Oral hygiene care for critically ill patients to prevent ventilator‐associated pneumonia
Abstract
Background
Ventilator‐associated pneumonia (VAP) is defined as pneumonia developing in people 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 oral hygiene care on incidence of ventilator‐associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs).
Search methods
We searched the following electronic databases: Cochrane Oral Health’s Trials Register (to 17 December 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 11), MEDLINE Ovid (1946 to 17 December 2015), Embase Ovid (1980 to 17 December 2015), LILACS BIREME Virtual Health Library (1982 to 17 December 2015), CINAHL EBSCO (1937 to 17 December 2016), 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) and VIP Database (January 2012 to 4 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials to 17 December 2015. We placed no restrictions on the language or date of publication when searching the electronic databases.
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 for at least 48 hours.
Data collection and analysis
At least two review authors independently assessed search results, extracted data and assessed risk of bias in included studies. We contacted study authors for additional information. We pooled data from trials with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, using random‐effects models unless there were fewer than four studies.
Main results
We included 38 RCTs (6016 participants). 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. We assessed the overall risk of bias as low in five trials (13%), high in 26 trials (68%), and unclear in seven trials (18%). We did not consider the risk of bias to be serious when assessing the quality of evidence (GRADE) for VAP incidence, but we downgraded other outcomes for risk of bias.
High quality evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 24% to about 18% (RR 0.75, 95% confidence intervals (CI) 0.62 to 0.91, P = 0.004, I2 = 35%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 9 to 50), which indicates that for every 17 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP would be prevented. There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.20, I2 = 0%, 14 RCTs, 2014 participants, moderate quality evidence), duration of mechanical ventilation (MD ‐0.09 days, 95% CI ‐1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence), or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI ‐1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.
We are uncertain as to the effects of toothbrushing (± antiseptics) on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (± antiseptics). There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost.
Only one trial (78 participants) 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.
Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias), and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions.
Authors' conclusions
OHC including chlorhexidine mouthwash or gel reduces the risk of developing ventilator‐associated pneumonia in critically ill patients from 24% to about 18%. 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 antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects.
PICOs
Plain language summary
Oral hygiene care for critically ill patients to prevent ventilator‐associated pneumonia
Review question
What are the effects of oral hygiene care on the incidence of ventilator‐associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs)? We aimed to summarise all the available appropriate research in order to identify evidence‐based care for these vulnerable patients.
Background
Critically ill people, who may be unconscious or sedated while they are treated in ICUs, often need to have machines to help them breathe (ventilators). The use of these machines for more than 48 hours may result in ventilator‐associated pneumonia (VAP). VAP is a potentially serious complication in these patients who are already critically ill.
Oral hygiene care, using a mouthrinse, gel, toothbrush, or combination, together with suctioning secretions, may reduce the risk of VAP in these patients.
Study characteristics
This review of studies was carried out through Cochrane Oral Health, and the evidence is current up to 17 December 2015.
We included 38 research studies but only a few (13%) of the studies were well conducted and described.
All of the studies took place in ICUs in hospitals. In total there were 6016 participants randomly allocated to treatment. Participants were critically ill and required assistance from nursing staff for their oral hygiene care. Most of the studies involved adults only, but the participants were children in three of the studies, and newborns in one study.
We grouped studies 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 antiseptics)
3. Powered compared with manual toothbrushing
4. Oral care solutions with other solutions
Key results
We found high quality evidence that chlorhexidine, either as a mouthrinse or a gel, reduces the risk of VAP from 24% to about 18%. For every 17 people on ventilators for more than 48 hours in intensive care, the use of oral hygiene care including chlorhexidine will prevent one person developing VAP. However, we found no evidence that oral hygiene care with chlorhexidine makes a difference to the numbers of patients who die in ICU, or to the number of days on mechanical ventilation or days in ICU.
We have only limited evidence on the effects of toothbrushing (with or without antiseptics) and oral care without toothbrushing (with or without antiseptics) on the risk of developing VAP. Three studies showed some weak evidence of a reduction in VAP with povidone iodine antiseptic mouthrinse compared to placebo/saline. Four studies showed some weak evidence of a reduction in VAP with saline rinse compared to saline swab.
There was insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with any unwanted side effects.
Quality of the evidence
The evidence presented was limited by how well the included studies were done and reported. Only 13% of the studies were well conducted and well described. For a number of outcomes, there was not enough information to draw a solid conclusion.
Authors' conclusions
Summary of findings
| Chlorhexidine (mouthrinse or gel) versus placebo/usual care for critically ill patients to prevent ventilator‐associated pneumonia (VAP) | ||||||
| Patient or population: critically ill adults and children receiving mechanical ventilation Comparison: placebo or usual care | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control (placebo or usual care) | Chlorhexidine (mouthrinse or gel) | |||||
| Ventilator‐associated pneumonia | 243 per 10001 | 180 per 1000 | RR 0.75 | 2451 | ⊕⊕⊕⊕ | This equates to an NNTB of 17 (95% CI 9 to 50) |
| Mortality | 222 per 10001 | 242 per 1000 | RR 1.09 | 2014 | ⊕⊕⊕⊝ | |
| Duration of ventilation | 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 | 800 | ⊕⊕⊝⊝ | ||
| Duration of ICU stay | The mean duration of ICU stay in the control groups ranged from 10 to 24 days | The mean duration of ICU stay in the intervention groups was | 833 | ⊕⊕⊕⊝ moderate 4 | ||
| Adverse effects | Most of the studies did not provide information on adverse events. Information on adverse events were identified from 2 studies. One study stated there were none, the other study reported on mild reversible irritation of the oral mucosa | ⊕⊝⊝⊝ | ||||
| *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) | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk is based on the median event rate in the control groups of the included studies. 2Downgraded one level due to serious risk of bias: eight studies at high risk of bias, four at unclear risk of bias and three at low risk of bias. The sensitivity analysis based on three low‐risk‐of‐bias studies gave similar effect estimate (RR = 1.13), but further research may change this estimate. 3Downgraded two levels due to serious imprecision and serious risk of bias: two studies at high risk of bias, three at low risk of bias. The sensitivity analysis based on three studies at low risk of bias gave an effect estimate of 0.84 days, which is not clinically important in the context of median duration of 12 days. 4Downgraded one level due to serious imprecision. 5Downgraded three levels due to very serious imprecision and serious inconsistency: only two studies reported on this outcome, and they did not report data adequately to enable us to evaluate the risk of adverse events. | ||||||
| Toothbrushing (± antiseptics) versus no toothbrushing (± antiseptics) for critically ill patients to prevent ventilator‐associated pneumonia (VAP) | ||||||
| Patient or population: critically ill patients receiving mechanical ventilation Comparison: no toothbrushing (± chlorhexidine) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No toothbrushing | Toothbrushing | |||||
| Incidence of VAP Follow‐up: mean 1 month | 367 per 10001 | 253 per 1000 | RR 0.69 | 889 | ⊕⊝⊝⊝ | |
| Mortality | 236 per 10001 | 205 per 1000 | RR 0.87 | 889 | ⊕⊕⊝⊝ | |
| Duration of ventilation | The mean duration of ventilation in the control groups ranged from 9.8 to 10 days | The mean duration of ventilation in the intervention groups was | 644 | ⊕⊕⊝⊝ | ||
| Duration of ICU stay | The mean duration of ICU stay in the control groups ranged from 13 to 15 days | The mean duration of ICU stay in the intervention groups was | 583 | ⊕⊝⊝⊝ | ||
| Adverse effects | Most of the studies did not provide information on adverse events. Information on adverse events was identified from one study which stated there was none. | ⊕⊝⊝⊝ | ||||
| *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) | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk is based on the outcomes in the control groups of the included studies | ||||||
Background
Description of the condition
Patients in intensive care units (ICUs) in hospital frequently require mechanical ventilation because their ability to breathe unassisted is impaired due to trauma, or as a 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 patient's 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 that 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; Mojon 2002; Scannapieco 1992).
VAP 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 the attributable mortality of VAP to be 10% (Melsen 2011). Cohort studies have found that duration of ICU stay is increased in patients who develop VAP, but it is unclear whether this is cause or effect (Apostolopoulou 2003; Cook 1998).
Antibiotics, administered either intra‐orally as topical pastes or systemically, have been used to prevent VAP, and these interventions are evaluated in other Cochrane systematic reviews (D'Amico 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 for at least 48 hours. 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 manual 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
Cochrane Oral Health undertook an extensive prioritisation exercise in 2014 to identify a core portfolio of titles that were the most clinically important reviews to maintain on the Cochrane Library (Worthington 2015). The periodontal expert panel identified this review as a priority topic (Cochrane OHG priority review portfolio).
Other Cochrane Reviews have evaluated the use of topical antibiotic pastes applied to the oral cavity (selective oral decontamination D'Amico 2009), probiotics (Hao 2015), 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). Hypersensitivity is a rare but potentially severe side effect of chlorhexidine. In view of recent reports in the UK of two cases of serious adverse events associated with irrigation of dry socket with chlorhexidine mouthrinse (Pemberton 2012), establishing the safety of oral hygiene care including chlorhexidine is also important.
The goal of this Cochrane Review was to evaluate all oral hygiene care interventions (excluding the use of antibiotics) used in ICU for patients on ventilators for at least 48 hours, 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 incidence of ventilator‐associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of oral hygiene care interventions. We did not consider quasi‐randomised studies for inclusion.
Types of participants
Critically ill patients in hospital settings receiving mechanical ventilation for a minimum of 48 hours, without ventilator‐associated pneumonia or respiratory infection at baseline. We included trials where only some of the participants were receiving mechanical ventilation if the outcome of ventilator‐associated pneumonia was reported, and data were available for those who had been treated with mechanical ventilation for a minimum of 48 hours and then developed nosocomial pneumonia.
We included trials where participants were undergoing a surgical procedure that involved mechanical ventilation (e.g. cardiac surgery) only if the oral hygiene care was given during the period of mechanical ventilation that had a minimum duration of 48 hours. We excluded trials where patients received a single preoperative 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.
Types of interventions
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Intervention group: received clearly‐defined oral care procedures such as nurse‐assisted toothbrushing, oral and pharyngeal cavity rinse, decontamination of oropharyngeal cavities with antiseptics;
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Control group: received no treatment, placebo, 'usual care', or a different specific oral hygiene care procedure.
We excluded 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).
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 (D'Amico 2009). We also excluded trials of probiotics administered to prevent respiratory infections, as these are covered in a separate review (Hao 2015).
Types of outcome measures
We included studies that aimed to assess at least one of our primary outcomes.
Primary outcomes
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Incidence of VAP (defined as pneumonia developing in a patient who has received mechanical ventilation for at least 48 hours)
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Mortality (either ICU mortality if these data were available, or 30‐day mortality)
Secondary outcomes
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Duration of mechanical ventilation or ICU stay, or both
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Systemic antibiotic use
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Oral health indices such as gingival index, plaque index, bleeding index, periodontal index, etc.
