The Importance of Oral Hygiene in Prevention of Ventilator-Associated Pneumonia (VAP): A Literature Review

Abstract

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection reported among mechanically ventilated patients. VAP is an emerging concept and remains a significant clinical problem for critically ill patients. Although VAP is often preventable, its effects on morbidity, mortality, length of hospital stay, and cost are enormous. VAP is not a new diagnosis, but education and research on the prevention of this serious problem are still continuing. Oropharyngeal colonization is the main risk factor for the development of VAP. Oral health can be compromised by critical illness and mechanical ventilation. It can also be influenced by nursing attentions. Therefore, education and focus on suitable oral care strategies are necessary. Moreover, nursing research to define the best process for all patients in ICU is needed. Whether nursing actions decrease VAP rates remains an empirical question that requires more research since no valid and reliable survey could be found in the literature for oral care practices on orally intubated critically ill patients. An oral care survey for orally intubated patients is hence essential to determine the best existing practices. Many studies have thus attempted to determine the effects of this intervention on the incidence of VAP. The present study aimed to review the literature focusing on oral hygiene in prevention of VAP. [PUBLICATION ABSTRACT]

Headnote

Abstract

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection reported among mechanically ventilated patients. VAP is an emerging concept and remains a significant clinical problem for critically ill patients. Although VAP is often preventable, its effects on morbidity, mortality, length of hospital stay, and cost are enormous. VAP is not a new diagnosis, but education and research on the prevention of this serious problem are still continuing. Oropharyngeal colonization is the main risk factor for the development of VAP. Oral health can be compromised by critical illness and mechanical ventilation. It can also be influenced by nursing attentions. Therefore, education and focus on suitable oral care strategies are necessary. Moreover, nursing research to define the best process for all patients in ICU is needed. Whether nursing actions decrease VAP rates remains an empirical question that requires more research since no valid and reliable survey could be found in the literature for oral care practices on orally intubated critically ill patients. An oral care survey for orally intubated patients is hence essential to determine the best existing practices. Many studies have thus attempted to determine the effects of this intervention on the incidence of VAP. The present study aimed to review the literature focusing on oral hygiene in prevention of VAP.

Key-words: Evidence-Based Practice, Oral Hygiene, Pneumonia, Ventilator-Associated.

Introduction

Pathogenic oral microflora plays an important role in several systemic diseases including cardiovascular diseases, endocarditis, respiratory problems, bacteremia, and ventilator-associated pneumonia (VAP) (Seymour & Whitworth 2002, Munro & Grap 2004). Within this group of diseases, nosocomial pneumonia has been increasingly studied and the relationship between VAP and microorganisms from the oral cavity has been progressively recognized (Taraghi et al., 2011). VAP is a form of nosocomial pneumonia that happens in patients receiving mechanical ventilation for longer than 48 hours (Augustyn, 2007). According to the most recent National Healthcare Safety Network report, in 1749 hospitals in the US, the mean incidence of VAP was 2 cases per 1000 ventilator days in 2009 (Dudeck et al., 2011). VAP was also responsible for half of antibiotic prescriptions in mechanically ventilated patients (Ashraf & Ostrosky-Zeichner 2012). The risk of developing VAP increases with the need for mechanical ventilation. VAP not only prolongs the length of hospital stay but also strikingly raises hospital costs. Moreover, its estimated mortality rate has been between 20% and 70% (Warren et al. 2003, Cason et al. 2007, Beraldo & Andrade 2008, Jamaati et al., 2010, Perrie et al., 2011, Coppadoro et al., 2012).

Occurrence of nosocomial infections is openly related to the adequacy of staff. Considering the importance of nursing care in VAP prevention and the great lack of nurses and the resultant increase in the number of less experienced nurses in the intensive care unit (ICU), education on VAP prevention is vital (Zack et al., 2002, Labeau et al., 2007, Ross & Crumpler 2007, Labeau et al., 2008). Nurses need to understand the pathophysiology of VAP, risk factors for this type of pneumonia, and policies that may prevent the disease. The purpose of this literature review was to highlight oral care interventions in prevention of VAP by nurses.

Epidemiology

However, the real incidence of VAP is difficult to assess but its incidence that reported in the literature ranges from 10 to 20% (Safdar et al., 2005, Coppadoro et al., 2012). Historically, surgical ICUs have had higher rates of VAP compared to medical ICUs (Craven, 2000).

Pathophysiology and etiology

According to the onset, VAP can be divided into 2 types of early and late. Early onset VAP occurs 48 to 96 hours after intubation and is associated with antibiotic-susceptible organisms. Late-onset VAP occurs more than 96 hours after intubation and is associated with antibiotic resistant organisms such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter species, and Enterobacter species. The latter type of VAP is accompanied by powerful pathogens and consequently has higher mortality (Augustyn, 2007).

