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Abstract
Introduction: Ventilator-associated pneumonia (VAP) remains a common hazardous complication in mechanically
ventilated patients and is associated with increased morbidity and mortality. We undertook a systematic review
and meta-analysis of randomized controlled trials to assess the effect of toothbrushing as a component of oral care
on the prevention of VAP in adult critically ill patients.
Methods: A systematic literature search of PubMed and Embase (up to April 2012) was conducted. Eligible studies
were randomized controlled trials of mechanically ventilated adult patients receiving oral care with toothbrushing.
Relative risks (RRs), weighted mean differences (WMDs), and 95% confidence intervals (CIs) were calculated and
heterogeneity was assessed with the I2 test.
Results: Four studies with a total of 828 patients met the inclusion criteria. Toothbrushing did not significantly
reduce the incidence of VAP (RR, 0.77; 95% CI, 0.50 to 1.21) and intensive care unit mortality (RR, 0.88; 95% CI, 0.70
to 1.10). Toothbrushing was not associated with a statistically significant reduction in duration of mechanical
ventilation (WMD, -0.88 days; 95% CI, -2.58 to 0.82), length of intensive care unit stay (WMD, -1.48 days; 95% CI,
-3.40 to 0.45), antibiotic-free day (WMD, -0.52 days; 95% CI, -2.82 to 1.79), or mechanical ventilation-free day (WMD,
-0.43 days; 95% CI, -1.23 to 0.36).
Conclusions: Oral care with toothbrushing versus without toothbrushing does not significantly reduce the
incidence of VAP and alter other important clinical outcomes in mechanically ventilated patients. However, the
results should be interpreted cautiously since relevant evidence is still limited, although accumulating. Further
large-scale, well-designed randomized controlled trials are urgently needed.
© 2012 Gu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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with chlorhexidine solution has been found to reduce the outcome was the incidence of VAP. Secondary outcomes
risk of VAP, according to some published meta-analyses included ICU mortality, duration of mechanical ventila-
[8-10]; however, the role of oral care with toothbrushing tion, length of ICU stay, antibiotic-free days, and mechani-
has received scant attention and remains unclear. Nowa- cal ventilation-free day.
days, there are published randomized controlled trials
(RCTs) regarding the effect of oral care with toothbrush- Quality scoring and risk-of-bias assessment
ing on the prevention of VAP. However, these studies The methodological quality of each trial was evaluated by
have a modest sample size and convey inconclusive using the Jadad scale [11]. This tool places emphasis on
results. So we undertook a systematic review and meta- the following three areas when defining the quality of an
analysis of RCTs to assess the effects of oral care with RCT: (a) randomization, (b) double-blinding, and (c)
toothbrushing on the incidence of VAP and other impor- description of withdrawals and drop-outs. A score of 1 is
tant clinical outcomes in adult critically ill patients given for each of the areas described. A further point is
receiving mechanical ventilation. obtained where the method of randomization or blinding
(or both) is given and is appropriate; where it is inap-
Materials and methods propriate, a point is deducted. The studies are said to be
Literature search and inclusion criteria of low quality if the Jadad score is not more than 2 and
Relevant RCTs were identified by searching PubMed of high quality if the score is at least 3 [12].
and Embase databases. Other websites, including Risk-of-bias assessment was performed in accordance
Cochrane Central Register of Controlled Trials, Google with guidelines outlined in the Cochrane Handbook for
Scholar, Chinese Biomedical Literature on disc, and Systematic Reviews of Interventions (version 5.1.0) [13].
http://ClinicalTrials.gov (up to July 2012), were also Two authors subjectively reviewed all studies and
searched. The structured search strategies used the fol- assigned a value of ‘ high’, ‘low’, or ‘unclear’ to the follow-
lowing format of search terms: (‘toothbrushing’ or ‘tooth ing: (a) selection bias (Was there adequate generation of
brushing’ or ‘dental’ or ‘teeth brushing’ or ‘brushing the randomization sequence? Was allocation conceal-
tooth’ or ‘brushing teeth’) and ’pneumonia’. The search ment satisfactory?); (b) performance and detection bias
was limited to human subjects and RCTs. No language (Was there blinding of participants, personnel, and out-
restriction was imposed. We also manually checked the come assessors?); (c) attrition bias (Were incomplete out-
reference lists of RCTs to include other potentially eligi- come data sufficiently assessed and dealt with?); (d)
ble trials. This process was performed iteratively until reporting bias (Was there evidence of selective outcome
no additional articles could be identified. The following reporting?); and (e) were any other sources of bias
inclusive selection criteria were applied: (a) study design: identified?