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Adverse effects of the interventions
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Caregivers' preferences for oral hygiene care
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Economic data
Search methods for identification of studies
To identify studies 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. The search strategy used a combination of controlled vocabulary and free‐text terms. The Embase subject search was linked to Cochrane Oral Health's filter for identifying clinical trials in EMBASE Ovid.
Electronic searches
We searched the following electronic databases.
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Cochrane Oral Health's Trials Register (searched 17 December 2015) (Appendix 1);
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Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 11) in the Cochrane Library (searched 17 December 2015) (Appendix 2);
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Ovid MEDLINE (1946 to 17 December 2015) (Appendix 3);
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Ovid Embase (1980 to 17 December 2015) (Appendix 4);
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CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 17 December 2015) (Appendix 5);
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LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; from 1982 to 17 December 2015) (Appendix 6);
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Chinese Biomedical Literature Database (1978 to 14 January 2013) (Appendix 7);
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China National Knowledge Infrastructure (1994 to 14 January 2013) (Appendix 8);
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Wan Fang Database (1984 to 14 January 2013) (Appendix 9);
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VIP Database (January 2012 to 4 May 2016) (Appendix 10).
We included all relevant publications irrespective of language. For this update, we did not conduct searches of the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure or the Wan Fang Database. We found these databases to be adequately covered by searches of the VIP Database.
Searching other resources
We searched the following trials registries for ongoing studies:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov; searched 17 December 2015) (see Appendix 11);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 17 December 2015) (see Appendix 12).
We manually checked all the references lists of the included studies to identify any additional studies.
We contacted the first or corresponding authors 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
At least two of six review authors independently examined each title and abstract of articles obtained from the searches. We resolved disagreements by discussion. We linked multiple reports from a study, and designated the report with the most complete follow‐up data as the primary source of data.
We obtained copies of potentially relevant reports and examined them in detail to determine whether the study fulfilled the eligibility criteria. We resolved any queries by discussion. We attempted to contact study authors to obtain additional information as necessary. We excluded studies when the only information available was from the abstract and this was insufficient to enable full assessment of risk of bias.
Data extraction and management
At least two of six review authors independently extracted data from each included study onto predesigned structured data extraction forms. We resolved any disagreements by discussion. We extracted the following items:
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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.
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Specific trial characteristics: we collected basic study design characteristics: sequence generation, allocation sequence concealment, blinding, incomplete outcome data and selective outcome reporting, etc., and presented them in the table of 'Characteristics of included studies. We included verbatim quotes on the first three issues from original reports.
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Participants: total number, setting, age, sex, country, ethnicity, socio‐demographic details (e.g. education level), diagnostic criteria for VAP and the presence of comorbid conditions.
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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. We also collected information on any co‐interventions administered.
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Outcomes: we collected the incidence of VAP or other respiratory diseases and mortality (directly and indirectly attributable), duration of mechanical ventilation, duration of ICU stay, systemic antibiotic use, oral health indices, and adverse outcomes resulting from the interventions, etc. We specified all outcome variables in terms of definition, timing, units and scales.
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Other results: we also collected summary statistics, sample size, key conclusions, comments and any explanations provided for unexpected findings by the study authors. We contacted the lead authors of included studies if there were issues to be clarified.
Assessment of risk of bias in included studies
At least two of six review authors assessed the risk of bias of each included study, using the Cochrane domain‐based, two‐part tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We contacted study authors for clarification or missing information where necessary. We resolved any disagreements concerning risk of bias by discussion. We completed a 'Risk of bias' table 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.
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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.
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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.
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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. We therefore assessed caregiver and outcome assessor blinding. Where no placebo was used, caregivers would be aware of the assigned intervention and 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 no placebo was used, we assumed that no blinding of caregivers occurred and we assessed this domain as being at high risk of bias.
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Blinding of outcome assessment (detection bias): if outcome assessor blinding was not mentioned in the trial report, we assessed this domain as being at unclear risk of bias.
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Incomplete outcome data (attrition bias): where the overall rate of attrition was high, we assessed the risk of attrition bias as high. If numbers of participants and/or reasons for exclusion were different in each arm of the study, we assessed the risk of attrition bias as high. If numbers of participants randomised or evaluated in each arm of the study were not reported, we assessed this domain as unclear.
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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 being at high risk of reporting bias.
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Other bias: any other potential source of bias that 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. We described any other potential sources of bias and assessed their risk of bias.
We summarised the risks of bias as follows.
| Risk of bias | Interpretation | In outcome | In included studies |
| Low risk of bias | Plausible bias unlikely to seriously alter the results | Low risk of bias for all key domains | Most information is from studies at low risk of bias |
| Unclear risk of bias | Plausible bias that raises some doubt about the results | Unclear risk of bias for one or more key domains | Most information is from studies at low or unclear risk of bias |
| High risk of bias | Plausible bias that seriously weakens confidence in the results | High risk of bias for one or more key domains | The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results |
We present the 'Risk of bias' graphically by: (a) proportion of studies with each judgement (low, high, or 'unclear risk of bias) for each domain, and (b) cross‐tabulation of judgements by study and by domain.
Measures of treatment effect
For dichotomous outcomes, we computed the effect measure as the risk ratio (RR) together with the 95% confidence interval (CI). For continuous outcomes, we used the mean difference (MD) with 95% CI to estimate the summary effect. If different scales were used, we calculated standardised mean differences.
Unit of analysis issues
The unit of analysis was the participant. The indices of plaque and gingivitis were measured as mean values for the participants. Episodes of care were also related back to individual participants.
Dealing with missing data
We contacted the lead author of studies requesting that they supply any missing data. We planned to obtain missing standard deviations using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of heterogeneity
To detect heterogeneity among studies in a meta‐analysis, we applied a Chi2 test with a 0.10 level of significance as the cut‐off value. We quantified the impact of statistical heterogeneity using the I2 statistic. To interpret the results, we used the thresholds of I2 recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011):
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
If considerable heterogeneity existed, we investigated it, using 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 in this review, including publication bias, time lag bias, multiple (duplicate) publication bias, and language bias.
Where there were more than 10 studies in an 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 1997 (continuous outcome) and Rücker 2008 (dichotomous outcome) (such analysis would have been done in Stata).
Data synthesis
We undertook meta‐analyses for similar comparisons and the same outcomes across studies. We used random‐effects models providing there were four or more trials in any one meta‐analysis.
Subgroup analysis and investigation of heterogeneity
We proposed one subgroup analysis a priori. We decided to undertake a subgroup analysis according to whether participants' teeth were cleaned or not, as we hypothesised that antiseptics would be less effective if toothbrushing was not used to disrupt dental plaque biofilm.
Sensitivity analysis
To determine whether the intervention effects of oral hygiene care were robust, we planned sensitivity analyses to assess the effect on the estimates of effect of studies with questionable diagnostic criteria for VAP, studies with high risk of bias, or by changing our assumptions about missing data.
If the results had not changed substantially in sensitivity analyses, we would have regarded our conclusions as stable with a higher degree of certainty. If sensitivity analyses had identified particular factors that greatly influenced the conclusions of the review, we would have explored the plausible causes of the uncertainties and interpreted the results with more caution.
Summary of findings
We adopted the GRADE system for evaluating quality of the evidence of systematic reviews (Guyatt 2008; Higgins 2011), using the software GRADEprofiler. We included the following outcomes in the 'Summary of findings' tables: incidence of VAP, mortality, duration of ventilation, duration of ICU stay, and adverse effects. We assessed the quality of the body of evidence with reference to the overall risk of bias of the included studies, the directness of the evidence, the consistency of the results, the precision of the estimates, and the risk of publication bias. We classified the quality of the body of evidence into four categories: high, moderate, low and very low.
Results
Description of studies
Results of the search
For this review update, after removal of duplicates, we identified 317 records from electronic databases and other resources. At least two review authors screened all records against the review inclusion criteria. We discarded 253 records and requested full‐text copies of 64 references. At least two review authors assessed these papers to determine their eligibility, and from these, we deemed 38 studies eligible for inclusion.
Three previously included studies (Grap 2004; McCartt 2010; Needleman 2011) have been excluded from this update (see Characteristics of excluded studies for details).Two studies are awaiting classification because we have not yet obtained adequate information about them. The study flow diagram is shown in Figure 1.
Study flow diagram
Included studies
We included 38 RCTs in this review.
Setting
Eight of the included studies were conducted in the USA (Bopp 2006; DeRiso 1996; Fields 2008; Grap 2011; Munro 2009; Prendergast 2012; Scannapieco 2009; Stefanescu 2013), nine in China (Chen 2008; Feng 2012; Hu 2009; Long 2012; Mo 2016; Tang 2013; Xu 2007; Xu 2008; Zhao 2012), five in Brazil (Bellissimo‐Rodrigues 2009; Caruso 2009; Jacomo 2011; Kusahara 2012a; Meinberg 2012), four in France (Fourrier 2000; Fourrier 2005; Seguin 2006; Seguin 2014) and three in Spain (Lorente 2012; Pobo 2009; Roca Biosca 2011), two in India (Panchabhai 2009; Sebastian 2012), two in Australia (Berry 2011; Berry 2013), and one each in Croatia (Cabov 2010), Taiwan (Yao 2011), Thailand (Tantipong 2008), Turkey (Ozcaka 2012), the Netherlands (Koeman 2006).
All studies took place in ICUs in hospitals. Most of the studies were two‐arm parallel group RCTs, but five studies had three arms (Berry 2011; Berry 2013; Scannapieco 2009; Seguin 2006; Xu 2007), and one study had four arms (Munro 2009).
Participants
There were 6016 participants randomly allocated to treatment in 37 RCTs, and the other trial (Fields 2008) did not state how many participants were included. The criteria for inclusion in these studies generally specified no prior intubation, no clinically‐apparent pneumonia at baseline (other than 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 2012a; Sebastian 2012); in one study, participants were neonates (Stefanescu 2013); and in the remaining studies, only adults participated.
In six studies, participants were either medical or surgical patients (Berry 2013; Koeman 2006; Meinberg 2012; Mo 2016; Munro 2009; Panchabhai 2009); in another five studies, participants were described as trauma patients (Grap 2011; Prendergast 2012; Scannapieco 2009; Seguin 2006; Seguin 2014); six studies recruited surgical patients only (Chen 2008; DeRiso 1996; Jacomo 2011; Kusahara 2012a; Yao 2011; Zhao 2012); nine studies recruited medical patients only (Cabov 2010; Fields 2008; Fourrier 2000; Fourrier 2005; Ozcaka 2012; Sebastian 2012; Stefanescu 2013; Tang 2013; Tantipong 2008); and in the remaining 12 studies, it was not clearly stated whether participants were medical, surgical, or trauma cases.
Nine of the included studies (Fields 2008; Fourrier 2000; Grap 2011; Lorente 2012; Munro 2009; Ozcaka 2012; Pobo 2009; Prendergast 2012; Roca Biosca 2011) specifically excluded edentulous participants, and the remaining studies did not report whether or not participants were dentate.