The pathophysiology of VAP involves 2 main routes: colonization of the respiratory and digestive tracts and microaspiration of discharges of the upper and lower portions of the airway (Taraghi et al., 2011). Bacterial migration of the lungs can be caused by spread of organisms from many different sources including the oropharynx, sinus cavities, nares, dental plaque, gastrointestinal tract, patient to patient contact, and the ventilator circuit (Kunis & Puntillo 2003). Inhalation of colonized bacteria from any of these sources can cause an active host response and, finally, VAP (Taraghi et al., 2011).

Risk Factors

The risk factors for VAP can be divided into 3 classifications, i.e. host-related, device-related, and personnel-related risk factors (Table 1) (Langer et al., 1989, Cook et al., 1998, Drakulovic et al., 1999, Akça et al., 2000, Arozullah et al., 2001, Pawar et al. 2003, Apostolopoulou et al., 2003, Kobashi & Matsushima 2003, Bullock et al., 2004, Alp et al., 2004, Grap et al., 2012, Tsai et al., 2012).

The presence of an endotracheal tube (ETT) inhibits normal coughing, normal swallowing, and the protection of the trachea contact by epiglottis closure. As respiratory pathogens continue to flourish within their protective plaque structures, they make their way into the subglottic pool and are placed around the ETT cuff for migration.

This process enables them to descent into the lungs and start infection. ETTs cause an abnormal interruption between the upper airway and the trachea. They thus bypass the structures in the extrathoracic airway and give the bacteria a direct path into the intrathoracic airway. Because the upper airway is bypassed, a decrease occurring in the body's ability to filter and moisten air. In addition, the mucociliary clearance can be impaired because of mucosal damage during intubation (De Rosa & Craven 2003). Mucus in the airways can become stagnant and serve as a medium for bacterial growth. Therefore, maintenance of aseptic technique when performing endotracheal suctioning is essential to prevent contamination of the airways (Augustyn, 2007).

Saline lavage of ETT before suctioning dislodges bacteria from the ETT into the lower airways and thus surges the risk for VAP (Moore, 2003). Saline lavage has long been considered as a means to liquefy secretions and prevent plugs of mucus in ETTs. Maintaining adequate hydration, ensuring suitable humidification of the ventilator circuit, and using nebulizer or mucolytic agents can help reduce the viscosity of secretions and remove the need for saline lavage (Akgul & Akyolcu 2002). Although some investigators have compared the effects of heat and moisture exchangers (HME filter) and heated humidifiers on the incidence of VAP, a final conclusion was not obtained about the form of humidity which collaborated with a higher incidence of VAP (Augustyn, 2007).

Diagnosis

The establishment of an appropriate diagnosis of VAP is one of the most crucial and challenging issues in the care of critically ill patients. Diagnosing VAP has remained difficult and controversial. The diagnosis can be made on the base of radiographic and clinical findings, results of microbiological tests of sputum, or aggressive testing such as bronchoscopy (Porzecanski & Bowton 2006). The chance of VAP rises if a patient has clinical signs such as fever, leukocytosis, and purulent sputum as well as abnormal findings on chest radiographs (Grossman & Fein 2000). A randomized trial of diagnostic plans for patients with suspected VAP, on 740 patients from 28 hospitals, showed that the use of quantitative culture of bronchoalveolar lavage fluid (BAL) would be related to an increased use of targeted therapy and improved clinical outcomes (Heyland et al., 2006).

Prevention

Many strategies have been incorporated into "VAP bundles". A VAP bundle is a set of treatments implemented simultaneously to reduce VAP incidence. Recent studies have proposed that the use of bundle treatments can result in considerable decreases in rates of VAP (Coppadoro et al. 2012, Westwell 2008, Morris et al., 2011, Brierley et al. 2012). Four elements VAP prevention bundle includes head-of-bed elevation, oral chlorhexidine, sedation holds, and weaning (Morris et al., 2011). Hutchins et al. mentioned that the use of an oral care protocol along with a ventilator bundle led to an 89.7% reduction in the VAP rate in mechanically ventilated patients from 2004 to 2007 (Hutchins et al., 2009).

