BMJ 2007;334:889 (28 April), doi:10.1136/bmj.39136.528160.BE (published 26 March 2007)
Ee Yuee Chan, nurse educator1, Annie Ruest, infectious diseases consultant2, Maureen O Meade, associate professor3, Deborah J Cook, professor3
1 Department of Nursing Services, Tan Tock Seng Hospital, Singapore , 2 Centre Hospitalier Universitaire de Qu?ec-H?el-Dieu, Departments of Medicine and Medical Biology, Qu?ec, Canada , 3 Departments of Medicine, Clinical Epidemiology, and Biostatistics, McMaster University, Hamilton, Canada
Correspondence to: E Y Chan ee_yuee_chan{at}ttsh.com.sg
Design Systematic review and meta-analysis.
Data sources Medline, Embase, CINAHL, the Cochrane Library, trials registers, reference lists, conference proceedings, and investigators in the specialty.
Review methods Two independent reviewers screened studies for inclusion, assessed trial quality, and extracted data. Eligible trials were randomised controlled trials enrolling mechanically ventilated adults that compared the effects of daily oral application of antibiotics or antiseptics with no prophylaxis.
Results 11 trials totalling 3242 patients met the inclusion criteria. Among four trials with 1098 patients, oral application of antibiotics did not significantly reduce the incidence of ventilator associated pneumonia (relative risk 0.69, 95% confidence interval 0.41 to 1.18). In seven trials with 2144 patients, however, oral application of antiseptics significantly reduced the incidence of ventilator associated pneumonia (0.56, 0.39 to 0.81). When the results of the 11 trials were pooled, rates of ventilator associated pneumonia were lower among patients receiving either method of oral decontamination (0.61, 0.45 to 0.82). Mortality was not influenced by prophylaxis with either antibiotics (0.94, 0.73 to 1.21) or antiseptics (0.96, 0.69 to 1.33) nor was duration of mechanical ventilation or stay in the intensive care unit.
Conclusions Oral decontamination of mechanically ventilated adults using antiseptics is associated with a lower risk of ventilator associated pneumonia. Neither antiseptic nor antibiotic oral decontamination reduced mortality or duration of mechanical ventilation or stay in the intensive care unit.
Previous meta-analyses of selective decontamination of the digestive tract found a significant reduction in rates of ventilator associated pneumonia among treated patients.6 7 8 9 10 11 12 13 14 The use of this intervention is, however, limited by concern about the emergence of antibiotic resistant bacteria.15 16 17 Oral decontamination alone therefore may be more attractive because it requires only a fraction of the antibiotics used in selective decontamination of the digestive tract. To date, trials of oral decontamination using antibiotics have generated conflicting results, some suggesting benefit18 19w1 and others showing no benefit.w2 w3
One alternative to oral decontamination with antibiotics is to use antiseptics, such as chlorhexidine gluconate or povidone iodine. In contrast to antibiotics, antiseptics act rapidly at multiple target sites and accordingly may be less prone to induce drug resistance.20 Observational studies suggest that antiseptic oral decontamination can reduce ventilator associated pneumonia,21 22 but randomised controlled trials are not convincing.23w4-w6 Recently a meta-analysis of four trials on chlorhexidine failed to show a significant reduction in rates of ventilator associated pneumonia.24 Two subsequent randomised controlled trials, however, suggested benefit from this approach.w7 w8
Current guidelines from the Centers for Disease Control and Prevention recommend topical oral chlorhexidine 0.12% during the perioperative period for adults undergoing cardiac surgery (grade II evidence).3 The routine use of antibiotic or antiseptic oral decontamination for the prevention of ventilator associated pneumonia, however, remains unresolved.3 Despite the lack of firm evidence favouring this preventive intervention, a recent survey across 59 European intensive care units from five countries showed that 61% of the respondents used oral decontamination with chlorhexidine.25
We carried out a systematic review and meta-analysis to estimate the effect of oral decontamination using topical antibiotics or antiseptics on ventilator associated pneumonia and mortality in mechanically ventilated adults.