Classification of the interventions
We classified the interventions into three broad groups.
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Chlorhexidine
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Chlorhexidine solution (applied as mouthrinse, spray or on a swab)
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Chlorhexidine gel
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Toothbrushing
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Powered
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Manual
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Other solutions
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Povidone iodine
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Saline
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Bicarbonate
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Triclosan
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Furacilin
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Listerine
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Biotene OralBalance
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These interventions were used either singly or in combinations. We evaluated the following comparisons.
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Chlorhexidine versus placebo/usual care, with or without toothbrushing (19 studies: Bellissimo‐Rodrigues 2009; Berry 2011; Bopp 2006; Cabov 2010; Chen 2008; DeRiso 1996; Fourrier 2000; Fourrier 2005; Grap 2011; Jacomo 2011; Koeman 2006; Kusahara 2012a; Meinberg 2012; Munro 2009; Ozcaka 2012; Panchabhai 2009; Scannapieco 2009; Sebastian 2012; Tantipong 2008)
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Toothbrushing versus no toothbrushing (in addition to usual care) (eight studies: Bopp 2006; Fields 2008; Lorente 2012; Long 2012; Munro 2009; Pobo 2009; Roca Biosca 2011; Yao 2011)
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Powered toothbrushing versus manual toothbrushing (one study: Prendergast 2012)
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Other solutions (15 studies)
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Saline (Caruso 2009; Hu 2009; Mo 2016; Seguin 2006; Tang 2013; Xu 2007; Xu 2008)
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Bicarbonate (Berry 2011; Berry 2013)
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Povidone iodine (Feng 2012; Seguin 2006; Seguin 2014)
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Triclosan (Zhao 2012)
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Furacilin (Feng 2012)
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Listerine (Berry 2013)
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Biotene OralBalance (Stefanescu 2013)
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There was some variation between the studies in the number of episodes of OHC per day, with most of the studies (79%) delivering two to four episodes of care daily. Thirteen studies (Berry 2011; Bopp 2006; DeRiso 1996; Fields 2008; Hu 2009;Jacomo 2011; Kusahara 2012a; Panchabhai 2009; Prendergast 2012; Scannapieco 2009; Xu 2007; Xu 2008; Yao 2011) delivered two episodes of OHC a day, nine studies (Bellissimo‐Rodrigues 2009; Cabov 2010; Fourrier 2000; Fourrier 2005; Long 2012; Lorente 2012; Munro 2009; Pobo 2009; Sebastian 2012) had three episodes a day, and eight studies (Chen 2008; Feng 2012; Koeman 2006; Meinberg 2012; Mo 2016; Ozcaka 2012; Tantipong 2008; Zhao 2012) had four episodes a day. One study delivered OHC every two hours (Berry 2013), another only once (Grap 2011), and in the remaining three studies it is unclear (Caruso 2009; Roca Biosca 2011; Tang 2013).
In some of the included studies, the intervention described as 'placebo' may have had some antibacterial activity, but this was considered by the trialists to be negligible compared to the active intervention. Placebo interventions included saline (Chen 2008; Feng 2012; Hu 2009; Ozcaka 2012; Seguin 2006; Tantipong 2008), potassium permanganate (Panchabhai 2009), half‐strength hydrogen peroxide (Bopp 2006), water/alcohol mixture (DeRiso 1996; Jacomo 2011), placebo gel (Fourrier 2005; Koeman 2006; Kusahara 2012a; Meinberg 2012; Sebastian 2012), base solution (Scannapieco 2009) or water (Berry 2011; Berry 2013). In one trial, the nature of the placebo was not specified (Bellissimo‐Rodrigues 2009).
In eight studies, the control group received usual/standard care (Caruso 2009; Fields 2008; Fourrier 2000; Hu 2009; Grap 2011; Munro 2009; Seguin 2006; Yao 2011) (for specific details see Characteristics of included studies), and in three studies, there was a head‐to‐head comparison between two potentially active interventions (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 34 of the included studies (Bellissimo‐Rodrigues 2009; Berry 2011; Berry 2013; Bopp 2006; Cabov 2010; Caruso 2009; Chen 2008; DeRiso 1996; Feng 2012; Fourrier 2005; Grap 2011; Hu 2009; Jacomo 2011; Koeman 2006; Kusahara 2012a; Long 2012; Lorente 2012; Meinberg 2012; Mo 2016; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012; Scannapieco 2009; Sebastian 2012; Seguin 2006; Seguin 2014; Stefanescu 2013; Tang 2013; 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). One study 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 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 (Fourrier 2000; Hu 2009). We sought clarification from the trial authors but have so far received no further data.
Diagnostic criteria for the outcome of ventilator‐associated pneumonia were specified in 33 studies. Seventeen studies used Pugin's 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 38.5º C or less than 35º C, white blood cell count greater than 11,000/mm3 or less than 4000/mm3, mucopurulent or purulent bronchial secretions, or more than 20% increase in fraction of inspired oxygen required to maintain saturation above 92% (Berry 2011; Berry 2013; Cabov 2010; Caruso 2009; Fourrier 2000; Fourrier 2005; Grap 2011; Koeman 2006; Kusahara 2012a; Meinberg 2012; Munro 2009; Pobo 2009; Scannapieco 2009; Seguin 2006; Seguin 2014; Tantipong 2008; Yao 2011). In Ozcaka 2012, no specific criteria were reported, but communication with the author confirmed that participants with new pulmonary infiltrates or opacities on the chest X‐ray were prediagnosed VAP and lower tracheal mini‐bronchoalveolar lavage (mini‐BAL) samples were taken and then participants were diagnosed according to CPIS criteria. Those who had a score of six or more and the presence of 104 or more colony‐forming units/mL of a target potential respiratory bacterial pathogen (PRP) in mini‐BAL were diagnosed with VAP.
A further six studies used the CDC criteria as described in Horan 2008 (Bellissimo‐Rodrigues 2009; DeRiso 1996; Fields 2008; Jacomo 2011; Panchabhai 2009; Sebastian 2012). Stefanescu 2013 used CDC criteria for diagnosis of neonatal VAP.
Six studies 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 38º 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 (Chen 2008; Feng 2012; Mo 2016; Tang 2013; Xu 2007; Xu 2008).
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. Prendergast 2012 had a single diagnostic criterion 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).
The remaining two studies with the outcome of VAP did not report their diagnostic criteria (Bopp 2006; Roca Biosca 2011).
Mortality
Twenty‐four studies reported the outcome of mortality, either as ICU mortality or 30‐day mortality (Bellissimo‐Rodrigues 2009; Cabov 2010; Caruso 2009; Fourrier 2000; Fourrier 2005; Jacomo 2011; Kusahara 2012a; Long 2012; Lorente 2012; Meinberg 2012; Mo 2016; Munro 2009; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012; Scannapieco 2009; Sebastian 2012; Seguin 2006; Seguin 2014; Stefanescu 2013; Tang 2013; Tantipong 2008; Yao 2011). Where ICU mortality was reported, we used these data; where ICU mortality was not reported, we used 30‐day mortality.
Measures of secondary outcomes
Duration of ventilation
Sixteen studies reported this outcome (Bellissimo‐Rodrigues 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; Tang 2013; Xu 2008; Zhao 2012). Berry 2013, Jacomo 2011, Meinberg 2012 and Sebastian 2012 reported the median duration of ventilation or the range for each group or both, but we could not combine these data in a meta‐analysis. Unless explicitly reported otherwise, we have assumed that all studies used similar methods to calculate these data including participants who died. Stefanescu 2013 only reported a P value for the difference between groups in duration of ventilation.
Duration of ICU stay
There were 15 studies reporting this outcome (Bellissimo‐Rodrigues 2009; Bopp 2006; Caruso 2009; Fourrier 2000; Fourrier 2005; Koeman 2006; Kusahara 2012a; Lorente 2012; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012; Seguin 2006; Seguin 2014; Zhao 2012). Berry 2013, Jacomo 2011, Meinberg 2012, and Sebastian 2012 reported the median ICU stay and the range for each group, but we could not combine these data in a meta‐analysis. Unless explicitly reported otherwise, we have assumed that all studies used similar methods to calculate these data including participants who died.
Systemic antibiotic therapy
There were five studies that reported some measure of systemic antibiotic use. DeRiso 1996 reported the number of participants in each group who required treatment of an infection with systemic antibiotics during their ICU stay; Seguin 2014 reported the number of participants who were treated with antibiotics; and Fourrier 2005 and Scannapieco 2009 both reported the mean number of days of systemic antibiotic use in the intervention and control groups. Berry 2013 only reported a P value for the difference among groups in antibiotic administration.
Oral health indices
Plaque indices were mentioned as outcomes in four studies (Ozcaka 2012; Roca Biosca 2011; Scannapieco 2009; Yao 2011). Complete data for plaque indices were reported in one study (Ozcaka 2012), and were supplied by the corresponding author of another study (Yao 2011). Scannapieco 2009 reported this outcome in graphs only, and Roca Biosca 2011 did not report any estimate of variance, so we could not use these data in this review.
Adverse effects
Only two of the included studies reported adverse effects of the interventions (Seguin 2014; Tantipong 2008); five studies reported that there were no adverse effects (Berry 2011; Berry 2013; Jacomo 2011; Ozcaka 2012; Sebastian 2012), and Stefanescu 2013 reported no significant difference between groups with respect to adverse events in buccal mucosa. The remaining studies did not mention adverse effects in their reports.
Excluded studies
In this update, we excluded 24 studies for the reasons summarised below. Three studies that we included in the previous version of the review are excluded from this version (Grap 2004; McCartt 2010; Needleman 2011).
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Twelve studies were excluded because they were not RCTs (Buckley 2013; Darnell 2015; Gu 2013; Labeau 2013; Liao 2015; Maury 2015; Pelucchi 2013; Sands 2015; Seo 2011; Swartz 2015; Tattevin 2015; Yun 2011).
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Five studies were excluded because they did not attempt to assess the incidence of VAP or mortality (Baradari 2012; Grap 2004; Kusahara 2012b; McCartt 2010; Needleman 2011).
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Four 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 (Anon 2012; Jafari 2007; MacNaughton 2004; Pivkina 2014).
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Bellissimo‐Rodrigues 2014 was excluded because the intervention was dental care (e.g. treatment of caries, tooth extraction), not oral hygiene care.
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Munro 2015 was excluded because the intervention was oral hygiene care prior to, not during, mechanical ventilation.
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Fan 2015 was excluded because the CHX solution used for interventions contained antibiotics.
For further information, see the Characteristics of excluded studies table, which also provides information on studies excluded in the last version of this review.
Risk of bias in included studies
Allocation
Sequence generation
Twenty‐eight of the included studies clearly described a random method of sequence generation and we assessed them at low risk of bias for this domain. The remaining 10 studies stated that allocation was random but provided no further details and we therefore assessed them at unclear risk of bias for this domain (Caruso 2009; Feng 2012; Fields 2008; Long 2012; Panchabhai 2009; Roca Biosca 2011; Tang 2013; Xu 2007; Xu 2008; Zhao 2012).