Although VAP has complex risk factors, many nursing interventions can reduce the incidence of VAP (Table 2) (Coppadoro et al., 2012, Morris et al., 2011, Bingham et al., 2010, Nseir et al., 2011, Rello et al., 2012). Plans to eliminate VAP, such as using non-invasive ventilation and oral care, using sucralfate rather than H2 antagonists for stress ulcer prophylaxis, and actions to prevent aspiration, e.g. semi-recumbent positioning or elevation of the head of the bed and constant subglottic suctioning, and kinetic bed therapy have all been revealed to decrease the risk of VAP (Heyland et al., 2002, Safdar et al., 2004). Early tracheostomy has been supported as one of the potential preventive measures for VAP. Although tracheostomy decreases the duration of ventilation and ICU stay (Griffiths et al. 2007), a recent randomized controlled trial failed to prove a reduction in VAP incidence when early tracheostomy (6-8 days after intubation) was performed (Terragni et al., 2010).

Several studies have evaluated the efficacy of VAP prevention using silver-coated ETTs. In a study, the use of a silver-coated ETT was related to lower rates of VAP and late-onset VAP (Kollef et al., 2008). Hence, the use of anti-bacterial coated ETT seems appropriate to treat patients expected to be ventilated for more than 48 hours. It is thus a cost-effective method which would probably result in VAP prevention (Shorr et al., 2009).

Care of the internal lumen of the ETT might be a new method to prevent VAP (Berra et al. 2012). The mucus shaver is a device able to keep the ETT free of secretions by mechanical elimination of the deposits. Although the elimination of biofilm with this device may be useful, no data is yet available to show a diminishing VAP incidence.

Modified cuffs have been suggested to improve tracheal sealing and decrease secretion drainage. No absolute clinical data is accessible about the use of materials other than polyvinyl chloride (PVC), such as polyurethane, silicone, or latex, to prevent VAP (Zanella et al., 2011). However, a retrospective study on more than 3000 patients indicated a relationship between the use of a polyurethane cuff and a reduction in VAP incidence (Miller et al., 2011).

Noninvasive Ventilation

Since VAP is connected with intubation, avoidance of intubation is the most effective non- pharmacological preventive measure. Girou et al. found that rates of nosocomial pneumonia and all nosocomial infections were much less in patients supported with noninvasive ventilation than those intubated and ventilated mechanically (8% vs. 22% and 18% vs. 60%; p=0.04 and p<0.001, respectively). In addition, the proportion of patients receiving antibiotics for nosocomial infection (8% vs. 26%; p=0.01), length of ICU stay (9 vs. 15 days; p=0.02), and crude mortality (4% vs. 26%; p=0.002) were all far lower among patients receiving noninvasive ventilation (Girou et al. 2000). Randomized trials have found similar results (Bersten et al. 1991, Heyland et al. 2002). They have shown that patients with exacerbations of chronic obstructive pulmonary disease (COPD) supported by noninvasive ventilation had a 62% descent in mortality compared to patients who were intubated and mechanically ventilated. Moreover, the need for endotracheal intubation was diminished in the first group (Massimo & Giorgio 2000, Lightowler et al. 2003).

Oral Care:

Accumulation of bacteria in the throat is one of the most important risk factors for VAP and the relation between VAP and oral microflora is thoroughly known (Fourrier et al., 1998). Oropharyngeal colonization is a strong independent predictive factor for colonization of trachea and bronchi (Taraghi et al., 2011, Berry et al., 2011, Zurmehly 2013). In 76% of VAP cases, the bacteria colonizing the mouth and lung are identical (Tablan et al., 2004, Berry et al., 2011). Scannapieco et al., showed that the potential pathogens that cause VAP, including Streptococcus aureus and Pseudomonas aeruginosa, were found in the oral cavity of ICU patients (Munro et al. 2006). George et al. reported that 42% of pathogens isolated from respiratory secretions of 26 patients with VAP had previously existed in their oropharynx (George et al. 1998). Many studies have evaluated the efficacy of oral decontamination for the prevention of nosocomial pneumonia. Policies for prevention of VAP via oral hygiene include subglottic suctioning and removing dental plaques and associated microbes with mechanical interventions (e.g. tooth brushing and rinsing of the oral cavity) and pharmacological interventions (e.g. use of antimicrobial agents) (Abele-Horn et al., 1997). Therefore, it seems that an effective way to prevent VAP is reducing the amount of oral microorganisms.

Nurses are the first line of protection in preventing bacterial colonization of the oropharynx and the gastrointestinal tract. Scrupulous hand washing for 10 seconds should be performed before and after all contacts with patients. In addition, gloves should be worn when contact with oral or endotracheal secretions is probable (Tablan et al., 2004). Hixson et al., suggested that even though oral hygiene is considered as typical nursing care, it is often disregarded in critically ill patients (Hixson et al. 1998). A reliable and comprehensive oral hygiene program is a VAP prevention strategy commonly recommended by Centers for Disease Control (CDC), (Hixson et al., 1998) the Association for Professionals in Infection Control and Epidemiology (APIC), (APIC 2004) the Institute for Healthcare Improvement (IHI), (IHI 2012) and the American Association of Critical Care Nurses (AACN) (Wiegand & Carlson 2005). It has been found that integration of routine oral care into standard practice may diminish VAP by as much as 60% (Scannapieco et al., 2001).