Study selection and data
extraction
We included published and
unpublished randomised controlled trials testing the effect of oral
decontamination on the incidence of pneumonia and mortality in adults
requiring mechanical ventilation in an intensive care unit. We
considered any type or combination of antibiotics or antiseptics. We
had no language restrictions. Trials on selective decontamination of
the digestive tract, observational studies, editorials, and
commentaries were excluded.
Two independent reviewers (EC and AR)
screened all titles and
abstracts for inclusion. One reviewer (AR) was blinded to author,
journal, institutional affiliation, and date of publication. We
then independently assessed each selected reference for detailed
evaluation. Interobserver agreement on the selection of articles
for inclusion was measured with Cohen's (unweighted)
statistic.26 Two reviewers (EC and AR) also independently
abstracted relevant trial characteristics, and disagreements were
resolved by discussion. We contacted authors of the primary studies
for clarifications as necessary.
Quality assessment
Two reviewers (EC and AR) independently appraised the quality of
included trials. We evaluated randomisation, allocation concealment,
blinding techniques, clarity of inclusion and exclusion criteria and
outcome definitions, similarity of baseline characteristics, and
completeness of follow-up. We considered randomisation to be true if
the allocation sequence was generated using computer programs, random
number tables, or random drawing of opaque envelopes. Alternate
treatment allocation was classified as non-random. Allocation was
considered concealed if it involved a telephone call to a central
site, used opaque sealed envelopes, or was executed centrally by the
pharmacy. Allocation was categorised as unconcealed when described as
open or directly managed by the study investigators or when the
methods were unclear. A
study was considered blinded when patients, caregivers, and
data collectors or outcome assessors were blinded, or when it
was reported as double blind by the authors. We contacted authors
to clarify methodology as necessary.
Data synthesis
We grouped trials according to the specified prophylactic agent used
for oral decontamination. The two broad categories were randomised
controlled trials in which oral antibiotics were tested against no
prophylaxis and oral antiseptics were tested against no prophylaxis.
The primary outcomes were incidence of ventilator associated pneumonia and mortality. We used the authors' definition for ventilator associated pneumonia if it included clinical and radiological criteria. As such, we excluded trials that used the clinical pulmonary infection score alone. We considered mortality in the intensive care unit in the absence of hospital mortality data. Secondary outcomes were the group mean duration of mechanical ventilation and stay in the intensive care unit. We also combined trials on antibiotics and antiseptics for the primary outcomes of ventilator associated pneumonia and mortality, in light of the a priori expectation of a similar magnitude and direction of treatment effect.
Meta-analysis was carried out using Review Manager 4.2 (Cochrane Collaboration, Oxford) and a random effects model.27 The pooled effects estimates for binary variables were expressed as relative risk with 95% confidence interval, whereas continuous variables were expressed as mean differences with 95% confidence intervals. We tested the difference in estimates of treatment effect between the treatment and control groups for each hypothesis using a two sided z test with statistical significance considered at P<0.05. We calculated the number of patients needed to treat (NNT, with 95% confidence interval) to prevent one episode of ventilator associated pneumonia during the period of mechanical ventilation, using the formula:
where RRR is the summary relative risk reduction and median CER is the median of the control events rates for all trials.
We used Cochran Q and I2 statistics to assess for heterogeneity of results.28 29 We predefined heterogeneity as low, moderate, and high with I2 of above 25%, 50%, and 75%.29 The a priori hypotheses to explain heterogeneity were method of allocation (smaller treatment effect in concealed compared with unconcealed allocation), blinding technique (smaller treatment effect in blinded compared with unblinded studies), patient population (smaller treatment effect in medical or mixed patients compared with selected surgical or trauma patients), and duration of ventilation (smaller treatment effect in patients with mean duration of ventilation of 48 hours or more compared with less than 48 hours). The purpose of the first two analyses was to evaluate whether two critical methodological qualities influenced results.30 We also carried out a post hoc subgroup analysis to investigate the influence of alternative approaches to the diagnosis of ventilator associated pneumonia (quantitative culture of bronchoalveolar lavage fluid or protected specimen brush compared with non-quantitative culture of endotracheal aspirate or other criteria).