Allocation concealment
Allocation concealment was clearly described in 19 of the included studies and we assessed them at low risk of bias for this domain. In 18 studies, allocation concealment was not described in sufficient detail to determine risk of bias and we rated these studies at unclear risk of bias (Cabov 2010; Caruso 2009; Chen 2008; Feng 2012; Fourrier 2000; Grap 2011; Long 2012; Lorente 2012; Mo 2016; Munro 2009; Panchabhai 2009; Sebastian 2012; Tang 2013; Tantipong 2008; Xu 2007; Xu 2008; Yao 2011; Zhao 2012). We assessed Bopp 2006 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 one study (Bopp 2006), unclear in 20 studies (Cabov 2010; Caruso 2009; Chen 2008; Feng 2012; Fields 2008; Fourrier 2000; Grap 2011; Long 2012; Lorente 2012; Mo 2016; Munro 2009; Panchabhai 2009; Roca Biosca 2011; Sebastian 2012; Tang 2013; Tantipong 2008; Xu 2007; Xu 2008; Yao 2011; Zhao 2012), and low in the remaining 17 studies.
Blinding
Twelve studies were described as double blind and we assessed them at low risk of performance bias (Bellissimo‐Rodrigues 2009; Cabov 2010; DeRiso 1996; Fourrier 2005; Jacomo 2011; Koeman 2006; Kusahara 2012a; Meinberg 2012; Ozcaka 2012; Scannapieco 2009; Sebastian 2012; Seguin 2014). There was insufficient information to determine whether blinding occurred in two studies (Caruso 2009; Zhao 2012). In the remaining 24 studies, blinding of the participants and their caregivers to the allocated treatment was not possible because the active and control treatments were so different, and no placebos were used. We assessed these studies at high 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; Berry 2013; Cabov 2010; Caruso 2009; DeRiso 1996; Fourrier 2000; Fourrier 2005; Hu 2009; Jacomo 2011; Kusahara 2012a; Lorente 2012; Meinberg 2012; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012; Scannapieco 2009; Sebastian 2012 ; Seguin 2014; Tantipong 2008; Yao 2011), which we assessed as being at low risk of detection bias. One of the included studies reported no blinding of outcome assessment and we assessed it at high risk of detection bias (Bopp 2006). In the remaining 15 studies, there was insufficient information provided and we rated the risk of detection bias as unclear.
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 25 of the included studies, 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 we assessed these studies at low risk of attrition bias (Bellissimo‐Rodrigues 2009; Bopp 2006; Cabov 2010; Caruso 2009; Chen 2008; Feng 2012; Fourrier 2005; Jacomo 2011; Koeman 2006; Kusahara 2012a; Long 2012; Lorente 2012; Meinberg 2012; Mo 2016; Ozcaka 2012; Pobo 2009; Sebastian 2012 ; Seguin 2006; Seguin 2014, Stefanescu 2013; Tang 2013; Xu 2007; Xu 2008; Yao 2011; Zhao 2012).
We rated nine of the included studies 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 was high and insufficient information was provided (Berry 2011; Berry 2013; Fields 2008; Grap 2011; Hu 2009; Munro 2009; 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
Twenty‐six of the included studies reported the outcomes specified in their Methods section in full, or this information was supplied by trial authors, and we assessed these studies at low risk of reporting bias (Bellissimo‐Rodrigues 2009; Berry 2011; Cabov 2010; Caruso 2009; DeRiso 1996; Feng 2012; Fourrier 2000; Fourrier 2005; Koeman 2006; Kusahara 2012a; Long 2012; Lorente 2012; Mo 2016; Ozcaka 2012; Panchabhai 2009; Pobo 2009; Prendergast 2012; Sebastian 2012; Seguin 2006; Seguin 2014; Stefanescu 2013; Tang 2013; Xu 2007; Xu 2008; Yao 2011; Zhao 2012).
Three studies did not report all the outcomes specified in their Methods sections (Grap 2011; Meinberg 2012; Roca Biosca 2011), two studies reported outcomes as percentages only, with unclear denominators for each arm (Berry 2013; Hu 2009), and one study did not report the number of participants evaluated (Fields 2008). We rated these six trials at high risk of reporting bias.
We assessed the remaining six trials at unclear risk of reporting bias, because there was insufficient information reported to make a clear judgement (Bopp 2006; Chen 2008; Koeman 2006; Munro 2009; Scannapieco 2009; Tantipong 2008).
Other potential sources of bias
We rated five studies at high risk of other bias. Three studies were stopped early (Berry 2011; Meinberg 2012; Pobo 2009). Berry 2011 was stopped due to withdrawal of one of the investigational products by a regulatory authority; Pobo 2009 was stopped after 37% of the planned 400 participants had been recruited because there appeared to be no difference between the study arms in the outcome of VAP. Meinberg 2012 was stopped due to "futility"; however we are unsure whether this was the main problem. 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 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 we assessed this study at high risk of other bias.
In 12 studies, we rated the risk of other bias as unclear (Berry 2013; Chen 2008; Fields 2008; Kusahara 2012a; Long 2012; Panchabhai 2009; Roca Biosca 2011; Stefanescu 2013; Tang 2013; Tantipong 2008; Yao 2011; Zhao 2012). The reasons for this are as follows:
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In Berry 2013 ineligible participants were included in the ITT analysis, but reasons for ineligibility in each group were not given;
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The participants in the treatment group in Chen 2008 received a co‐intervention that was not given to the control group;
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In both Fields 2008 and Roca Biosca 2011 the study reports contained insufficient information for us to be confident that study methodology was robust;
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In Stefanescu 2013 more infants in the control group received a complete course of antenatal steroids compared to infants in the Biotene OralBalance group (P = 0.045). A complete course of antenatal steroids improves antenatal lung maturity and function and may reduce the risk of VAP. This imbalance is likely to lead to an underestimate of the benefit of the active treatment;
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In Kusahara 2012a 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;
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Panchabhai 2009 reported baseline characteristics only for those participants completing the study;
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In Tang 2013, a detailed description about the intervention methods and frequency of oral care in each group was not reported.
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Tantipong 2008 included participants treated in different units of the hospital where care and co‐interventions are likely to have been different;
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In Yao 2011 there is no information as to how the edentulous participants in each arm were treated;
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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.
We assessed the remaining 21 studies at low risk of other bias.
Overall risk of bias
Overall, we rated just five of the included studies (13%) at low risk of bias for all domains (Bellissimo‐Rodrigues 2009; Fourrier 2005; Koeman 2006; Ozcaka 2012; Seguin 2014), and seven studies (18%) were at unclear risk of bias for at least one domain. Over two‐thirds of the included studies (26 studies, 68%) were at high risk of bias in at least one domain (see Figure 2; Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary graph: review authors' judgements about each risk of bias item for each included study
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 (± antiseptics) versus no toothbrushing (± antiseptics) 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 19 studies included in this review, but only 18 studies could be included in meta‐analysis for VAP. One study was a very small pilot study with no usable outcome data (Bopp 2006, n = 5).
Concentration of the chlorhexidine used was 2% in three studies (Koeman 2006; Tantipong 2008; Meinberg 2012), 1% in one study (Sebastian 2012), 0.20% in five studies (Berry 2011; Cabov 2010; Fourrier 2000; Fourrier 2005; Panchabhai 2009), unclear in one study (Chen 2008), and 0.12% in the remaining studies.
We assessed 10 of the 19 studies at high risk of bias (Berry 2011; Bopp 2006; Chen 2008; Fourrier 2000; Grap 2011; Meinberg 2012; Munro 2009; Panchabhai 2009; Scannapieco 2009; Tantipong 2008), four studies at low risk of bias (Bellissimo‐Rodrigues 2009; Fourrier 2005; Koeman 2006; Ozcaka 2012), and the remaining five studies at unclear risk of bias.
We subgrouped these studies 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 meta‐analysis of 18 studies (nine studies at high risk of bias, five at unclear risk of bias and four at low risk of bias) showed a reduction in VAP with use of chlorhexidine (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.62 to 0.91, P = 0.004, I2 = 35%; 2451 participants) (Analysis 1.1). This equates to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 9 to 50).
Seven studies (1037 participants) compared chlorhexidine solution (0.12% or 0.2%) with either placebo (six studies) or 'usual care' (Grap 2011) without toothbrushing. Six of these studies reported the use of a swab, either to clean the mouth prior to chlorhexidine application or to ensure that the chlorhexidine solution was applied to all oral surfaces. In the remaining study (Chen 2008) the mode of application is unclear. The meta‐analysis showed a reduction in VAP in the chlorhexidine group (RR 0.71, 95% CI 0.53 to 0.94, P = 0.02, I2 = 28%) (Analysis 1.1, Subgroup 1.1.1).
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 (RR 0.66, 95% CI 0.41 to 1.05, P = 0.08, I2 = 38%) (Analysis 1.1, Subgroup 1.1.2).
Three studies (405 participants) compared chlorhexidine solution (2%, 0.12% or 0.2%) with placebo (with toothbrushing in both groups). The meta‐analysis showed no evidence of a difference in VAP between the groups group (RR 0.69, 95% CI 0.29 to 1.63, P = 0.40, I2 = 45%) (Analysis 1.1, Subgroup 1.1.3).
Two further studies (Meinberg 2012; Kusahara 2012a, including 52 adults and 96 children), at high and unclear risk of bias, compared chlorhexidine gel (2% and 0.12%) with placebo (with toothbrushing in both groups) and found no difference in the incidence of VAP (RR 1.22, 95% CI 0.83 to 1.79, P = 0.32, I2 = 0%) (Analysis 1.1, Subgroup 1.1.4).