Subglottic Suction

Among the VAP prevention strategies, reduction of aspiration with continuous aspiration of subglottic secretions (CASS) can be effective (Dodek 2004). A recent meta-analysis on approximately 2500 patients emphasized the importance of subglottic secretion drainage systems in preventing VAP, restricting ICU stay, and decreasing days of ventilation (Muscedere et al. 2011). Another meta-analysis by Dezfulian et al., (2005) demonstrated that CASS is effective in preventing early onset VAP. A controlled trial by Kollef et al. revealed that CASS prevented early onset VAP but not late onset VAP (Wunderink, 1999). Since studies evaluating CASS have not produced consistent results, its role in the prevention of VAP remains controversial. However, its use has been recommended in the updated Canadian Critical Care Trials group (Muscedere et al., 2008) and the guidelines of the British Society for Antimicrobial Chemotherapy (Masterton et al., 2008). Continuous aspiration has been shown to cause mucosal damage in animal models (Berra et al., 2004). Consequently, intermittent aspiration systems are mostly preferred. A multicenter study showed a reduction in VAP rate in the group treated with intermittent secretion drainage (Lacherade et al., 2010).

Tooth Brushing

Dental plaque may serve as a base for pathogens in ICU patients since it may be colonized by possible respiratory pathogens such as MRSA and Pseudomonas aeruginosa (Gipe et al., 1995, Grap et al., 2003). Fundamentally, dental plaque and associated microorganisms can be removed by local decontamination with the topical use of tooth brushing (Chan et al., 2007). While some studies have shown the effectiveness of tooth brushing in reducing VAP, some others could not establish such an effect (Munro et al., 2009, Zamora, 2011, Lorente et al., 2012, Alhazzani et al., 2013). Removing dental plaque organisms during tooth brushing might provide a larger pool of organisms for translocation from the mouth to subglottic secretions or the lung (Lorente et al., 2012). A review of the association between oral care and bloodstream infections in patients receiving mechanical ventilation, especially in patients with poor dental health, proposed the need for further investigation (Jones & Munro 2008).

In a clinical study, Yao et al. showed that after 7 days of twice daily tooth brushing with purified water, cumulative VAP rates were significantly lower in the experimental group compared to the control group (17% vs. 71%; p < 0.05). They hence suggested twice daily tooth brushing with purified water to decrease VAP and improve oral hygiene (Yao et al. 2011). A literature search on 8 studies indicated that tooth brushing was recommended as a high standard of oral care for mechanically ventilated patients since it decreased VAP when used with chlorhexidine (Roberts & Moule 2011). It seems that tooth brushing needs to be accompanied by an antimicrobial mouthwash. On the other hand, in a recent randomized controlled trial, Lorente et al., reported that adding manual tooth brushing to chlorhexidine oral care was not beneficial in prevention of VAP (Lorente et al., 2012). Ames has recently mentioned that powered toothbrushes with a rotation oscillation action decreased plaque and gingivitis more effectively than manual toothbrushes (Ames, 2011). Pediatric toothbrushes may be easier to use in intubated patients and would improve quality of oral care (Fitch et al., 1999).

Chlorhexidine Mouthwash

Among the variety of synthetic mouthwashes in the market, chlorhexidine (CHX) is the most effective anti-microbial mouthwash and has been approved by the American Food and Drug Administration (FDA) (Paknejad et al., 2006) and the American Dental Association (ADA) (Salehi et al., 2005). CHX is considered as the gold standard amongst mouthwashes and is now widely used as the standard of care for intubated patients (Coppadoro et al., 2012). CHX has a wide range of activity against gram-positive microorganisms including multiresistant pathogens such as MRSA and vancomycin-resistant enterococci (VRE) (Katz et al., 2001, Koeman et al., 2006). Many studies have been performed on antibacterial effects of CHX mouthwash. Veksler and Arweiler demonstrated that CHX significantly reduced the number of oral bacteria (Veksler et al., 1998, Arweiler et al., 2001). Scannapieco et al. evaluated the effects of CHX on oral pathogenic bacteria in 115 mechanically ventilated trauma patients and showed that CHX reduced Staphylococcus aureus and negative agents such as Pseudomonas aeruginosa and Acinetobacter in dental plaques (as a source of bacteria) by 0.12% (Scannapieco et al., 2009).