We compared relative risk estimates between subgroups using a two sided z test on the log relative risks, and expressed as a ratio of relative risks with its 95% confidence interval.31
The three trials with three arm comparisons were analysed as follows. In two studies,w1 w8 owing to the similarity of the control arms, we pooled them and compared the results with the treatment group. In the third studyw7 we excluded one of the two control arms from analysis because it incorporated both antibiotics and chlorhexidine.
To evaluate potential publication bias we constructed a funnel plot for the primary outcome of ventilator associated pneumonia, using odds ratio as the measure of effect, and visually inspected it for asymmetry. We also carried out Egger's regression intercept and Begg's rank correlation tests to assess this asymmetry formally. Analysis was done using Comprehensive Meta-analysis version 2.2.040 (Biostat, Englewood, NJ). We considered a one tailed P value of less than 0.05 as significant.
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The diagnostic criteria for ventilator
associated pneumonia
differed across trials (table 1
). Several trials used quantitative microbiology to
confirm ventilator associated pneumonia: threew1 w2 w8
required a quantitative culture of bronchoalveolar lavage fluid or
protected specimen brush, two used quantitative cultures of
bronchoalveolar lavage fluid or endotracheal aspirate,w5
w6 and one used quantitative cultures of tracheal aspirates.w10
The other trials used either semiquantitative techniquesw3 w7
w11 or did not require microbiological confirmation,w9 whereas
in one trial the criteria were unclear.w4 Except for three trials,
the inclusion criteria included an anticipated duration of mechanical
ventilation of 48 hours or more. Patients were ventilated for a
mean duration of more than 48 hours in all but one trial.w9 Seven
trials reported duration of mechanical ventilation as
means and standard deviations; eight trials reported duration
of stay in the intensive care unit as such. One trialw1
reported both of these outcomes as median and range values; these
results were not included in the pooled analyses.
Interobserver agreement on the selection
of trials for potential
inclusion based on reading the titles and abstracts was excellent
(Cohen's unweighted
=0.84, 95% confidence interval 0.64 to 1.03). Interobserver
agreement on the inclusion of relevant studies after detailed
evaluation was also excellent (
=1).
Eight of nine authors responded to our
requests and provided
additional information on trial design, key quality features,
and outcome data. Table 2
shows the methodological quality of included
trials.
Primary outcomes
Ventilator associated pneumonia
Results from 11 trials (3242 patients)
were available to examine the effects of oral decontamination on
rates of ventilator associated pneumonia. Meta-analysis of four
trials (1098 patients) testing antibiotic oral decontamination did
not show a statistically significant reduction in ventilator
associated pneumonia rates (relative risk 0.69, 0.41 to 1.18; P=0.18;
I2=59.4%; fig 2
). Pooled analysis of the seven trials (2144
patients) that tested the effect of antiseptic oral decontamination
on ventilator associated pneumonia showed a significant reduction
(relative risk 0.56, 0.39 to 0.81; P=0.002; I2=48.2%). The
11 trials combined favoured oral decontamination (relative risk 0.61,
0.45 to 0.82; P<0.001; I2=52.5%). Fourteen patients (NNT
14, 10 to 31) would need to receive oral decontamination with one of
these methods to prevent one case of ventilator associated pneumonia.
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Overall mortality
Results of all 11 trials were available for the analysis of mortality
(fig 3
). Meta-analysis of the four trials that tested
antibiotic prophylaxis found no effect on overall mortality
(relative risk 0.94, 0.73 to 1.21; P=0.63; I2=34.8%). The
pooled analysis of the seven antiseptic trials (2144 patients) also
showed no effect on mortality (0.96, 0.69 to 1.33; P=0.82; I2=42.7%).
Pooling the 11 studies produced similar results (0.97, 0.80 to 1.18;
P=0.74; I2=34.3%).