Munro 2009 reported results from some of the participants randomised into a study with a factorial design. This study showed a reduction in VAP that 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 (Additional Table 1).
| Comparison | Number of participants | Outcome | Data | Effect estimate (95% CI) |
| Listerine versus sodium bicarbonate versus sterile water (Berry 2013) | Listerine group: 127; Sodium bicarbonate group: 133; Sterile water group: 138 | Duration of mechanical ventilation | No significant difference between groups in median ventilation hours (81 hours, SD 1058) | |
| Duration of ICU stay | No significant difference between groups in median length of ICU stay (5 days, SD 29) | |||
| Systemic antibiotic use | No significant difference between groups (P = 0.21) | |||
| Adverse events | No adverse events were reported associated with interventions | |||
| CHX + toothbrushing versus control (Bopp 2006) | CHX + toothbrushing group: 2; Control group:3 | Incidence of VAP | 0 cases in CHX + toothbrushing group and 1 case in control group | |
| Duration of ventilation | Mean 5.5 days (SD 0.3896) in toothbrushing group and mean 5 days (SD 0.8051) in control group | |||
| Duration of ICU stay | Mean 18 days (SD 1.6695) in toothbrushing group and mean 10.3 days (SD 2.6971) in control group | |||
| CHX versus placebo (Koeman 2006) | CHX: 127; Placebo:130 | Mortality
| HR | HR 1.12 (95% CI 0.72 to 1.17)
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| CHX versus placebo (Meinberg 2012) | CHX group: 28; Placebo group: 24 | Duration of mechanical ventilation | Median days in CHX group 8.5 (interquartile range, 7.3 to 14.7) and median days in placebo group 6 (4 to 12.7) (P = 0.17) | |
| Duration of ICU stay | Median days in CHX group 12 (interquartile range, 9 to 29) and median days in placebo group 11 (5 to 16) (P = 0.36) | |||
| Powered toothbrush + CHX versus CHX alone (Roca Biosca 2011) | Powered toothbrush group: 29; CHX alone group: 32 | Plaque index | Mean in toothbrush group 1.68 and mean in control group 1.91; | |
| Incidence of VAP | OR 0.78 (95% CI 0.36 to 1.68, P = 0.56) | |||
| CHX (once daily or twice daily) versus placebo (Scannapieco 2009) | CHX 1x/day group: 47; CHX 2x/day group: 50; Placebo group: 49 | Plaque index | No difference between the 3 groups (data presented graphically) | |
| Biotene OralBalance versus control (Stefanescu 2013) | Biotene OralBalance group: 20; Control group: 21 | Duration of mechanical ventilation | No difference between groups (P = 0.77) | |
| Adverse events | No significant difference between groups with respect to adverse events in buccal mucosa |
CHX = chlorhexidine; CI = confidence interval; CPIS = Clinical Pulmonary Infection Score; HR = hazard ratio; ICU = intensive care unit; OR = odds ratio; P = probability; SD = standard deviation; VAP = ventilator‐associated pneumonia
Mortality
The outcome of mortality was reported in 14 studies (2014 participants), and overall the meta‐analysis showed no evidence of a difference between chlorhexidine and placebo/usual care with minimal heterogeneity (RR 1.09, 95% CI 0.96 to 1.23, P = 0.20 , I2 = 0%) (Analysis 1.2). Nor was there evidence of a difference in mortality between (P = 0.93) or within the subgroups (chlorhexidine mouthrinse/gel with or without toothbrushing) (Analysis 1.2; Additional Table 1).
Duration of ventilation
From the five studies (800 participants) that reported data in a way that could be combined in meta‐analysis, there is no evidence of a difference in the duration of ventilation (days) between groups receiving chlorhexidine compared to those receiving placebo/usual care (mean difference (MD) ‐0.09 days, 95% CI ‐1.73 to 1.55 days, P = 0.91, I2 = 36%) (Analysis 1.3). There was no evidence of a difference in duration of ventilation in any of the subgroups.
A further study (Meinberg 2012), comparing chlorhexidine gel and placebo, also found no difference in duration of ventilation (Additional Table 1).
Duration of ICU stay
There was no evidence of a difference between those receiving chlorhexidine compared to placebo/usual care in the outcome of duration of ICU stay (days) (MD 0.21 days, 95% CI ‐1.48 to 1.89 days, P = 0.81, I2 = 9%; six RCTs, 833 participants). There was no evidence of a difference in two subgroups (Analysis 1.4, Subgroup 1.4.1; Subgroup 1.4.2) and insufficient evidence to determine whether or not there was a difference in Analysis 1.4, Subgroup 1.4.3.
Another study (Meinberg 2012) compared chlorhexidine gel with placebo and also found no difference in duration of ICU stay (Additional Table 1).
Use of systemic antibiotics
Two trials (374 participants) reported this outcome, but there was insufficient evidence to determine whether or not there is a difference in duration of systemic antibiotic therapy between the chlorhexidine and control groups (MD 0.23 days, 95% CI ‐0.85 to 1.30, P = 0.68, I2 = 50%; fixed‐effect model). There was moderate heterogeneity, probably due to the differences between the two studies in the mode of chlorhexidine used (Analysis 1.5).
Oral health indices: plaque index
Two of the studies in this group reported the outcome of plaque index (Ozcaka 2012; Scannapieco 2009), but only Ozcaka 2012 reported numerical data. Neither study found a difference in plaque indices between the chlorhexidine and control groups (Analysis 1.6; Additional Table 1).
Adverse effects
Two studies in this group reported adverse effects. Tantipong 2008 found mild reversible irritation of the oral mucosa in 10% of the chlorhexidine participants compared to 1% of the control group participants (Analysis 1.7). Berry 2011 stated that there were no adverse events in either group.
Adverse effects were not mentioned in the other studies in this group.
Other outcomes
The outcomes of caregivers' preferences and cost were not reported.
Heterogeneity
The moderate statistical heterogeneity found for the outcome of VAP incidence is likely to be due to clinical differences between these studies, attributable to variability in the frequency, application method, volume, and concentration of chlorhexidine solution (Analysis 1.1).
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 used a single application by swab of a very small volume of chlorhexidine preoperatively (Grap 2011). One of the seven studies was in children aged from birth to 14 years (Jacomo 2011); the other studies recruited adults.
In Subgroup 1.1.2, there was also moderate heterogeneity, that may be due to variations in the way the intervention was delivered. Three of the five studies in this subgroup administered 0.2% chlorhexidine gel three times daily following rinsing of the mouth and aspiration of rinse (Cabov 2010; Fourrier 2000; Fourrier 2005). The other two studies used a gel with higher chlorhexidine concentration (2% and 1% respectively) and applied the gel using a swab (Koeman 2006; Sebastian 2012).
Sensitivity analysis
For the primary outcomes, we conducted a sensitivity analysis excluding studies at high risk of bias. The estimate remained similar for both VAP incidence (RR 0.79, 95% CI 0.60 to 1.04, P = 0.09, I2 = 28%; 1414 participants) compared with 0.75, and mortality (RR 0.99, 95% CI 0.78 to 1.24, P = 0.92, I2 = 18%; 1157 participants) compared with 1.09 (Analyses not shown).
A meta‐analysis of the three studies of children (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 (RR 1.04, 95% CI 0.72 to 1.51, P = 0.82, I2 = 0%) or mortality (RR 0.81, 95% CI 0.54 to 1.20, P = 0.29, I2 = 0%) (Jacomo 2011; Kusahara 2012a; Sebastian 2012) (Analyses not shown).
In addition, we also carried out sensitivity analyses by grouping the included studies by chlorhexidine concentration. Results of these subgroup analyses suggest no evidence of a difference between subgroups or any dose‐response relationship in either incidence of VAP (P = 0.83) or mortality (P = 0.59) (Analyses not shown).
Publication bias
Each of the subgroups in this comparison contained a small number of studies and it was therefore not appropriate to produce a funnel plot to investigate possible publication bias.
Comparison 2: Toothbrushing versus no toothbrushing (with or without antiseptics)
The eight studies included in this comparison (Bopp 2006; Fields 2008; Long 2012; Lorente 2012; Munro 2009; Pobo 2009; Roca Biosca 2011; Yao 2011) had toothbrushing as part of the intervention versus no toothbrushing in the control group. The studies were all at high risk of bias. Three studies used powered toothbrushes (Pobo 2009; Roca Biosca 2011), and five used manual toothbrushes. Bopp 2006 was a very small pilot study (n = 5) and the data from this study are recorded in Additional Table 1; Fields 2008 reported no numerical data at all. 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
There was no evidence of a difference in the incidence of VAP due to toothbrushing in the combined meta‐analysis of five studies (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11 , I2 = 64%, 889 participants, high risk of bias) (Analysis 2.1) or the combined meta‐analysis of four studies for chlorhexidine (RR 0.77, 95% CI 0.50 to 1.21, P = 0.26, I2 = 62%, 828 participants, high risk of bias) (analysis not shown) (Lorente 2012; Munro 2009; Pobo 2009; Yao 2011), with the substantial statistical heterogeneity likely to be explained by the differences between the studies in exposure to antiseptics.
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 the participant's bed being elevated 30° to 45°, 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 (RR 0.49, 95% CI 0.16 to 1.53, P = 0.22, I2 = 75%) (Analysis 2.1, Subgroup 2.1.1), with the heterogeneity probably due to the additional exposure to chlorhexidine in both groups of only one of the studies.
In Lorente 2012 (436 participants), 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 (Analysis 2.1, Subgroup 2.1.2).
Munro 2009, a study with a factorial design in 192 participants, 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).
A further study (Long 2012; 61 participants) compared toothbrushing plus povidone iodine with povidone iodine alone, and found some evidence for a benefit for toothbrushing (Analysis 2.1, Subgroup 2.1.4). The results of this study have not been replicated, so should be interpreted with caution.
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 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 six months. Roca Biosca 2011 recruited 117 participants and reported a summary estimate for the outcome of VAP, with no difference between powered toothbrushing and no toothbrushing (Additional Table 1).
Mortality
Five studies (889 participants) evaluated the effect of toothbrushing, as an addition to oral care, on the outcome of mortality (Long 2012; Lorente 2012; Munro 2009; Pobo 2009; Yao 2011). The comparisons were different in each trial and there was no evidence of a difference in mortality with or without toothbrushing (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24 , I2 = 0%) (Analysis 2.2).
Duration of ventilation
Meta‐analysis of two trials of chlorhexidine (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%; fixed‐effect model) (Analysis 2.3). A further trial of povidone iodine also failed to show a benefit for toothbrushing for this outcome (Long 2012).
Duration of ICU stay
Meta‐analysis of two trials (583 participants) that reported the outcome of mean duration of ICU stay found no evidence of a difference between the groups (MD ‐1.82 days, 95%CI ‐3.95 to 0.32 days, P = 0.10, I2 = 0%, fixed‐effect model, Analysis 2.4). The data from Bopp 2006 are reported in Additional Table 1.
Use of systemic antibiotics
This outcome was not reported by any of the studies in this group.
Oral health indices: plaque score
One study (Yao 2011) also reported the outcome of plaque score in each group after seven to eight days. The study failed to show evidence of reduced plaque in the toothbrushing group (Analysis 2.5).
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
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.
Other outcomes
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 for 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, systemic antibiotic therapy, caregivers' preferences for oral hygiene care or cost were not reported in the study.
Comparison 4: Other oral care solutions
Thirteen studies were included in this comparison, with a total of 2702 participants randomised to treatments (Berry 2011; Berry 2013; Caruso 2009; Feng 2012; Hu 2009; Mo 2016; Seguin 2006; Seguin 2014; Stefanescu 2013; Tang 2013; Xu 2007; Xu 2008; Zhao 2012). Twelve of these studies were at high risk of bias and Seguin 2014 was at low risk of bias. The studies evaluated the effects of other solutions with a potential antiseptic effect on the outcomes of VAP, mortality, duration of ventilation, and duration of ICU stay.
Incidence of VAP
Three studies (356 participants) compared povidone iodine rinse with a saline rinse or placebo (Feng 2012; Seguin 2006; Seguin 2014). They showed evidence of a reduction in VAP (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, fixed‐effect model) (Analysis 4.1, Subgroup 4.1.1).
Seguin 2006 (67 participants) also compared povidone iodine rinse with usual care (suction alone with no rinse) and found a reduction in VAP (Analysis 4.1, Subgroup 4.1.2). The result of this study has not been replicated, so should be interpreted with caution.