RCT; (b) study population: adult critically ill patients
receiving mechanical ventilation; (c) intervention: oral Statistical analysis
care with toothbrushing (regardless of approach and Differences were expressed as relative risks (RRs) with
liquid applied); (d) comparison intervention: oral care 95% confidence intervals (CIs) for dichotomous out-
without toothbrushing; and (e) outcome measure: the comes and as weighted mean differences (WMDs) with
incidence of VAP. 95% CIs for continuous outcomes. Heterogeneity across
studies was tested by using the I2 statistic, which was a
Data extraction and outcome measures quantitative measure of inconsistency across studies.
Two authors (W-JG and LP) independently extracted the Studies with an I2 statistic of 25% to 50% were considered
following data from each RCT: first author, publication to have low heterogeneity, those with an I 2 statistic of
year, number of patients (intervention/control), type of 50% to 75% were considered to have moderate heteroge-
ICU/study population, severity of illness at ICU admission neity, and those with an I2 statistic of greater than 75%
(intervention/control), study design, intervention group were considered to have a high degree of heterogeneity
(oral care with toothbrushing), control group (oral care [14]. An I2 value of greater than 50% indicates significant
without toothbrushing), definition of VAP, the incidence heterogeneity [15]. A fixed-effects model was used, and a
of VAP, and other important clinical outcome data. random-effects model was used in the case of significant
Extracted data were entered into a standardized Excel file heterogeneity (I2 > 10%). Whenever heterogeneity was
(Microsoft Corporation, Redmond, WA, USA) and were present, several sensitivity analyses were carried out to
checked by a third author (Y-ZG). When the same popula- identify potential sources. We also investigated the influ-
tion was reported in several publications, we retained only ence of a single study on the overall pooled estimate by
the most informative article or complete study to avoid omitting one study in each turn. Owing to the limited
duplication of information. Any disagreements were number (below 10) of studies included in each analysis,
resolved by discussion and consensus. The primary publication bias was not assessed. A P value of less than
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0.05 was considered statistically significant. Risk-of-bias no standard definition was used in reported studies. The
assessment was conducted by using Review Manager ver- median Jadad score of the studies included was 3 (range
sion 5.0 (The Cochrane Collaboration, Software Update, of 2 to 3). Risk-of-bias analysis (Figure 2) revealed that
Oxford, UK), and other statistical analyses were per- only two of the included studies [22,23] adequately
formed by using STATA version 11.0 (Stata Corporation reported the randomization protocol and that none
LP, College Station, TX, USA). described a method used to conceal the allocation
sequence in sufficient detail to exclude selection bias.
Results
Study identification and selection Primary outcome: ventilator-associated pneumonia
The initial search yielded 148 relevant publications, of All four RCTs reported VAP in study patients. The
which 140 were excluded for duplicate studies and var- aggregated results of these four studies suggest that oral
ious reasons (reviews, non-randomized studies, or not care with toothbrushing was not associated with a sig-
relevant to our analysis) on the basis of the titles and nificant reduction in the incidence of VAP (RR 0.77,
abstracts (Figure 1). The remaining eight were retrieved 95% CI 0.50 to 1.21; P = 0.26) (Figure 3). The test for
for full text review, and four of them were excluded heterogeneity was significant (P for heterogeneity = 0.05;
because one did not report outcomes of interest [16], one I2 = 61.6%). Subsequently, we performed sensitivity ana-
pertained to electric rather than manual toothbrushing lyses to explore potential sources of heterogeneity.
[17], one was currently ongoing [18], and one was dupli- Exclusion of the trial conducted by Yao and colleagues
cated data [19]. Thus, four RCTs were included in the [22] resolved the heterogeneity but did not change the
final analysis [20-23]. results (RR 0.95, 95% CI 0.75 to 1.22; P = 0.71; P for
heterogeneity = 0.71; I2 = 0%) [22]. Further exclusion of
Study characteristics, quality, and bias assessment any single study did not materially alter the overall com-
The main characteristics of the four RCTs included in bined RR, which ranged from 0.64 (95% CI 0.34 to 1.20;
the meta-analysis are presented in Table 1 and the out- P = 0.16) to 0.72 (95% CI 0.38 to 1.35; P = 0.31).
come data of each included trial are described in Table 2.