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Publication bias
The funnel plot for ventilator associated pneumonia was asymmetrical,
suggesting the existence of unpublished small studies with negative
findings (fig 5
). Formal statistical tests did not, however,
support the presence of publication bias: Egger's regression
intercept (intercept ?1.32, ?3.59 to 0.95; one tailed P=0.111)
and Begg's rank correlation (Kendall's
with continuity correction ?0.22; one tailed P=0.175).
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We found that neither antibiotic nor antiseptic oral decontamination influenced overall mortality, duration of mechanical ventilation, or duration of stay in an intensive care unit. Our review was underpowered to detect any effect on mortality, and the small sample size limited the interpretation of the secondary outcomes.
Comparison with previous studies
Previous meta-analyses examining the effect of prophylaxis using
selective decontamination of the digestive tract reported a
significant reduction in the incidence of ventilator associated
pneumonia.6
7 8 9 10 11 12
13 14 The most recent meta-analysis indicated
that such an intervention combined with prophylactic intravenous
antibiotics reduces overall mortality.14 In comparison our
review suggests that oral antiseptic prophylaxis alone can
significantly reduce the incidence of ventilator associated
pneumonia, but not mortality. Our meta-analysis on antiseptics
differs from the findings of Pineda et al, who pooled four trials
on chlorhexidine and did not report lower rates of ventilator
associated pneumonia (odds ratio 0.42, 0.16-1.06; P=0.07).24
Our results also extend those of Chlebicki et al, who did not find a
statistically significant benefit using the more conservative random
effects model after pooling seven trials on chlorhexidine (relative
risk 0.70, 0.47-1.04; P=0.07), although their results were
significant with the fixed effects model.39
Our systematic review included a larger dataset with two more recent
trials,w8 w9 involved clarification of data from several
authors, and explored heterogeneity with more subgroup analyses.
Possible explanations and
implications
The lack of effect on secondary
outcomes may raise concern about the accuracy with which ventilator
associated pneumonia was diagnosed, given that the antiseptic trials,
despite showing a substantial reduction in ventilator associated
pneumonia rates, failed to show similar benefit for these secondary
outcomes. It is possible that the combination of clinical,
radiological, and microbiological criteria without the use of
quantitative investigations using cultures of bronchoalveolar lavage
fluid, which may have a high sensitivity but low specificity,40
may contribute to an overestimation of the ventilator associated
pneumonia rates in these trials, and a greater observed treatment
effect.
To ensure that the lack of effect on
patients' secondary outcomes
did not arise from the differences in the diagnostic criteria
used by the primary trials, we carried out a post hoc subgroup
analysis on the basis of diagnostic criteria for ventilator
associated pneumonia (differentiating between trials using invasive
quantitative culture of bronchoalveolar lavage fluid or protected
specimen brush versus other less invasive approaches). Only one
of the antiseptic trials used invasive quantitative criteria,
rendering further analysis not possible. Our analysis for the
antibiotic trials was inconclusive, showing a trend towards a
greater treatment effect for the trials that used the more invasive
diagnostic criteria (table 3
). An analysis combining all trials on antibiotics
and antiseptics also suggested the same trend (invasive quantitative
criteria's relative risk 0.45, 0.21 to 0.98 v less invasive
criteria's relative risk 0.66, 0.47 to 0.93), although the comparison
of these relative risks was not conclusive (ratio of relative risks
0.68, 0.29 to 1.58; P=0.37). Nevertheless, a recent large multicentre
trial found no difference in clinical outcomes or subsequent overall
antibiotic use when a diagnostic approach of quantitative culture of
bronchoalveolar lavage fluid was compared with non-quantitative
culture of endotracheal aspirate among non-immunocompromised patients
not suspected of harbouring high risk organisms.41
Our a priori subgroup analyses suggest that trials with an unblinded design and those enrolling surgical or trauma patients tended to yield qualitatively larger treatment effects than blinded trials and those enrolling medical or mixed critically ill patients. The former result is consistent with previous work showing that trials of lower methodological quality tend to report greater treatment effects.42 Specific surgical or trauma patients often have fewer comorbidities than medical or mixed patients, which may explain the trend towards a greater treatment effect in the former population. However, these subgroup results are best viewed as hypothesis generating.