Four studies (488 participants) (Mo 2016; Tang 2013; Xu 2007; Xu 2008), all at high risk of bias, which compared a saline rinse with a saline‐soaked swab found some weak evidence that saline rinse reduced the incidence of VAP (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, fixed‐effect model) (Analysis 4.1, Subgroup 4.1.3).
Two studies (Caruso 2009; Seguin 2006; 324 participants), both at high risk of bias, compared a saline rinse with usual care (no rinse) and found a reduction in VAP (RR 0.60, 95% CI 0.39 to 0.91, P = 0.02, I2 = 64%, fixed‐effect model) (Analysis 4.1, Subgroup 4.1.4). 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 VAP.
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 153 participants) that the combined rinse plus swab reduced the incidence of VAP (RR 0.41, 95% CI 0.23 to 0.72, P = 0.002, I2 = 0%, fixed‐effect model) (Analysis 4.1, Subgroup 4.1.5).
Two studies (Berry 2011; Berry 2013; 425 participants), both at high risk of bias, compared bicarbonate rinse plus toothbrushing with a water rinse plus toothbrushing and found no evidence of a difference in the incidence of VAP (RR 1.48, 95% CI 0.57 to 3.82, P = 0.42, I2 = 20%, fixed‐effect model) (Analysis 4.1, Subgroup 4.1.6).
A single study compared triclosan rinse with saline rinse and found no difference in the outcome of VAP over the duration of the study (Zhao 2012) (Analysis 4.1, Subgroup 4.1.7). The results of this study have not been replicated, so should be interpreted with caution.
A single three‐arm study compared povidone iodine, furacilin and usual care (Feng 2012). It found both antiseptics combined with toothbrushing were more effective than usual care (Analysis 4.1, Subgroup 4.1.1 and Analysis 4.1, Subgroup 4.1.9) with little difference between the two antiseptic solutions (Analysis 4.1, Subgroup 4.1.8).
A single study (Berry 2013; 265 participants), comparing Listerine with water, and Listerine with bicarbonate, found no evidence of a difference in VAP incidence (Analysis 4.1, Subgroups 4.1.10 and 4.1.11).
Another single study (Stefanescu 2013; 41 participants) compared Biotene OralBalance with control and found no difference in incidence of VAP (Analysis 4.1, Subgroup 4.1.12).
Mortality
Seven studies reported mortality in the following comparisons (Analysis 4.2).
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Povidone iodine versus saline/placebo: two studies (217 participants) (RR 1.00, 95% CI 0.66 to 1.50, P = 0.98, I2 = 65%; fixed‐effect model), no evidence to suggest a difference in mortality.
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Povidone iodine versus usual care: single study (67 participants), no evidence to suggest a difference.
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Saline rinse versus saline swab: two studies (270 participants) (RR 0.29, 95% CI 0.12 to 0.69; P = 0.005, I2 = 0%; fixed‐effect model), suggesting a significant reduction in mortality for saline rinse.
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Saline rinse versus usual care: two studies (324 participants) (RR 1.10, 95% CI 0.87 to 1.39, P = 0.43, I2 = 2%; fixed‐effect model), no evidence to suggest a difference in mortality.
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Saline rinse plus swab versus saline swab (usual care): single study (47 participants), no evidence to suggest a difference.
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Biotene OralBalance versus control: single study (41 participants), no evidence to suggest a difference.
Duration of ventilation
Six studies reported duration of ventilation (days) in the following comparisons (Analysis 4.3).
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Povidone iodine versus saline/placebo: single study (67 participants), no evidence to suggest a difference.
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Povidone iodine versus usual care: single study (67 participants), no evidence to suggest a difference.
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Saline rinse versus usual care: two studies (324 participants) (MD ‐0.40 days, 95% CI ‐2.55 to 1.75 days, P = 0.72, I2 = 0%), no evidence to suggest a difference in duration of ventilation.
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Saline rinse plus swab versus saline swab (usual care): single study (47 participants) suggesting a statistically significant effect in favour of shorter duration for the saline rinse plus swab.
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Saline rinse versus saline swab: two studies (176 participants) (MD ‐6.83 days, 95% CI ‐8.94 to ‐4.72 days; P < 0.00001, I2 = 65%) suggest saline rinse leads to shorter duration of ventilation.
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Triclosan rinse versus saline: single study (324 participants) suggesting that triclosan leads to shorter duration of ventilation than saline.
Berry 2013, comparing Listerine with water, and Listerine with bicarbonate, found no difference among groups in median ventilation hours. Another study (Stefanescu 2013), comparing Biotene OralBalance and control, also found no difference between groups in duration of ventilation. (Additional Table 1)
Duration of ICU stay
Four studies reported duration of ICU stay (days) in the following comparisons (Analysis 4.4).
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Povidone iodine versus saline/placebo: two studies (217 participants) (MD ‐0.35 days, 95% CI ‐3.90 to 3.21 days, P = 0.85, I2 = 0%; fixed‐effect model), no evidence to suggest a difference.
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Povidone iodine versus usual care: single study (67 participants), no evidence to suggest a difference.
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Saline rinse versus usual care: two studies (324 participants) (MD ‐1.17 days, 95% CI ‐3.95 to 1.60 days, P = 0.41, I2 = 32%; fixed‐effect model), no evidence to suggest a difference in duration of ICU stay.
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Triclosan rinse versus saline: single study (324 participants), suggesting that triclosan leads to shorter stay in ICU than saline.
Another study (Berry 2013), comparing Listerine with water, and Listerine with bicarbonate, found no difference among groups in median ICU length of stay (Additional Table 1).
Use of systemic antibiotics
Seguin 2014, comparing povidone iodine and placebo, showed no evidence of a difference in the number of participants treated with systemic antibiotics (Analysis 4.5). Berry 2013, comparing Listerine with water, and Listerine with bicarbonate, found no difference among groups in antibiotic administration. See Additional Table 1.
Adverse effects
Seguin 2014 found no evidence of a difference in the occurrence of acute respiratory distress syndrome, agitation and/or hypertension, epistaxis, oxygen desaturation and aspiration (Analysis 4.6). Berry 2013 found no adverse events associated with interventions. Stefanescu 2013, comparing Biotene OralBalance and control, found no significant difference between groups with respect to adverse events in buccal mucosa. See Additional Table 1.
Discussion
Summary of main results
We included 38 randomised controlled trials in this updated review and these studies evaluate four main groups of interventions in the oral hygiene care of critically ill patients receiving mechanical ventilation for at least 48 hours in intensive care units.
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Chlorhexidine (CHX) antiseptic versus placebo/usual care (with or without toothbrushing)
There is high quality evidence from 18 RCTs that the use of chlorhexidine (either as a mouthrinse or a gel) reduces the incidence of ventilator‐associated pneumonia (VAP) from 24% to about 18% (summary of findings Table for the main comparison). There is no evidence that use of chlorhexidine is associated with a difference in mortality (moderate‐quality evidence), duration of mechanical ventilation (low‐quality evidence) or duration of ICU stay (moderate quality evidence). There is insufficient evidence to determine the effect of chlorhexidine on the other secondary outcomes of this review.
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Toothbrushing versus no toothbrushing (with or without antiseptics)
Based on five RCTs (very low quality evidence), we found no evidence of a difference in the incidence of VAP due to toothbrushing. There is also no evidence for a difference between toothbrushing or no toothbrushing for the outcomes of mortality (low quality evidence), duration of ventilation (low quality evidence) or duration of ICU stay (very low quality evidence) (summary of findings Table 2).
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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.
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Oral care with other solutions
The studies in this comparison, most of which are at high overall risk of bias, made different comparisons. For the reduction of VAP, there is some weak evidence that povidone iodine rinse is more effective than saline/placebo, use of saline rinse is more effective than saline swab, use of both a saline swab and a saline rinse may be more effective than a saline swab alone, and use of saline rinse may be more effective than usual care. There is no evidence of a difference between bicarbonate rinse and a water rinse.
For the outcome of mortality, we found no evidence of a difference between povidone iodine rinse and saline/placebo or between saline rinse and usual care. We found some very weak evidence of a difference between saline rinse and saline swab.
For the duration of ventilation, we found no evidence of a difference between saline rinse and usual care, and some weak evidence that saline rinse leads to shorter duration of ventilation compared to saline swab. For the duration of ICU stay, we found no evidence of a difference between povidone iodine and saline/placebo or between saline rinse and usual care.
Overall completeness and applicability of evidence
In this review, we have included studies that 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 to which group participants are in 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 participants and between individual caregivers. Where there was no blinding, we assessed studies as being at high risk of performance and detection bias.
There are some other variables which may have influenced the outcomes in the included studies. These include the number of episodes of OHC a day, the 'dose' of the antiseptic, and whether participants were dentate or edentulous. Most of the studies (79%) stated that they delivered between two and four episodes of OHC per day. Nine studies specified that edentulous people were excluded, one study focused on newborns, but most of the included studies did not report whether or not participants were dentate. We investigated whether there was a dose‐response effect and could find no evidence for this.
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 based on variable diagnostic criteria. Most of the included studies (33/38) stated the criteria used to diagnose VAP, of which the two most common were some version of the clinical pulmonary infection score (CPIS) based on Pugin's criteria (Cook 1998; Pugin 1991) (17 studies) and Centers for Disease Control (CDC) criteria as described in Horan 2008 (six studies). Six studies conducted in China used Chinese Society of Respiratory Diseases (CSRD) criteria for diagnosis of VAP (Chen 2008; Feng 2012; Mo 2016; Tang 2013; Xu 2007; Xu 2008).
Currently there is no clearly accepted gold standard for the diagnosis of VAP, and when different criteria are applied to the same cohort of patients, the estimated VAP prevalence could vary widely (Klompas 2007). In light of the limited sensitivity and specificity of the traditional VAP diagnosis, the US Centers for Disease Control (CDC) has recently developed a new surveillance criterion, ventilator‐associated event (VAE), to incorporate all complications (including VAP) leading to the worsening of gas exchange in mechanically‐ventilated patients. However, the advent of a more objective and definitive diagnosis of VAP may depend on further development of biomarker technologies, which may not occur in the near future. (Waters 2015)
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. This is in contrast to a review by Price 2014, which claimed that CHX is possibly associated with increased mortality. There has been some debate in the literature about the attributable mortality of VAP, but a recent survival analysis of nearly 4500 patients found that ICU mortality 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 we 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 risks 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, could not 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 described the toothbrushing intervention in detail, and noted that nurses delivering the intervention received specific training. While the presence of ventilator tubes in the mouths of trial participants makes effective toothbrushing difficult, it seems likely that, despite this, 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, our Cochrane Review has not evaluated duration of ICU stay in patients who develop VAP. The studies in our review reported mean length of ICU stay and the standard deviation for each arm of the study. We have combined these in meta‐analyses based on an assumption that 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.
