteria, extracting data, assessing risk of bias, contributing to the discussion
section.
123
Ping Wang, Huixu Xie, Qi Zhang: Undertaking searches, screening search results, appraising risk of bias, extracting data.
E Chen and Yan Wu, Ian Needleman: Appraising quality of those papers for which Xie and Wang disagreed, participating in the
discussion prior to preparation of the first draft.
Linda Ng: Electronic and handsearching for nursing journal articles.
DECLARATIONS OF INTEREST
Ian Needleman is the first author of one of the studies included in this review. The assessment of risk of bias and the data extraction of
this study was undertaken by two other review authors.
None known.
SOURCES OF SUPPORT
Internal sources
West China College of Stomatology of Sichuan University and the Chinese Cochrane Center, China.
This review was supported by the West China College of Stomatology, Sichuan University academically and in manpower resource;
statistical analysis was supported by the Chinese Cochrane Center
The University of Manchester, UK.
Manchester Academic Health Sciences Centre (MAHSC), UK.
The Cochrane Oral Health Group is supported by MAHSC and the NIHR Manchester Biomedical Research Centre
External sources
Cochrane Oral Health Group Global Alliance, UK.
All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Orthodontic Society,
UK; British Society of Paediatric Dentistry, UK; Canadian Dental Hygienists Association, Canada; National Center for Dental
Hygiene Research & Practice, USA and New York University College of Dentistry, USA) providing funding for the editorial process (
http://ohg.cochrane.org/)
CMB funding SR0510, Project of Development of Systematic Review supported by Chinese Medical Board of New York, USA.
National Institute for Health Research (NIHR), UK.
CRG funding acknowledgement:
The NIHR is the largest single funder of the Cochrane Oral Health Group
Disclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the
Department of Health
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Clarifications were made to the criteria for studies eligible to be included in this review.
Participants in trials should not have a respiratory infection at baseline.
The interventions to be included in this review must include an oral hygiene care component. Trials where the intervention
being evaluated was a type of suction system or variation of method, timing, or place where mechanical ventilation was introduced
(e.g. emergency room or ICU) were excluded.
Minimum duration of mechanical ventilation of 48 hours, in order for the diagnosis of nosocomial pneumonia, diagnosed either
during period of ventilation or within 48 hours of extubation, to be considered ventilator-associated pneumonia.
124
Outcome of mortality defined as either all cause ICU mortality or where this was not available, all cause 30-day mortality. We
considered that the effect of the underlying condition(s) on mortality would be similar in each randomised treatment group during
this period.
In order to avoid duplication, trials where the intervention was selective decontamination of the digestive tract with antibiotics
were excluded as these interventions are included in another Cochrane review (DAmico 2009).
Likewise trials where the intervention was probiotics were excluded as these interventions are included in another Cochrane
review (Hao 2011).
The text in the methods section of this review about the risk of bias assessment has been updated in line with the latest version of the
Cochrane Hanbook for Systematic Reviews of Interventions and additional details about the process followed have been added.
INDEX TERMS
Medical Subject Headings (MeSH)
Critical
Illness; Chlorhexidine [therapeutic use]; Intensive Care Units; Mouthwashes [therapeutic use]; Oral Hygiene [ methods];
Pneumonia, Ventilator-Associated [ prevention & control]; Randomized Controlled Trials as Topic; Respiration, Artificial [ adverse
effects]; Toothbrushing [instrumentation; methods]
MeSH check words

Adult; Child; Humans
125

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Oral hygiene care for critically ill patients to prevent

ventilator-associated pneumonia (Review)

Oral hygiene care for critically ill patients to prevent

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Illustrative comparative risks* (95% CI)

Quality of the evidence

This equates to an NNT of

160 per 1000

257 per 1000

The mean duration of

The mean duration of ventilation in the intervention

Duration of ICU stay

The mean duration of ICU

Description of the condition

Description of the intervention

How the intervention might work

ual or powered toothbrush, removes plaque from teeth and gums

Why it is important to do this review

We included in the review all randomised controlled trials (RCTs)

Criteria for considering studies for this review

1. Incidence of VAP (defined as pneumonia developing in a

1. Duration of mechanical ventilation or ICU stay or both.

Search methods for identification of studies

We contacted the first author of the included studies, other experts

Data collection and analysis

Other results: we also collected summary statistics, sample size,

concealment we assessed it as unclear for this domain.

Low risk of bias

Unclear risk of bias

High risk of bias

We presented the risk of bias graphically by: (a) proportion of

Measures of treatment effect

Unit of analysis issues

Subgroup analysis and investigation of heterogeneity

One subgroup analysis was proposed a priori when discussing how

To detect heterogeneity among studies in a meta-analysis, a

Assessment of reporting biases

To determine whether the intervention effects of oral hygiene care

Results of the search

these 937 were discarded and full-text copies of 71 references were

Figure 3. Study flow diagram

and in the remaining 13 studies it was not clearly stated whether

We included 35 RCTs in this review.

Nine of the included studies were conducted in the USA (Bopp

The interventions in the included studies were in three broad

Chlorhexidine solution (applied as mouthrinse, spray

Kusahara 2012;Sebastian 2012), base solution (Scannapieco 2009)

Measures of primary outcomes

20% increase in fraction of inspired oxygen required to maintain

Measures of secondary outcomes

Duration of ICU stay

Systemic antibiotic therapy

by the corresponding author in one study (Yao 2011), one study

Risk of bias in included studies

Twenty-six of the included studies described clearly a random

Allocation concealment was clearly described in 19 of the included

Incomplete outcome data

Twenty-three of the included studies (Bellissimo-Rodrigues 2009;