In 2005, the guidelines of the American Thoracic Society noted the benefits of oral chlorhexidine washes in decreasing rates of VAP in patients who had undergone coronary artery bypass graft surgery (ATS 2005). Various studies have been performed to assess the effects of CHX on dental biofilm and gingival infection. Although their results were promising regarding the reduction in plaque accumulation and colonization by various bacterial types (Scannapieco et al., 2009, Fourrier et al., 2000, Vianna et al., 2004, Segers et al., 2006), the effects of CHX on VAP remain controversial (DeRiso et al., 1996, Fourrier et al. 2000, Munro et al. 2007). In a meta-analysis, Pineda et al. demonstrated that the use of oral decontamination with CHX neither caused significant reduction in the incidence of VAP, nor altered the mortality rate (Pineda et al., 2006). Koeman et al., (2006) and Ozçaka et al., (2012) suggested that topical oral decontamination with CHX reduced the incidence of VAP. In a systematic review and meta-analysis, Labeau et al. showed that the use of CHX resulted in a significant risk reduction of VAP relative risk (RR): 0.67; 95% confidence interval (CI): 0.50-0.88; p=0.004 (Labeau et al., 2011). Another systematic review and meta-analysis by Zamora reported similar findings (Zamora, 2011). It seems that moderating oropharyngeal colonization by CHX, at least theoretically, reduced the probability of VAP. However, its influence on mortality reduction has not yet been clarified (Chlebicki & Safdar 2007). In a systematic review on 8 randomized controlled trials, Snyders et al. indicated a 36% higher chance of VAP in the control group compared to the CHX group (RR: 0.64, 95% CI: 0.44-0.91). They also introduced the use of 2% chlorhexidine as the most effective method to reduce the incidence of VAP. However, there was no evidence of the efficacy of CHX on mortality (Snyders et al., 2011). Among the various concentrations of CHX (0.12%, 0.2%, and 2%), favorable outcomes were more pronounced with CHX 2%. (Ashraf & Ostrosky-Zeichner 2012, Andrews & Steen 2013). We recommend physicians and nurses to promote routine use of oral CHX (0.12%-2%) for oral hygiene in ventilated patients.

Herbal Mouthwashes in ICU

Adverse effects and resistance to synthetic mouthwashes have been reported as a problem in ICU patients (Munro et al., 2006, Allaker & Douglas 2008). Some studies have thus been performed to find antibacterial materials with plant origin. Taraghi et al., (2011) showed that an herbal mouthwash of persica® (miswak extract), reduced the number of bacterial colonies and were effective on S. aureus and Streptococcus pneumonia in ICU patients under mechanical ventilation. They determined and compared the immediate antibacterial effects of persica® mouthwash 10%, CHX gluconate 0.2%, and normal saline in mechanically ventilated ICU patients. Their results showed that all 3 mouthwashes reduced the colony count numbers after the intervention. Both CHX gluconate 0.2% and persica® 10% were similarly effective on Staphylococcus aureus and Streptococcus pneumonia (Taraghi et al., 2011). Furthermore, the World Health Organization (WHO) recommends and encourages the use of chewing persica sticks (miswak) as an effective oral hygiene procedure (Amoian et al., 2010). Gholipour Baradari et al., reported that the herbal mouthwash Matrica® (Camicell(TM)) reduced the number of bacterial colonies and was effective on Streptococcus aureus and Streptococcus pneumonia in ICU patients under mechanical ventilation. They hence concluded that the mouthwash could be used as an alternative to chemical mouthwashes. Their results showed that CHX and Matrica® reduced the number of bacterial colonies and were effective on Streptococcus aureus and Streptococcus pneumoniae. However, CHX had greater antibacterial effects than Matrica® (Baradari et al., 2012).

Further Research

A number of policies have been suggested for VAP prevention. Nevertheless, only a few have been confirmed to be effective and many others must be further evaluated in large clinical trials before definite recommendations can be made. Antimicrobial coated ETT, alternative cuff forms and materials, and ETT secretion removal are among the strategies which need to be particularly assessed. Additional studies would be of great value in the continuing contest to decrease the rates of VAP.

We recommend all ICUs to use an oral hygiene protocol based on the best available evidence-based practice. They are also suggested to employ interventions to prevent VAP from the beginning of intubation and until extubation. Furthermore, we recommend future studies with the aim of comparing herbal mouthwashes, e.g. persica and Matrica®, to prevent the occurrence of VAP.

References

References:

Abele-Horn M, Dauber A, Bauernfeind A. (1997). Decrease in nosocomial pneumonia in ventilated patients by selective oropharyngeal decontamination (SOD). Intensive Care Med, 23:187-95.