Our 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 reported the cost of the chlorhexidine gluconate solution by participant was USD 3.15 (Jacomo 2011), while the cost associated with a single incident of VAP was estimated at USD 10,000 to 40,000 (Hillier 2013; Waters 2015). Reducing the incidence of VAP using relatively inexpensive additions to usual care is likely to be cost‐effective, as well as avoiding additional morbidity for the patient.
The increasing incidence of bacteria which are resistant to current antibiotics is of concern worldwide, and one of the reasons for bacterial resistance is the overuse of systemic antibiotics (Gyssens 2011). Oral hygiene care using antiseptics such as chlorhexidine, to reduce the risk of VAP, could potentially also result in a reduced requirement for these patients to be treated with systemic antibiotics. Because only four of the 38 studies included in this review provided data about the duration of antibiotic use in study participants, we do not have sufficient information to determine whether there was any effect on systemic antibiotic use.
It is interesting that only one of the 19 studies that evaluated chlorhexidine reported adverse reactions to chlorhexidine (mild reversible irritation of the oral mucosa) (Tantipong 2008). Hypersensitivity is a rare but potentially severe side effect of chlorhexidine (Pemberton 2012). In over 2000 participants included in these studies there was no report of hypersensitivity to chlorhexidine. However, it is notable that in six of the included studies (DeRiso 1996; Jacomo 2011; Kusahara 2012a; Ozcaka 2012; Scannapieco 2009; Sebastian 2012), a prior history of hypersensitivity to chlorhexidine was an exclusion criterion during participant recruitment. In view of recent reports in the UK of two cases of serious adverse events associated with irrigation of dry socket with chlorhexidine mouthrinse, it is recommended that all members of the dental team prescribing chlorhexidine products are aware of the potential for both minor and serious adverse side effects (Pemberton 2012).
Quality of the evidence
All the included studies were prospective, randomised controlled trials, but only five of them (13%) were assessed at low risk of bias (Bellissimo‐Rodrigues 2009; Fourrier 2005; Koeman 2006; Ozcaka 2012; Sebastian 2012) for all domains. However, we did not consider that the impact of bias reduced our confidence in the outcome of VAP incidence. Although more than two‐thirds of included studies had a high risk of bias for at least one domain, sensitivity analysis by risk of bias did not alter the size or direction of the effect for VAP (see summary of findings Table for the main comparison). This provides support for our decision to consider the quality of the evidence for this outcome to be high. In contrast, we downgraded the quality of evidence for duration of ventilation and stay in ICU, because we could not rule out bias having a greater impact on these resource use outcomes. Most studies did not provide information on adverse events, and the scant information we could obtain from two studies prompted us to downgrade the quality of evidence to very low.
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, with no restrictions on language. We searched the reference lists of included studies and contacted many of the study authors 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.
For this review we also chose very broad inclusion criteria, which has resulted in a clinically heterogeneous group of studies including adults, children and neonates, and a range of indications for ICU care, including medical conditions, surgery and trauma where patients were ventilated for over 48 hours. 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 between studies in oral hygiene care practices. There was also potential variation in the methods used for intubation and for the calculation of duration outcomes (e.g. duration of mechanical ventilation, duration of ICU stay) (Contentin 2014), both of which were not always clearly specified.
One other potential bias in this review is the variation in and the subjective nature of criteria/methods used for VAP diagnosis (Klompas 2007). Also, 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 previous meta‐analysis by Pineda 2006 found that the use of chlorhexidine for oral decontamination did not reduce the incidence of nosocomial pneumonia. However, their meta‐analysis included only four studies and the outcome was nosocomial pneumonia rather than VAP. Another systematic 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.
One recent systematic review (Price 2014) has looked at the effects of selective digestive/oropharyngeal decontamination and topical oropharyngeal chlorhexidine on the prevention of death in general intensive care, and claimed that CHX is possibly associated with increased mortality (odds ratio (OR) 1.25, 95% CI 1.05 to 1.50). Reasons for the discrepancy between this finding and ours mainly include differences in the review scope (e.g. whether focused on adults, general intensive care only) and review methodology (e.g. inclusion of studies for which only abstracts are available). With less strict eligibility criteria for settings and participants and more stringent inclusion criteria for the reporting and methodology of primary studies, we believe that our finding is more generalisable and reflects the current evidence base. More trials are needed of the association between CHX usage and ICU mortality, to provide more insight into this issue.
Two more recent systematic reviews have looked at the effects of chlorhexidine with different concentrations. One claimed that the use of higher concentration chlorhexidine was associated with higher mortality (Klompas 2014), and the other stated that chlorhexidine with the concentration of 0.12% had the best effect in reducing VAP incidence (Zhang 2013). However, these findings were all based on trivial differences in point estimates, with wide confidence intervals for each estimate and statistically non‐significant differences between concentrations. The results of our sensitivity analyses do not support the dose‐response relationships that they proposed, and confirm that differences between concentrations were statistically non‐significant.
Two published meta‐analyses of toothbrushing to reduce VAP included four trials and found no evidence for a difference in incidence of VAP, again possibly due to low statistical power (Alhazzani 2013; Gu 2012). Our review reaches similar conclusions.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary graph: review authors' judgements about each risk of bias item for each included study
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 1 Incidence of VAP.
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 2 Mortality.
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 3 Duration of ventilation (days).
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 4 Duration of ICU stay (days).
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 5 Duration of systemic antibiotic therapy (days).
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 6 Plaque index.
Comparison 1 Chlorhexidine versus placebo/usual care, Outcome 7 Adverse effects.
Comparison 2 Toothbrushing versus no toothbrushing, Outcome 1 Incidence of VAP.
Comparison 2 Toothbrushing versus no toothbrushing, Outcome 2 Mortality.
Comparison 2 Toothbrushing versus no toothbrushing, Outcome 3 Duration of ventilation (days).
Comparison 2 Toothbrushing versus no toothbrushing, Outcome 4 Duration of ICU stay (days).
Comparison 2 Toothbrushing versus no toothbrushing, Outcome 5 Plaque score.
Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 1 Incidence of VAP.
Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 2 Mortality.
Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 3 Duration of ventilation (days).
Comparison 3 Powered toothbrush versus manual toothbrush, Outcome 4 Duration of ICU stay (days).
Comparison 4 Other oral care solutions, Outcome 1 Incidence of VAP.
Comparison 4 Other oral care solutions, Outcome 2 Mortality.
Comparison 4 Other oral care solutions, Outcome 3 Duration of ventilation (days).
Comparison 4 Other oral care solutions, Outcome 4 Duration of ICU stay (days).
Comparison 4 Other oral care solutions, Outcome 5 Number of participants treated with systemic antiboitics.
Comparison 4 Other oral care solutions, Outcome 6 Adverse effects.
| Chlorhexidine (mouthrinse or gel) versus placebo/usual care for critically ill patients to prevent ventilator‐associated pneumonia (VAP) | ||||||
| Patient or population: critically ill adults and children receiving mechanical ventilation Comparison: placebo or usual care | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control (placebo or usual care) | Chlorhexidine (mouthrinse or gel) | |||||
| Ventilator‐associated pneumonia | 243 per 10001 | 180 per 1000 | RR 0.75 | 2451 | ⊕⊕⊕⊕ | This equates to an NNTB of 17 (95% CI 9 to 50) |
| Mortality | 222 per 10001 | 242 per 1000 | RR 1.09 | 2014 | ⊕⊕⊕⊝ | |
| Duration of ventilation | 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 | 800 | ⊕⊕⊝⊝ | ||
| Duration of ICU stay | The mean duration of ICU stay in the control groups ranged from 10 to 24 days | The mean duration of ICU stay in the intervention groups was | 833 | ⊕⊕⊕⊝ moderate 4 | ||
| Adverse effects | Most of the studies did not provide information on adverse events. Information on adverse events were identified from 2 studies. One study stated there were none, the other study reported on mild reversible irritation of the oral mucosa | ⊕⊝⊝⊝ | ||||
| *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) | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk is based on the median event rate in the control groups of the included studies. 2Downgraded one level due to serious risk of bias: eight studies at high risk of bias, four at unclear risk of bias and three at low risk of bias. The sensitivity analysis based on three low‐risk‐of‐bias studies gave similar effect estimate (RR = 1.13), but further research may change this estimate. 3Downgraded two levels due to serious imprecision and serious risk of bias: two studies at high risk of bias, three at low risk of bias. The sensitivity analysis based on three studies at low risk of bias gave an effect estimate of 0.84 days, which is not clinically important in the context of median duration of 12 days. 4Downgraded one level due to serious imprecision. 5Downgraded three levels due to very serious imprecision and serious inconsistency: only two studies reported on this outcome, and they did not report data adequately to enable us to evaluate the risk of adverse events. | ||||||
| Toothbrushing (± antiseptics) versus no toothbrushing (± antiseptics) for critically ill patients to prevent ventilator‐associated pneumonia (VAP) | ||||||
| Patient or population: critically ill patients receiving mechanical ventilation Comparison: no toothbrushing (± chlorhexidine) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No toothbrushing | Toothbrushing | |||||
| Incidence of VAP Follow‐up: mean 1 month | 367 per 10001 | 253 per 1000 | RR 0.69 | 889 | ⊕⊝⊝⊝ | |
| Mortality | 236 per 10001 | 205 per 1000 | RR 0.87 | 889 | ⊕⊕⊝⊝ | |
| Duration of ventilation | The mean duration of ventilation in the control groups ranged from 9.8 to 10 days | The mean duration of ventilation in the intervention groups was | 644 | ⊕⊕⊝⊝ | ||
| Duration of ICU stay | The mean duration of ICU stay in the control groups ranged from 13 to 15 days | The mean duration of ICU stay in the intervention groups was | 583 | ⊕⊝⊝⊝ | ||
| Adverse effects | Most of the studies did not provide information on adverse events. Information on adverse events was identified from one study which stated there was none. | ⊕⊝⊝⊝ | ||||
| *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) | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Assumed risk is based on the outcomes in the control groups of the included studies | ||||||
| Comparison | Number of participants | Outcome | Data | Effect estimate (95% CI) |
| Listerine versus sodium bicarbonate versus sterile water (Berry 2013) | Listerine group: 127; Sodium bicarbonate group: 133; Sterile water group: 138 | Duration of mechanical ventilation | No significant difference between groups in median ventilation hours (81 hours, SD 1058) | |
