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Ventilator-associated pneumonia (VAP) is one of the most frequently encountered causes of hospital-acquired infection and results in high morbidity among intubated patients. Few trials have investigated the efficacy of oral care with chlorhexidine (CHX) mouthwash for the prevention of VAP in the paediatric population.
The objective of this study was to assess the efficacy of CHX mouthwash in the prevention of VAP and to determine risk factors for VAP in children aged 1 month to 18 years admitted to the paediatric intensive care unit (PICU).
This was a prospective, randomised, controlled, double-blind trial performed in the PICU. Patients were randomised into two groups receiving CHX (0.12%) (n = 88) or placebo (0.9% NaCl) (n = 86) and were followed up for VAP development. The main outcome measures were incidence of VAP, duration of hospital stay, duration of PICU stay, duration of ventilation, mortality, and the characteristics of organisms isolated in cases with VAP.
No difference was observed in the incidence of VAP and the type and distribution of organisms in the two groups (p > 0.05). In the CHX and placebo groups, we identified 21 and 22 patients with VAP, respectively. Incidence per 1000 ventilation days was 29.5 events in the CHX group and 35.1 events in the placebo group. Gram-negative bacteria were most common (71.4% in CHX vs. 54.5% in placebo). The use of 0.12% CHX did not influence hospital stay, PICU stay, ventilation, and mortality (p > 0.05). Multivariate analysis identified duration of ventilation as the only independent risk factor for VAP (p = 0.001).
The use of 0.12% CHX did not reduce VAP frequency among critically ill children. The only factor that increased VAP frequency was longer duration on ventilation. It appears that low concentration of CHX is not effective for VAP prevention, especially in the presence of multiresistant bacteria.
Ventilator-associated pneumonia (VAP), as the name suggests, is a type of nosocomial pneumonia that develops after mechanical ventilation (MV) and is a serious problem among patients in the intensive care unit (ICU).
Many factors have been associated with VAP risk in children admitted to the PICU, including genetic syndromes, reintubation need, self-extubation, steroid use, bloodstream infection, prior antibiotic therapy, and bronchoscopy.
Currently, the Centres for Disease Control and Prevention (CDC) recommends oral hygiene with 0.12% chlorhexidine (CHX) in the perioperative period of cardiac surgery, but there are no recommendations for its routine use in the prevention of nosocomial pneumonia in critically ill patients.
For the paediatric population, the Institute for Healthcare Improvement (INH) in its ‘100.000 lives’ campaign recommends oral hygiene policy to be incorporated as a component of ventilator care bundles – especially with the use of CHX for children older than 2 months.
A meta-analysis including critically ill children identified that care bundles were effective in reducing VAP rates; however, the study could not determine which elements of the care bundles were most effective.
The mixed results observed in most adult trials and the lack of sufficient studies on the use of CHX for VAP prevention in children prompted the conduct of this randomised controlled trial (RCT) where the aim was to determine whether CHX mouthwash would reduce VAP incidence among children on MV. The secondary objectives of the study were to determine risk factors associated with VAP development, to identify the effects of VAP on the clinical outcome of patients, and to assess whether the oral care protocol influenced microorganisms responsible for VAP.
2.1 Study setting and population
This was a single-centred, randomised, placebo-controlled double-blind clinical trial (Registration number; NCT04527276) conducted in our PICU between February 2019 and January 2020. We designed and conducted the trial in accordance with The Consolidated Standards of Reporting Trials (CONSORT) Statement.
The study was designed as a parallel RCT, and informed consent was obtained from each patient's legally authorised representative. The study protocol was approved by the local ethics committee (Registration number: 2018/0346).
Consecutive paediatric patients aged 1 month to 18 years who required MV for at least 48 h were included in the study within 24 h of intubation and initiation of MV. Exclusion criteria were the following: did not consent to participate in the study, known hypersensitivity to CHX, presence of tracheotomy, undergoing MV for less than 48 h, MV for more than 24 h before PICU admission, readmission to PICU, suspected or diagnosed immunodeficiency, history of malignant disease (active or at remission), diagnosed with oral mucositis or periodontal disease, diagnosed with chronic pulmonary and/or cardiac diseases, severe oral/facial trauma, and using immunosuppressive drugs (such as corticosteroids). We included patients with preexisting pneumonia as they remain susceptible to new infections during ventilation and contribute to the burden of patients with nosocomial pneumonia.