Akça O, Kolta K, Uzel S. (2000). Risk factors for early- onset, ventilator-associated pneumonia in critical care patients: selected multiresistant versus nonresistant bacteria. Anesthesiology, 93:638-45.

Akgul S & Akyolcu N. (2002). Effects of normal saline on endotracheal suctioning. J Clin Nurs, 11:826-30.

Alhazzani W, Smith O, Muscedere J, Medd J, Cook D. (2013). Toothbrushing for critically ill mechanically ventilated patients: a systematic review and meta- analysis of randomized trials evaluating ventilator- associated pneumonia. Crit Care Med, 41:646-55

Allaker RP & Douglas CWI. (2008). Novel anti-microbial therapies for dental plaque-related diseases. Int J Antimicrob Agents, 33:8-13.

Alp E, Guven M, Yildiz O, Aygen B, Voss A, Doganay M. (2004), Incidence, risk factors and mortality of nosocomial pneumonia in intensive care units: a prospective study. Ann Clin Microbiol Antimicrob, 3:17.

American Thoracic Society. (2005). Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare- associated pneumonia. Am J Respir Crit Care Med, 171:388-416.

Ames NJ. (2011). Evidence to Support Tooth Brushing in Critically Ill Patients. Am J Crit Care, 20:242-50.

Amoian B , Moghadamnia AA, Barzi S, Sheykholeslami S, Rangiani A. (2010). Salvadora Persica extract chewing gum and gingival health: Improvement of gingival and probe-bleeding index. Complementary Therapies in Clinical Practice, 16: 121-23.

Andrews T & Steen C. (2013). A review of oral preventative strategies to reduce ventilator-associated pneumonia. Nurs Crit Care, 18:116-22.

APIC (2004) Prevention Ventilator Associated Pnemonia 2004 Brochure [Internet]. [cited 2012 Nov 29]. Available from: http://www.apic.org/Resource_/EducationalBrochureF orm/ c32ad147-d1ed-4043-8ad1- 8476b710f5e8/File/Preventing-Ventilator-Associated- Pneumonia-Brochure.pdf

Apostolopoulou E, Bakakos P, Katostaras T, Gregorakos L. (2003). Incidence and risk factors for ventilator-associated pneumonia in 4 multidisciplinary intensive care units in Athens, Greece. Respir Care, 48:681-8.

Arozullah A, Khuri S, Henderson W, Daley J. (2001). Participants in the National Veterans Affairs Surgical Quality Improvement Program: Development and validation of a multi-factorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med, 135:847-57.

Arweiler NB, Netuschil L, Reich E. (2001). Alcohol-free mouthrinse solutions to reduce supragingival plaque regrowth and vitality. A controlled clinical study. Journal of Clinical Periodontology, 28: 168-74.

Ashraf M, Ostrosky-Zeichner L. (2012). Ventilator- Associated Pneumonia: A Review. Hospital Practice, 40:93-105.

Augustyn B (2007) Ventilator-Associated Pneumonia: Risk Factors and Prevention. Crit Care Nurse 27: 32-9.

Baradari AG, Khezri HD, Arabi S. (2012). Comparison of antibacterial effects of oral rinses chlorhexidine and Matrica® in patients admitted to intensive care unit. Bratisl Lek Listy, 113:556-60.

Berra L, Coppadoro A, Bittner EA, Kolobow TH, Laquerriere P, Pohlmann JR, Bramati S, Moss J, Pesenti A. (2012). A clinical assessment of the Mucus Shaver: a device to keep the endotracheal tube free from secretions. Crit Care Med, 40:119-24.

Berra L, De Marchi L, Panigada M, Yu ZX, Baccarelli A, Kolobow T. (2004). Evaluation of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med, 32:2071-78.

Beraldo CC & Andrade D. (2008). Oral hygiene with chlorhexidine in preventing pneumonia associated with mechanical ventilation. J Bras Pneumol, 34:707-14.

Berry AM, Davidson PM, Nicholson L, Pasqualotto C, Rolls K. (2011). Consensus based clinical guideline for oral hygiene in the critically ill. Intensive Crit Care Nurs, 27:180-5.

Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. (1991). Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med, 325:1825-30.

Brierley J, Highe L, Hines S, Dixon G. (2012). Reducing VAP by instituting a care bundle using improvement methodology in a UK paediatric intensive care unit. Eur J Pediatr, 171:323-30.

Bingham M, Ashley J, De Jong M, Swift C. (2010). Implementing a Unit-Level Intervention to Reduce the Probability of Ventilator-Associated Pneumonia. Nurs Res, 59: 40-7.