These studies were published between 2009 and 2012. Secondary outcomes
The sizes of the RCTs ranged from 53 to 436 patients Oral care with toothbrushing was not associated with
(total of 828). The selected trials examined various popu- decreases in ICU mortality (three RCTs; RR 0.88, 98%
lations in ICUs, including surgical [21], medical-surgical CI 0.70 to 1.10; P = 0.26; P for heterogeneity = 0.61)
[20,22], and mixed (medical, surgical/trauma, and neu- (Figure 4), duration of mechanical ventilation (three
roscience) [23]. All of these patients received mechanical RCTs; WMD -0.88 days, 95% CI -2.58 to 0.82; P = 0.31;
ventilation for more than 24 hours, and none had pneu- P for heterogeneity = 0.98) (Figure 5), length of ICU
monia. The definition of VAP varied across studies, and stay (three RCTs; WMD -1.48 days, 95% CI -3.40 to
0.45; P = 0.13; P for heterogeneity = 0.75) (Figure 6),
antibiotic-free day (two RCTs; WMD -0.52 days, 95%
CI -2.82 to 1.79; P = 0.66; P for heterogeneity = 0.75)
(Figure 7), and mechanical ventilation-free day (two
RCTs; WMD -0.43 days, 95% CI -1.23 to 0.36; P = 0.29;
P for heterogeneity = 0.56) (Figure 8). There was no evi-
dence of heterogeneity for these secondary outcomes (all
P values > 0.56; I2 = 0%).
Discussion
Our meta-analysis suggests that oral care with tooth-
brushing did not significantly reduce the incidence of
VAP in adult critically ill patients receiving mechanical
ventilation. In addition, oral care with toothbrushing
was not associated with a markedly reduced ICU mor-
tality, duration of mechanical ventilation, length of ICU
stay, antibiotic-free day, or mechanical ventilation-free
day.
Several high-quality non-randomized studies focusing
Figure 1 Selection process for randomized controlled trials on toothbrushing for VAP prevention are summarized
included in the meta-analysis.
in Table 3. All of them reported that oral care with
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Gu et al. Critical Care 2012, 16:R190
Table 1 Main characteristics of randomized controlled trials included in the meta-analysis of toothbrushing for ventilator-associated pneumonia prevention
Author/ Number Type of ICU/Study Severity of Intervention group Control group Definition of VAP Study Funding Length Rate of
Year of population illness (I/C) design/ bias of successful
patients Jadad follow- follow-up
(I/C) score up,
days
Munro 192 (97/ Medical-surgical/ APACHE III 0.12% CHX and toothbrushing 0.12% CHX 5 mL by CPIS > 6 Non- No 3 46%
et al. 95) adult patients score: 76.4 (that is, soft pediatric toothbrush oral swab twice blind,
[20] requiring MV > 24 ± 23.3/76.2 and toothpaste; brushing tooth by daily or usual care RCT/2
(2009) hours, with no ± 3.3 and tooth, on anterior and posterior
current pneumonia 76.2 ± 25.5/ surfaces, the palate, and the
80.4 ± 28.7 tongue)
Pobo et 147 (74/ Surgical/adult APACHE II 0.12% CHX and toothbrushing Oral care every 8 hours New or progressive pulmonary Single- No 28 100%
al. [21] 73) patients requiring score: 18.8 every 8 hours (that is, electric with 0.12% CHX opacities together with purulent blind,
(2009) MV > 48 hours, ± 7.1/18.7 ± toothbrush; brushing tooth by respiratory secretions plus fever > RCT/3
with no current 7.3 tooth, on anterior and posterior 38°C or leukocytosis > 10,000
pneumonia surfaces, the gum line, and the cells/mL
tongue)
Yao et 53 (28/ Medical-surgical/ APACHE II Usual care using cotton swabs, Usual care using cotton CPIS > 6 Single- No 9 68%
al. [22] 25) adult patients score: 19.6 elevating the head of the bed, swabs, elevating the blind,
(2011) requiring MV > 48 ± 5.2/19.4 ± moisturizing the lips, and before- head of the bed, pilot,
to 72 hours, with 4.4 and-after hypopharyngeal moisturizing the lips, RCT/3
no current suctioning; toothbrushing (that is, and before-and-after
pneumonia electric and soft pediatric hypopharyngeal
toothbrush; brushing tooth with suctioning
purified water, teeth facial sides
cleansed with electric toothbrush,
and lingual sides, gums, mucosa,
and tongue cleansed with
pediatric toothbrush)
Lorente 436 (217/ Medical, surgical/ APACHE II 0.12% CHX and toothbrushing Oral cleansing every 8 New onset of bronchial purulent Single- No Not 100%
et al. 219) trauma, and score: 17.88 (that is, manually brushing tooth hours with 0.12% CHX sputum; body temperature > 38°C blind, reported
[23] neuroscience/adult ± 8.84/ by tooth, on the anterior and or < 35.5°C; white blood cell RCT/3
(2012) patients requiring 19.16 ± posterior surfaces, the gum line, count > 10,000/mm3 or < 4,000/
MV > 24 hours, 9.88 and the tongue for a period of 90 mm3; chest radiograph showing
with no current seconds) new or progressive infiltrates;
pneumonia significant quantitative culture of
respiratory secretions by tracheal
aspirate (> 106 CFU/mL)
APACHE, Acute Physiology and Chronic Health Evaluation; CFU, colony-forming units; CHX, chlorhexidine; CPIS, clinical pulmonary infection score; I/C, intervention/control; ICU, intensive care unit; MV, mechanical
ventilation; RCT, randomized controlled trial; VAP, ventilator-associated pneumonia.