The finding that antiseptic oral decontamination can reduce the incidence of ventilator associated pneumonia could have important implications for lower healthcare costs and a reduced risk of antibiotic resistance compared with the use of antibiotics. It may not be prudent to adopt this practice routinely for all critically ill patients until strong data on the long term risk of selecting antiseptic and antibiotic resistant organisms are available. Nevertheless, antiseptic oral decontamination seems promising.
Strengths and weaknesses of the
study
The strengths of this review include the
comprehensive search for relevant randomised controlled trials,
duplicate screening, selection, assessment of methodological quality
and data abstraction, and use of the random effects model (which
takes heterogeneity into account) to combine trial results. We
separated and then combined the antibiotic and antiseptic trials,
anticipating that the underlying pathophysiology could lead to a
similar treatment effect across the trials,43 and because
an overall treatment effect is of interest in examining the relation
between oral flora and lung infection during critical illness.
We inspected funnel plots to evaluate
potential publication bias for ventilator associated pneumonia. We
also undertook formal statistical tests. These did not show the
presence of publication bias for the combined 11 antibiotics and
antiseptic trials. However, the power of these tests is generally
low. Although our literature search was comprehensive, it is possible
that we missed other relevant trials. In addition, these trials were
heterogeneous with respect to populations enrolled, regimens used,
outcome definitions, and analysis strategies, contributing to
differing relative risks across the trials. Other limitations of the
trials we included were exclusions after randomisation, mainly due to
early extubation, early deaths, or protocol violations. Some trials
did not explicitly report whether the number of patients analysed
reflected the total number of patients randomised (table 2
) such that we were unable to abstract the intention
to treat analyses from all trials. Finally, we could not obtain
unpublished data from some authors on the mean duration of mechanical
ventilation and stay in an intensive care unit.
Unanswered questions and future
research
Our systematic review supports the
use of antiseptic oral decontamination. Research to date does not
address which antiseptic is preferred, since all but one trial
evaluated chlorhexidine. We cannot recommend precise methods for
chlorhexidine administration owing to the wide variation of treatment
regimens among studies. These included varying concentrations (0.12%,
0.2%, 2%), sites of application, forms of agent (oral rinse, gel),
and frequencies and techniques of application. Nevertheless, our
findings suggest that the
concentration of chlorhexidine may be a consideration. In trials
with cardiac surgery patients at low risk for developing ventilator
associated pneumonia owing to a short duration of intubation,
chlorhexidine 0.12% was effective in reducing ventilator associated
pneumonia.w4 w9 However, among medical or mixed intensive care
populations, a higher concentration may be necessary. Chlorhexidine
was not effective in most of these trials at 0.2% concentrationw6
w11 but was effective at 2%.w7
As for the only trial that used povidone iodine, the agent was found
to be effective in preventing ventilator associated pneumonia among
98 patients with head injuries with a persistent score of 8 or less
on the Glasgow coma scale requiring mechanical ventilation for 48
hours or more.w8
To our knowledge no trial directly compares antiseptic with antibiotic oral decontamination. Further investigations comparing antibiotic with antiseptic oral decontamination while incorporating stringent infection surveillance would be worthwhile. Whether either antibiotic or antiseptic oral decontamination favourably influence important patient outcomes such as duration of mechanical ventilation or duration of stay in the intensive care unit should be evaluated in rigorously designed and adequately powered randomised trials.
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Contributors: All authors contributed to the concept, design, and critical revision of the manuscript. EC and AR carried out the search, selected the articles, and extracted the data. EC carried out the statistical analyses with input from AR, drafted the review, and is guarantor.
Funding: EC is supported by a scholarship award from Tan Tock Seng Hospital and National Healthcare Group HMDP, Singapore. AR is supported by a postdoctoral fellowship award from the Fonds de Recherche en Sant?du Qu?ec and from Universit?Laval. DJC holds a Canada Research Chair. Statement of the independence of researchers from funders: The authors' work was independent of the funders (the funding source has no involvement).
Competing interests: None declared.
Ethical approval: Not required.