Bullock TK, Waltrip TJ, Price SA, Galandiuk S. (2004). A retrospective study of nosocomial pneumonia in postoperative patients shows a higher mortality rate in patients receiving nasogastric tube feeding. Am Surg, 70:822-6.

Cason CL, Tyner T, Saunders S, Broome L. (2007). Nurses' implementation of guidelines for ventilator- associated pneumonia from the Centers for Disease Control and Prevention. Am J Crit Care, 16:28-36.

Chan EY, Ruest A, Meade MO, Cook DJ. (2007). Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis. BMJ, 334:889.

Chlebicki MP & Safdar N. (2007). Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med, 35:595-602.

Cook DJ, Walter SD, Cook RJ, Griffith LE, Guyatt GH, Leasa D, Jaeschke RZ, Brun-Buisson CH. (1998). Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med, 129:433-40.

Coppadoro A, Bittner E, Berra L. (2012). Novel preventive strategies for ventilator-associated pneumonia (Review). Critical Care, 16:210.

Craven DE. (2000). Epidemiology of ventilator-associated pneumonia. Chest, 117:186-7.

DeRiso AJ, Ladowski JS, Dillon TA, Justice JW, Peterson AC. (1996). Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery. Chest 109:1556- 61.

De Rosa FG &Craven DE. (2003). Ventilator-associated pneumonia: current management strategies. Infect Med, 20:248-59.

Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S. (2005). Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta- analysis. Am J Med, 118: 11-18.

Dodek P, Keenan S, Cook D, Heyland D, Jacka M, Hand L, Muscedere J Foster D, Mehta N, Hall R. (2004). Evidence-based clinical practice guideline for the prevention of ventilator- associated pneumonia. Ann Intern Med, 141: 305-13.

Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Noqué S, Ferrer M. (1999). Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet, 354:1851-8.

Dudeck MA, Horan TC, Peterson KD, Allen-Bridson K, Morrell GC, Pollock DA, Edwards JR. (2011). National Healthcare Safety Network (NHSN) report, data summary for 2009, device-associated module. Am J Infect Control, 39:349-67.

Fitch JA, Munro CL, Glass CA, Pellegrini JM. (1999). Oral care in the adult intensive care unit. Am J Crit Care, 8:314-18.

Fourrier F, Cau-Pottier E, Boutigny H, Roussel-Delvallez M, Jourdain M, Chopin C. (2000). Effects of dental plaque antiseptic decontamination on bacterial colonization and nosocomial infections in critically ill patients. Intensive Care Med, 26:1239-47.

Fourrier F, Duvivier B, Boutigny H, Rourrel-Delvallez M, Chopin C. (1998). Colonization of dental plaque: a source of nosocomial infections in intensive care unit patients. Crit Care Med, 26: 301-8.

George DL, Falk PS, Wunderink RG, Leeper KV, Meduri GU, Steere EL. (1998). Epidemiology of ventilator- acquired pneumonia based on protected bronchoscopic sampling. Am J Respir Crit Care Med, 158:1839-47.

Gipe B, Donnelly D, Harris S (1995) A survey of dental health in patients with respiratory failure. Am J Respir Crit Care Med, 151: 340.

Girou E, Schortgen F, Delclaux C, Brun-Buisson C, Blot F, Lefort Y. (2000). Association of noninvasive ventilation with nosocomial infections and survival in critically ill patients . JAMA, 284: 2361-67.

Grap MJ, Munro CL, Ashtiani B, Bryant S. (2003). Oral care interventions in critical care: frequency and documentation. Am J Crit Care, 12:113-8.

Grap MJ, Munro CL, Unoki T, Hamilton VA, Ward KR. (2012). Ventilator-associated pneumonia: the potential critical role of emergency medicine in prevention. J Emerg Med, 42:353-62.

Griffiths J, Barber VS, Morgan L, Young JD. (2005). Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. BMJ, 330:1243.

Grossman RF & Fein A. (2000). Evidence-based assessment of diagnostic tests for ventilator- associated pneumonia: executive summary. Chest, 117:177-81.

Heyland D, Cook D, Dodek P, Muscedere J, Day A (2006) A Randomized Trial of Diagnostic Techniques for Ventilator-Associated Pneumonia. N Engl J Med, 335: 2619-30.

Heyland DK, Cook DJ, Dodek PM. (2002), Prevention of ventilator-associated pneumonia: Current practice in Canadian intensive care units. J Crit Care, 17: 161-7.

Hixson S, Sole ML, King T. (1998). Nursing strategies to prevent ventilator-associated pneumonia. AACN Clin Issues, 9:76-90.