All patients were consecutively randomised (1:1) to receive either 0.12% CHX rinse solution or placebo applications using a computer-generated balanced randomisation table. Unlabelled standardised tubes containing placebo or 0.12% CHX were serially numbered and bagged for each patient with respect to randomisation. The preparation of bagged treatments and their numbering were done by personnel not involved in the study. The placebo rinse contained 0.9% NaCl (normal saline [NS]) and was identical to the 0.12% CHX rinse solution with respect to appearance, consistency, and smell. The patients, physicians, outcome assessors, and data analysts were blinded to the intervention. Randomisation and numbering of the tubes were done by personnel not involved in the study, and the allocation sequence remained concealed through the entire duration of the study.
The standard care protocols in the PICU were as follows: semirecumbent body position to maintain head elevation ≥30°, hand hygiene, replacement of ventilator circuits with malfunction, periodic verification of intracuff pressure every 8 h to maintain a pressure of 25 cm H2O,
assessment of nasogastric tubes, measurment of residual gastric volume every 6 h, administration of stress ulcer prophylaxis, aseptic endotracheal tube suctioning, and sedation monitoring/evaluation.
2.2 The oral care procedure
Before beginning the study, nurses received a training program for VAP prevention, procedure/technique for oral hygiene, and use of oral mucosa assessment score under supervision of paediatric residents. They were trained in the method of application of solutions according to CDC guidelines to ensure uniform treatments. Nurses were blinded and were unaware of whether they were applying CHX or NS during the study. Endotracheal suctioning was performed via open suctioning using fresh suction catheters in each application. We used passive humidifiers with disposable ventilator circuits. Selective decontamination of the digestive tract and continuous aspiration of subglottal contents were not performed in any of the patients.
Both groups (0.12% CHX and placebo) received treatments at 4-h intervals; nurses used the whole content of the 5-ml tubes. The rationale for using lower concentration of CHX was to reduce the possibility of side effects, such as mucosal erosion, while maintaining a comparable therapeutic effect.
In both groups, nurses performed oral cleansing as follows: first, the endotracheal cuff pressure was tested to ensure proper pressure before oral care, and oropharyngeal secretions were aspirated to remove any accumulated secretions. Then, rinse solutions were applied to cleanse all areas of the oral cavity, including the anterior and posterior pharynx, gums, teeth, tongue, and buccal mucosa, with standard disposable applicator (foam swab), followed by removal of excess solution from the mouth by a sterile catheter. Strict hand hygiene was ensured during the procedures. The period of application was from the day of intubation until extubation. Presence of any adverse effect of the solutions was recorded. The Beck Oral Assessment Scale (BOAS) was used twice daily to evaluate the oral health of both groups. The BOAS has five subdimensions and examines the lips, gums, oral mucosa, tongue, teeth, and saliva. The total score from this tool ranges from 5 to 20; a lower score indicates better oral health and need for fewer interventions, while a higher score indicates need for more frequent intervention.
The validity of the BOAS score in the PICU setting has not been demonstrated, and research is needed to test the efficacy and efficiency of this instrument in practice; nonetheless, we used the BOAS to be able to standardise oral assessment and guide nurses in providing oral interventions.
Beside education of nursing staff before study initiation, the research group periodically observed PICU staff to confirm protocol adherence. The BOAS forms were completed by PICU nurses and monitored by residents, adding another level to ensure adherence to intervention and study design.
For the diagnosis of VAP, the patient was required to have received at least 48 h of MV and to develop new and persistent radiographic evidence of focal infiltrates at 48 h or later, after the initiation of MV.
Diagnosis of pneumonia at admission was based on clinical and radiological features. In patients with underlying pneumonia, worsening of the clinical and radiological findings according to the CDC criteria was used to suspect VAP.