| Duration of ICU stay | No significant difference between groups in median length of ICU stay (5 days, SD 29) | |||
| Systemic antibiotic use | No significant difference between groups (P = 0.21) | |||
| Adverse events | No adverse events were reported associated with interventions | |||
| CHX + toothbrushing versus control (Bopp 2006) | CHX + toothbrushing group: 2; Control group:3 | Incidence of VAP | 0 cases in CHX + toothbrushing group and 1 case in control group | |
| Duration of ventilation | Mean 5.5 days (SD 0.3896) in toothbrushing group and mean 5 days (SD 0.8051) in control group | |||
| Duration of ICU stay | Mean 18 days (SD 1.6695) in toothbrushing group and mean 10.3 days (SD 2.6971) in control group | |||
| CHX versus placebo (Koeman 2006) | CHX: 127; Placebo:130 | Mortality
| HR | HR 1.12 (95% CI 0.72 to 1.17)
|
| CHX versus placebo (Meinberg 2012) | CHX group: 28; Placebo group: 24 | Duration of mechanical ventilation | Median days in CHX group 8.5 (interquartile range, 7.3 to 14.7) and median days in placebo group 6 (4 to 12.7) (P = 0.17) | |
| Duration of ICU stay | Median days in CHX group 12 (interquartile range, 9 to 29) and median days in placebo group 11 (5 to 16) (P = 0.36) | |||
| Powered toothbrush + CHX versus CHX alone (Roca Biosca 2011) | Powered toothbrush group: 29; CHX alone group: 32 | Plaque index | Mean in toothbrush group 1.68 and mean in control group 1.91; | |
| Incidence of VAP | OR 0.78 (95% CI 0.36 to 1.68, P = 0.56) | |||
| CHX (once daily or twice daily) versus placebo (Scannapieco 2009) | CHX 1x/day group: 47; CHX 2x/day group: 50; Placebo group: 49 | Plaque index | No difference between the 3 groups (data presented graphically) | |
| Biotene OralBalance versus control (Stefanescu 2013) | Biotene OralBalance group: 20; Control group: 21 | Duration of mechanical ventilation | No difference between groups (P = 0.77) | |
| Adverse events | No significant difference between groups with respect to adverse events in buccal mucosa | |||
| CHX = chlorhexidine; CI = confidence interval; CPIS = Clinical Pulmonary Infection Score; HR = hazard ratio; ICU = intensive care unit; OR = odds ratio; P = probability; SD = standard deviation; VAP = ventilator‐associated pneumonia | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of VAP Show forest plot | 18 | 2451 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.62, 0.91] |
| 1.1 Chlorhexidine solution versus placebo (no t'brushing in either group) | 7 | 1037 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.53, 0.94] |
| 1.2 Chlorhexidine gel versus placebo (no t'brushing in either group) | 5 | 669 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.41, 1.05] |
| 1.3 Chlorhexidine solution versus placebo (t'brushing both groups) | 3 | 405 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.29, 1.63] |
| 1.4 Chlorhexidine gel versus placebo (t'brushing both groups) | 2 | 148 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [0.83, 1.79] |
| 1.5 Chlorhexidine solution versus usual care (some t'brushing in each group) | 1 | 192 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.56, 1.02] |
| 2 Mortality Show forest plot | 14 | 2014 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.96, 1.23] |
| 2.1 Chlorhexidine solution versus placebo (no t'brushing in either group) | 6 | 973 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.88, 1.39] |
| 2.2 Chlorhexidine gel versus placebo (no t'brushing in either group) | 4 | 414 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.59, 1.50] |
| 2.3 Chlorhexidine solution versus placebo (t'brushing both groups) | 3 | 479 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.77, 1.41] |
| 2.4 Chlorhexidine gel versus placebo (t'brushing both groups) | 2 | 148 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.59, 1.68] |
| 3 Duration of ventilation (days) Show forest plot | 5 | 800 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐1.73, 1.55] |
| 3.1 Chlorhexidine solution versus placebo (no t'brushing in either group) | 2 | 183 | Mean Difference (IV, Random, 95% CI) | ‐1.34 [‐3.70, 1.03] |
| 3.2 Chlorhexidine gel versus placebo (no t'brushing in either group) | 3 | 543 | Mean Difference (IV, Random, 95% CI) | 1.26 [‐0.78, 3.30] |
| 3.3 Chlorhexidine solution versus placebo (t'brushing both groups) | 1 | 74 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐4.20, 1.60] |
| 4 Duration of ICU stay (days) Show forest plot | 6 | 833 | Mean Difference (IV, Random, 95% CI) | 0.21 [‐1.48, 1.89] |
| 4.1 Chlorhexidine solution versus placebo (no t'brushing in either group) | 2 | 194 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐4.07, 1.62] |
| 4.2 Chlorhexidine gel versus placebo (no t'brushing in either group) | 3 | 543 | Mean Difference (IV, Random, 95% CI) | 0.53 [‐1.56, 2.61] |
| 4.3 Chlorhexidine gel versus placebo (t'brushing both groups) | 1 | 96 | Mean Difference (IV, Random, 95% CI) | 5.0 [‐2.20, 12.20] |
| 5 Duration of systemic antibiotic therapy (days) Show forest plot | 2 | 374 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [‐0.85, 1.30] |
| 5.1 Chlorhexidine gel versus placebo (no t'brushing in either group) | 1 | 228 | Mean Difference (IV, Fixed, 95% CI) | ‐1.18 [‐3.41, 1.05] |
| 5.2 Chlorhexidine solution versus placebo (t'brushing both groups) | 1 | 146 | Mean Difference (IV, Fixed, 95% CI) | 0.65 [‐0.58, 1.88] |
| 6 Plaque index Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 7.1 Reversible mild irritation of oral mucosa | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of VAP Show forest plot | 5 | 889 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.44, 1.09] |
| 1.1 Powered toothbrush + usual care (± CHX) versus usual care (± CHX) | 2 | 200 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.16, 1.53] |
| 1.2 Toothbrush + CHX versus CHX alone | 1 | 436 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.51, 1.54] |
| 1.3 Toothbrush (+ some CHX) versus no toothbrush (+ some CHX) | 1 | 192 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.78, 1.40] |
| 1.4 Toothbrush + povidone iodine versus povidone iodine alone | 1 | 61 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.13, 0.98] |
| 2 Mortality Show forest plot | 5 | 889 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.70, 1.09] |
| 2.1 Powered toothbrush + usual care versus usual care | 2 | 200 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.17, 9.91] |
| 2.2 Toothbrush + CHX versus CHX alone | 2 | 528 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.69, 1.17] |
| 2.3 Toothbrush alone versus no treatment | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.51, 2.60] |
| 2.4 Toothbrush + povidone iodine versus povidone iodine alone | 1 | 61 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.15, 2.22] |
| 3 Duration of ventilation (days) Show forest plot | 3 | 644 | Mean Difference (IV, Fixed, 95% CI) | ‐0.11 [‐0.90, 0.68] |
| 3.1 Toothbrush + CHX versus CHX alone | 2 | 583 | Mean Difference (IV, Fixed, 95% CI) | ‐0.85 [‐2.43, 0.73] |
| 3.2 Toothbrush + povidone iodine versus povidone iodine alone | 1 | 61 | Mean Difference (IV, Fixed, 95% CI) | 0.13 [‐0.78, 1.04] |
| 4 Duration of ICU stay (days) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Toothbrush + CHX versus CHX alone | 2 | 583 | Mean Difference (IV, Fixed, 95% CI) | ‐1.82 [‐3.95, 0.32] |
| 5 Plaque score Show forest plot | 1 | Std. Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1 Powered toothbrush versus usual care | 1 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of VAP Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Powered t'brush + comp oral care versus manual t'brush + std oral care | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Mortality Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Powered t'brush + comp oral care versus manual t'brush + std oral care | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Duration of ventilation (days) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Powered t'brush + comp oral care versus manual t'brush + std oral care | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Duration of ICU stay (days) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Powered t'brush + comp oral care versus manual t'brush + std oral care | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of VAP Show forest plot | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Povidone iodine versus saline/placebo | 3 | 356 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.50, 0.95] |
| 1.2 Povidone iodine versus usual care | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.06, 0.63] |
| 1.3 Saline rinse versus saline swab | 4 | 488 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.37, 0.62] |
| 1.4 Saline rinse versus usual care | 2 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.39, 0.91] |
| 1.5 Saline rinse + swab versus saline swab (usual care) | 2 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.23, 0.72] |
| 1.6 Bicarbonate rinse versus water | 2 | 425 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.57, 3.82] |
| 1.7 Triclosan rinse versus saline | 1 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.71, 1.12] |
| 1.8 Furacilin versus povidone iodine | 1 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.23, 1.04] |
| 1.9 Furacilin versus saline | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.14, 0.58] |
| 1.10 Listerine versus water | 1 | 265 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.36, 3.28] |
| 1.11 Listerine versus bicarbonate | 1 | 260 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.35, 3.16] |
| 1.12 Biotene versus control | 1 | 41 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.28, 1.41] |
| 2 Mortality Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Povidone iodine versus saline/placebo | 2 | 217 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.66, 1.50] |
| 2.2 Povidone iodine versus usual care | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.31, 2.40] |
| 2.3 Saline rinse versus saline swab | 2 | 270 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.12, 0.69] |
| 2.4 Saline rinse + swab versus saline swab (usual care) | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.11, 1.28] |
| 2.5 Saline rinse versus usual care | 2 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.87, 1.39] |
| 2.6 Biotene versus control | 1 | 41 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.13, 3.76] |
| 3 Duration of ventilation (days) Show forest plot | 6 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 Povidone iodine versus saline | 1 | 67 | Mean Difference (IV, Fixed, 95% CI) | ‐1.0 [‐4.36, 2.36] |
| 3.2 Povidone iodine versus usual care | 1 | 67 | Mean Difference (IV, Fixed, 95% CI) | ‐3.0 [‐7.67, 1.67] |
| 3.3 Saline rinse versus usual care | 2 | 324 | Mean Difference (IV, Fixed, 95% CI) | ‐0.40 [‐2.55, 1.75] |
| 3.4 Saline rinse + swab versus saline swab | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | ‐3.91 [‐5.85, ‐1.97] |
| 3.5 Saline rinse versus saline swab | 2 | 176 | Mean Difference (IV, Fixed, 95% CI) | ‐6.83 [‐8.94, ‐4.72] |
| 3.6 Triclosan rinse versus saline | 1 | 324 | Mean Difference (IV, Fixed, 95% CI) | ‐5.24 [‐5.64, ‐4.84] |
| 4 Duration of ICU stay (days) Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Povidone iodine versus saline/placebo | 2 | 217 | Mean Difference (IV, Fixed, 95% CI) | ‐0.35 [‐3.90, 3.21] |
| 4.2 Povidone iodine versus usual care | 1 | 67 | Mean Difference (IV, Fixed, 95% CI) | ‐4.0 [‐10.99, 2.99] |
| 4.3 Saline rinse versus usual care | 2 | 324 | Mean Difference (IV, Fixed, 95% CI) | ‐1.17 [‐3.95, 1.60] |
| 4.4 Triclosan rinse versus saline | 1 | 324 | Mean Difference (IV, Fixed, 95% CI) | ‐4.97 [‐5.55, ‐4.39] |
| 5 Number of participants treated with systemic antiboitics Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 6 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Acute respiratory distress syndrome | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.0 [0.62, 195.61] |
| 6.2 Agitation and/or hypertension | 1 | 167 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.12, 1.86] |
| 6.3 Epistaxis | 1 | 167 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.01, 2.63] |
| 6.4 Oxygen desaturation | 1 | 167 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.06, 15.17] |
| 6.5 Aspiration | 1 | 167 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.90 [0.12, 70.07] |