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Gu et al. Critical Care 2012, 16:R190
Table 2 Outcome data of studies included in the meta-analysis of toothbrushing for ventilator-associated pneumonia prevention (intervention versus control)
Study Primary outcome Secondary outcomes
Incidence of VAP ICU mortality Length of ICU stay, days Duration of MV, days Antibiotic-free day, days MV-free day, days
Munro et al. [20] (2009) 48/97 vs. 45/95 22/97 vs. 22/95 NR NR NR NR
Pobo et al. [21] (2009) 15/74 vs. 18/73 16/74 vs. 23/73 12.9 ± 8.7 vs. 15.5 ± 9.6 8.9 ± 5.8 vs. 9.8 ± 6.1 7.6 ± 8.4 vs. 7.8 ± 7.6 9.5 ± 12.2 vs. 11.3 ± 12.3
Yao et al. [22] (2011) 4/28 vs. 14/25 NR 12.5 ± 6.1 vs. 13.5 ± 6.8 12.0 ± 11.0 vs. 13.6 ± 15.6 NR NR
Lorente et al. [23] (2012) 21/217 vs. 24/219 62/217 vs. 69/219 12.07 ± 15.55 vs. 13.04 ± 17.27 9.18 ± 14.13 vs. 9.93 ± 15.39 7.43 ± 14.84 vs. 8.39 ± 16.83 4.03 ± 3.22 vs. 4.42 ± 3.93
ICU, intensive care unit; MV, mechanical ventilation; NR, not reported; VAP, ventilator-associated pneumonia.
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Figure 4 Forest plot showing the effect of toothbrushing on Figure 8 Forest plot showing the effect of toothbrushing on
intensive care unit mortality. References cited are Munro et al. mechanical ventilation-free day. References cited are Pobo et al.
[20], Pobo et al. [21], and Lorente et al. [23]. CI, confidence interval; [21] and Lorente et al. [23]. CI, confidence interval; WMD, weighted
RR, relative risk. mean difference.
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toothbrushing was associated with a different degree of Our study provides additional interesting clues that may
reduction in the incidence of VAP compared with no be useful for future research on the topic. Remarkably, the
oral care [24-26]. However, the limitations of these stu- study conducted by Yao and colleagues [22] included in
dies are that non-randomized study design was used our meta-analysis used unique oral care protocols. Unlike
(case control [24] or pre/post-intervention observational other trials, that study did not include chlorhexidine and
study [25,26]). Moreover, it is not possible to discrimi- found that an oral care protocol of toothbrushing with
nate the influence of toothbrushing alone, since oral purified water can effectively reduce the incidence of VAP
care in the intervention group involved the simultaneous and improve oral health and hygiene. Thus, one may focus
use of both other preventive measures (for example, an on this specific oral care protocol (toothbrushing alone
antibacterial agent) and toothbrushing. without chlorhexidine) to better address the isolated effect
The principal finding of our meta-analysis seems to of toothbrushing. More large-scale and well-performed
contradict the aforementioned studies on the topic. In RCTs are warranted.
particular, the present meta-analysis included four RCTs Our meta-analysis showed that oral care with tooth-
involving 828 patients and indicated that oral care with brushing did not alter other important clinical outcomes,
toothbrushing was not associated with a reduction in including ICU mortality, duration of mechanical ventila-
the incidence of VAP in critically ill patients receiving tion, length of ICU stay, antibiotic-free day, and mechani-
mechanical ventilation. Substantial heterogeneity was cal ventilation-free day. These results are not conclusive
observed among these studies, and this was not surpris- inasmuch as further adequately powered studies are
ing given the differences in characteristics of popula- needed. In fact, these included studies are not adequately
tions, oral care protocols, and study designs. Our powered to examine these secondary outcome measures
sensitivity analyses suggest that the trial conducted by since they were not the primary outcomes and were the
Yao and colleagues [22] probably contributed to the het- only clinically significant endpoints consistently reported
erogeneity. This study differed from the others in some in many of the studies analyzed in the present meta-ana-
aspects. On one hand, this trial adopted oral care proto- lysis. Further studies should pay more attention to these
cols without chlorhexidine; on the other hand, the small clinical endpoints other than just the incidence of VAP.
number of cases and participants increased the possibi- Most of the included RCTs did not report complications
lity that chance accounted for the results. of toothbrushing during the study period. Toothbrushing
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doi:10.1186/cc11675
Cite this article as: Gu et al.: Impact of oral care with versus without
toothbrushing on the prevention of ventilator-associated pneumonia: a
systematic review and meta-analysis of randomized controlled trials.
Critical Care 2012 16:R190.