Briefly, the chest radiographs of patients must have shown at least one of the following abnormalities: new or progressive and persistent infiltrate, consolidation, cavitation, and/or pneumatoceles (in infants ≤1 year of age). In addition to abnormal chest radiographs, the patient should exhibit fever (38° C) with no other recognised cause or leukopenia (<4000 white blood cells/mm3) or leucocytosis (≥12,000 WBC/mm3), with the presence of at least two of the following criteria: new onset of purulent sputum, change in the properties of sputum, increased respiratory secretion or increased suctioning requirements, new onset or worsening cough, dyspnoea or tachypnoea, rales or bronchial breath sounds, worsening gas exchange (oxygen desaturations [e.g., PaO2/FiO2 levels of ≤240], increased oxygen requirements, or increased ventilation demand). The aforementioned criteria can be used to diagnose VAP in children; however, specific diagnostic criteria for VAP have been developed for infants ≤1 year of age and children >1 and ≤ 12 years of age.
All VAP diagnoses were confirmed by clinical microbiologists who were blinded to the study. They received the patient's deidentified clinical information and microbiological analysis results only and verified diagnosis based on objective VAP criteria.
The frequency of VAP was defined as the number of events per 1000 ventilator days. VAP incidence was calculated as follows: (The number of cases with VAP/overall number of days with ventilator) x 1000 = VAP per 1000 ventilator days.
Microbiological analyses of endotracheal aspirate samples were performed in all patients participating in the study. They were collected on the 1st and 3rd days of MV, on suspicion of VAP, in any clinical indication, and before changing antibiotic therapy or at the initiation of antibiotic therapy. As VAP was defined as pneumonia occurring >48 h after intubation and MV, this was the time frame after which a change in the clinical and radiological findings was used to suspect VAP, and the presence of a different microbial growth on tracheal aspirate cultures was used to confirm the diagnosis. Samples were processed according to standard microbiological procedures and analysed semiquantitatively. The presence of >10,000 colony-forming units (CFUs) per mL were deemed significant.
Microbial cultures of tracheal aspirates were performed routinely by the hospital's laboratory attendant who had no knowledge of the study design and patients’ treatments.
2.5 Primary and secondary outcome measures
Demographic data, body mass index, and clinical information, including primary diagnosis at admission, presence of pneumonia at admission, presence of other infections at admission, antibiotic/antifungal use, and enteral feeding (with time of initiation; corresponding to the start of enteral nutrition after MV sustained for at least 24 h) were recorded. Severity of illness was assessed by using the Pediatric Risk of Mortality III (PRISM III) score, and the % predictive death rate (% PDR) was also calculated within 24 h of PICU admission.
Antibiotic/antifungal use was defined in the presence of an episode of clinical or suspected infection requiring treatment administration.
The primary outcome measure was incidence of VAP along with its characteristics (early- or late-onset VAP and day of VAP diagnosis) in each group. Secondary outcome measures were risk factors for VAP development, the type of organism cultured on the endotracheal aspirate, duration of PICU stay, duration of hospital stay, duration of MV, and PICU survival rate.
The patients were followed up for a period of 14 days starting from the initiation of intubation (enrolment), during which VAP development was assessed. Patients who were extubated earlier than 14 days were followed up for 48 h after extubation.
Based on the estimated frequency of VAP in our PICU (35%) and an expected 50% reduction in the frequency of VAP, the sample size was calculated as 132 with 85% power and 5% α error. Sample size was calculated using the G∗Power, version 3.1.6, software (Heinrich-Heine-Universität Düsseldorf).
2.7 Statistical analysis
The SPSS Statistics for Windows, version 17.0 (Chicago, SPSS Inc.) software for the Windows operating system was used to perform statistical analysis. Baseline demographic and clinical characteristics were compared, and the primary and secondary outcomes were analysed with regard to the two treatment groups. Baseline characteristics were compared by the intention-to-treat (ITT) analysis. Descriptive statistics were used to summarise the characteristics of the studied population. Categorical variables are given as number (count) and percentages, and continuous variables are given as median and interquartile range (IQR) (25%–75%). As continuous variables of the independent groups were not distributed normally, the Mann–Whitney U test was used for comparisons. Chi-square tests were used to compare the proportions of categorical variables between groups. Independent risk factors that could influence the incidence of VAP were determined by using multivariate logistic regression analysis – backward conditional method. Independent variables were selected from variables that showed p < 0.10 significance level in univariate analysis. Before the analysis, we have selected only one factor from the variables which show correlation coefficient higher than 0.70. Between-groups comparisons of the survival times were performed with the log-rank test. Kaplan–Meier analyses (log-rank tests) were used to calculate hazard ratio (HR) for microorganisms identified in tracheal aspirate samples. Any p-value <0.05 was considered to demonstrate statistical significance.
Of the 276 patients admitted to the PICU during the study period, 232 were eligible for enrolment. The exclusion of 58 patients was performed according to aforementioned criteria, illustrated in Fig. 1. Of the 174 patients enrolled and randomised, 86 received NS and 88 CHX. After completion of the study, there was a total of 70 patients in the CHX group and 68 patients in the placebo group for VAP measurements (Fig. 1). Eighteen patients in each group were excluded from the protocol owing to being intubated for duration shorter than 48 h or having died before 48 h of MV; all of these patients were included in the ITT analysis. No patients were withdrawn from the protocol owing to adverse effects of MV.
Baseline data of the patients that were randomised for inclusion (ITT analysis), including demographic clinical variables, and BOAS scores were found to be comparable in the CHX and placebo groups (Table 1). VAP was diagnosed in 43 patients, 21 of whom were in the CHX group (30%) and 22 in the placebo group (32.4%). The VAP incidence rate was found to be 29.5/1000 ventilator days for the CHX group and 35.1/1000 ventilator days for the placebo group. Comparison showed that the groups were similar in this regard (p = 0.63) (Table 2). The median day of VAP diagnosis in the CHX group was 5 (IQR: 3.5–7.5) days as compared with 5.5 (IQR: 3–10) days in the placebo group. Onset time for VAP (early or late) did not differ between the study groups (p = 0.765) (Table 2).
Table 1Baseline demographics and clinical characteristics by intention-to-treat analysis.
The distribution of organisms causing VAP is detailed in Table 3. There were no significant differences in terms of the rate and the type of organisms (p > 0.05). According to comparisons of groups with log-rank test, compared with placebo, the CHX group had a daily hazard ratio of 1.374 (95% confidence interval [CI]: 0.63–2.9; p = 0.424) for gram-negative organisms and 0.41 (95% CI: 0.08–2.10; p = 0.290) for gram-positive organisms, and the difference was nonsignificant (Fig. 2). Furthermore, no significant differences were observed in other secondary outcomes, including duration of PICU stay, duration of hospital stay, duration of ventilation, and PICU survival rate (Table 3).
Table 3Secondary outcome data of the patients from both CHX and placebo groups.
Determination of risk factors for VAP development was performed by univariate regression analysis (Table 4). Being aged younger than 12 months (odds ratio [OR]: 2.10, 95% CI: 1.140–3.381; p = 0.017), late initiation of enteral nutrition (OR: 1.25, 95% CI: 1.068–1.481; p = 0.006), longer duration of PICU stay (OR: 1.02, 95% CI: 1.01–1.03; p < 0.001), longer duration of hospital stay (OR: 1.02, 95% CI: 1.00–1.03; p < 0.001), and longer duration of ventilation (OR: 1.03, 95% CI: 1.01–1.05; p < 0.01) were determined to be associated with increased risk of VAP development. The mortality rate was 7% in patients who developed VAP, while the mortality rate was 12.6% in patients without VAP (OR: 0.55, 95% CI: 0,17–1,78). p = 0.322). No association was found between VAP and PICU mortality (data not shown).
Table 4Determination of risk factors on VAP development by univariate regression analysis.
Results of multivariate regression analysis are presented in Table 5. The duration of ventilation was found to be the only independent risk factor associated with VAP development, with an OR of 0.89 (95% CI: 0.84–0.95; p = 0.001).
Table 5Multivariate analysis of factors affecting VAP development (backward conditional method – step 3).
95.0% CI for Exp (B)
Duration of ventilation (d)
OR: odds ratio; CI: confidence interval.
Other variables included in the model, chlorhexidine group (p = 0.557), and time to start enteral nutrition (p = 0.484) were found to be nonsignificant.
This study primarily evaluated the efficacy of oral care with 0.12% CHX solution in reducing the incidence of VAP. We demonstrated no signiﬁcant difference in VAP development and secondary outcomes (organisms identified in tracheal aspirate culture, PICU stay, hospital stay, duration of ventilation, and PICU mortality) between the two groups, indicating that CHX had no superiority compared with NS in reducing VAP incidence.
There are no universally accepted guidelines on the methods of optimal oral care in the PICU, and thus, there is little evidence to support the use of various measures in the prevention of VAP, especially for the paediatric population. Different concentrations of CHX have been used for the prevention of VAP in adults. Studies utilising CHX concentrations of 0.2% failed to demonstrate significant reduction in VAP rates,
Owing to the absence of consensus in adult studies regarding effective CHX concentration, and also because the CDC and INH recommend 0.12% CHX for VAP prevention, we aimed to evaluate the efficacy of 0.12% CHX to ensure that adverse effects would be avoided. Also, we preferred the rinse form of CHX to enable double-blinded randomisation.
Deviating from previous studies in adult ICUs, our study was carried out in critically ill children admitted to the PICU. The paediatric population has an important distinction from adult subjects, as their oral cavities are smaller, less accessible, and also less likely to tolerate extended manoeuvres in this area (such as cleansing of the oral mucosa by an adult). However, standard oral care given to both groups resulted in equally good oral assessment scores in our study. The BOAS value reflects the condition of the oral cavity and can be used to guide oral care in critically ill patients.
Research is needed to test its validity in various populations, including patients admitted to the PICU; however, assessment of the oral mucosal score before oral care is a good practical recommendation with no apparent drawback.
however, it is evident that these outcomes are associated with whole care bundle being applied and therefore cannot be directly attributed to oral care alone. There are only a few studies evaluating the efficacy of oral care with CHX in this population.
found that the use of 0.12% CHX did not modify VAP incidence in mechanically ventilated children, demonstrating that lower CHX concentration may not be effective in the prevention of VAP. This is supported by the suggestion that CHX only has bacteriostatic action at lower concentrations, while it may be bactericidal at higher concentrations.
and a paediatric cohort study in which preintervention and postintervention data after the initiation of a VAP prevention bundle (using 2% CHX) were compared both reported a lack of significant reduction in VAP rates in the PICU.
Similarly, our study did not reveal a significant difference in the incidence or timing of VAP development in the two study groups. Our result may be attributable to the critical health conditions of children in the study population. Previously established beneficial effects of CHX in adult patients may be associated with the inclusion of patients who were undergoing elective procedures, who were often in much better clinical statuses than critically ill children,
Grap et al. tested 0.12% CHX on VAP prevention and demonstrated that single application was effective in early-onset VAP and for pathogens such as Staphylococcus aureus and Streptococcus pneumoniae, but higher concentration was needed for gram-negative organisms.
This was supported by a trial evaluating 0.12% CHX in children, which concluded that the effect of CHX on VAP prevention was limited because the predominant microorganisms were not gram-positive bacteria.
In the present study, although most children had multiresistant gram-negative bacteria, there was no significant difference between groups in terms of the distribution of organisms. Our study does not provide any evidence regarding efficacy of CHX in gram-negative bacteria. The outer membrane of gram-negative bacteria may act as a barrier, preventing CHX entry, and efflux proteins could facilitate resistance.
The use of CHX at low concentration along with the isolation of resistant bacteria and the fact that all patients had severe illness are factors that could be associated with the lack of differences in our study. We believe more studies using higher CHX concentrations are necessary to test the effects of CHX on multiresistant gram-negative organisms, especially in critically ill children.
Regarding secondary outcomes (duration of PICU stay, hospital stay, duration of ventilation, and PICU mortality), there were no significant differences between the CHX and placebo groups, as demonstrated by ITT analysis. Our results support previous paediatric studies that reported similar outcomes.
Some of the known risk factors for the development of VAP are use of opiates for sedation, sustained neuromuscular blockade, use of enteral nutrition, previous antibiotic therapy, the technique used for endotracheal suctioning, reintubation, ventilator circuit changes, gastroesophageal reflux, subglottal or tracheal stenosis, being a young infant or being older than 10 years, and having trauma or surgical problems.
Children admitted to the PICU have a number of distinguishing characteristics that may increase the risk of VAP. Compared with adult ICU patients, children have risks such as the use of uncuffed endotracheal tube ( ETT) or nasal ETT , open circuit suctioning, saline lavage during suctioning, and novel oral properties due to continuing dental development.
Late initiation of enteral nutrition, longer PICU stay, longer hospital stay, and longer duration of MV were found to be risk factors for VAP development by univariate analysis. Similar results were found by Elward et al.,
the risk for mortality can be reduced by general infection prevention measures, prevention of cross-transmission, policy of restricted antimicrobial use, early recognition, and prompt initiation of empirical antimicrobial therapy.
In the present study, we did not find any relationship between VAP development and PICU mortality. This finding is presumably related to early diagnosis and swift use of appropriate antibiotics with respect to antibiotherapy guidelines.
At this point, we believe it is critical to note that there are studies that suggest the use of CHX mouthwash may increase the risk of mortality in adult ICUs,
Although this may appear controversial and, therefore, has led to debates on this topic, a recent study has suggested that mouthwashes could alter the nitric oxide homoeostasis of the oral region owing to eradication of the majority of oral bacterial flora, ultimately causing a nitric oxide–deficient condition.
A reduction in nitric oxide bioavailability may have various injurious effects and has been associated with the occurrence or worsening of high-mortality pathologies, including atherosclerosis, diabetes, and sepsis. The loss of normal physiological characteristics and natural oral flora may result in adverse effects rather than preventive effects. Thus, we believe readers should be aware of this relationship when considering the use of mouthwash (not only CHX-based solutions) in the PICU setting, especially when designing future studies on this topic.
Analysis of independent risk factors revealed longer duration of ventilation to be the sole factor that was significant for VAP development in our group of patients. Similar results have been found in previous studies.
There were some limitations in the present study. First, heterogeneity of the patient population can be considered as an important factor; however, this feature undoubtedly reflects the characteristics of the PICU setting. Second, it is very possible that the administration of CHX rinse significantly alters culture results with tracheal aspirate samples, owing to its direct effects on the flora of the oropharynx. Even though such effects have not been found to be at significant levels, we did not determine the effect of CHX on oropharyngeal colonisation. Additionally, the CHX concentration in aspirated samples was not assessed. Third, the placebo group received 0.9% NaCl, and this solution is known to cause dryness in the oral mucosa, especially with prolonged use; thus, the placebo application may have been effective on oral characteristics, even though it was highly unlikely to have an impact with the frequency of use during the study. Fourth, even though we strictly adhered to routine MV care, the frequency of aspiration in our patients (which may influence VAP rate) was not analysed. Intracuff pressure was checked every 8 h, but some guidelines have indeed suggested more frequent verification of cuff pressure.
Finally, we did not test the sensitivity of organisms to CHX. Doing so may have contributed to a better understanding of the role of CHX and its effect on oral pathogens.
In spite of these limitations, we believe our study has several strengths. The research was carried out among intubated children in a PICU, a setting where evidence is lacking on this topic. We were able to achieve effective randomisation, blinding, and follow-up. We also used strict and objective criteria for the diagnosis of VAP. A considerable sample size capable of statistical discrimination was achieved in this single-centred study. Although the heterogeneity of the PICU population is without doubt a limitation for reliable analysis in specific patient groups, it may also be seen as a strength that enables the evaluation of the generalised role of CHX in patients on MV. Furthermore, the adherence to standard protocols provided good control of the PICU environment and patient features, which facilitates better observation of group characteristics.
We found that 0.12% CHX mouthwash did not prevent the development of VAP and did not affect the type of organism isolated in the tracheal aspirate samples of children on MV. Although it has been well established that ventilator care bundles are effective in preventing VAP, we conclude that use of CHX at low concentration has no benefit in terms of VAP development in critically ill children with multiresistant bacteria. To elucidate the possible role of CHX mouthwash for prevention of VAP in critically ill children, we need more evidence obtained from larger trials, preferably evaluating different concentrations and longer or more frequent interventions. With these data, we recommend implementation of ventilator care bundles as the primary measure to prevent VAP. Following routine mouth care policy with individualised oral care approach could also contribute to better overall care in the PICU. Since longer duration on MV was found to be the only risk factor for VAP development in the present study, it is of utmost important to perform careful evaluation of patients every day to determine the need for MV support and wean patients when possible.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Zeynep Karakaya: Methodology, statistical analysis, Writing – original draft, responsible for the overall content, Writing – review & editing. Muhterem Duyu: Methodology, quality assessment, contributed to the writing of the manuscript, revised the manuscript for important intellectual content, Writing – review & editing. Meryem Nihal Yersel: Data extraction, quality assessment, Writing – review & editing.
Conflict of Interest
The authors declare that they have no conflicts of interest.
The pathogenesis of ventilator-associated pneumonia: its relevance to developing effective strategies for prevention.