Hutchins K, Karras G, Erwin J, Sullivan KL. (2009). Ventilator-associated pneumonia and oral care: a successful quality improvement project. Am J Infect Control, 37:590-7.

IHI (2012). How-to Guide: Prevent Ventilator-Associated Pneumonia. Cambridge, MA: Institute for Healthcare Improvement [Internet]. [cited 2012 Nov 29]. Available from: http://www.ihi.org/knowledge/Pages/Tools/HowtoGui dePreventVAP.aspx

Jamaati HR, Malekmohammad M, Hashemian MR, Nayebi M, Basharzad N. (2010). Ventilator- Associated Pneumonia: Evaluation of Etiology, Microbiology and Resistance Patterns in a Tertiary Respiratory Center. Tanaffos, 9: 21-7.

Jones DJ & Munro CL. (2008). Oral care and the risk of bloodstream infections in mechanically ventilated adults: a review. Intensive Crit Care Nurs, 24:152-61.

Katz SL, Ho SL, Coates AL. (2001). Nebulizer choice for inhaled colistin treatment in cystic fibrosis. Chest, 119:250-55.

Kobashi Y & Matsushima T. (2003). Clinical analysis of patients requiring long-term mechanical ventilation of over three months: ventilator-associated pneumonia as a primary complication. Intern Med, 42:25-32.

Koeman M, Van der Ven AJ, Hak E, Joore HC, Kaasjager K, De Smet AG. (2006). Oral decontamination with chlorhexidine reduces the incidence of ventilator- associated pneumonia. Am J Respir Crit Care Med, 173:1348-55.

Kollef MH, Afessa B, Anzueto A, Veremakis CH, Kerr KM, Margolis BD, Craven DE, Roberts PR, Arroliga AC, Hubmayr RD. (2008). Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA, 300:805-13.

Kunis KA & Puntillo KA. (2003). Ventilator-associated pneumonia in the ICU: its pathophysiology, risk factors, and prevention. Am J Nurs, 133: 64.

Labeau S, Vandijck D, Rello J, Adam S, Rosa A, Wenisch C, BÃckman C, Agbaht K, Csomos A, Seha M. (2007). Evidence-based guidelines for the prevention of ventilator-associated pneumonia: results of a knowledge test among intensive care nurses. Intensive Care Med, 33:1463-67.

Labeau S, Vandijck D, Rello J, Adam S, Rosa A, Wenisch C, BÃckman C, Agbaht K, Csomos A, Seha M. (2008). Evidence-based guidelines for the prevention of ventilator-associated pneumonia: results of a knowledge test among European intensive care nurses. J Hosp Infect, 70:180-5.

Labeau SO, Van de Vyver K, Brusselaers N, Dirk Vogelaers P, Stijn I Blot P. (2011). Prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta- analysis. Lancet Infect Dis, 11: 845 - 54.

Lacherade JC, De Jonghe B, Guezennec P, Debbat K, Hayon J, Monsel A, Fangio P, De Vecch CA, Ramaut CA, Outin H. (2010). Intermittent subglottic secretion drainage and ventilator- associated pneumonia: a multicenter trial. Am J Respir Crit Care Med, 182:910-17.

Langer M, Mosconi P, Cigada M. (1989). Long-term respiratory support and risk of pneumonia in critically ill patients. Intensive Care Unit Group of Infection Control. Am Rev Respir Dis, 140:302-5.

Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. (2003). Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ, 326:185.

Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N. (2012). Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis, 31:2621-29.

Massimo A & Giorgio C. (2000) Noninvasive ventilation in intensive care unit patients. Current Opinion in Critical Care, 6: 11-16.

Masterton RG, Galloway A, French G, Street M, Armstrong J, Brown E, Cleverley J, Dilworth P, Fry C, Gascoigne AD. (2008). Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, 62:5-34.

Miller MA, Arndt JL, Konkle MA, Chenoweth CE, Iwashyna TJ, Flaherty KR, Hyzy RC. (2011). A polyurethane cuffed endotracheal tube is associated with decreased rates of ventilator-associated pneumonia. J Crit Care, 26:280-86.

Moore T (2003) Suctioning techniques for the removal of respiratory secretions. Nurs Stand 18:47-55.

Morris AC, Hay AW, Swann DG, Everingham K, McCulloch C, McNulty J, Brooks O, Laurenson IF, Cook B, Walsh TS. (2011). Reducing ventilator- associated pneumonia in intensive care: Impact of implementing a care bundle. Crit Care Med, 39:2218- 24.

Munro CL & Grap MJ (2004) Oral health and care in the intensive care unit: state of the science. Am J Crit Care, 13:25-33.

Munro CL, Grap MJ, Elswick RK Jr, McKinney J, Sessler CN, Hummel RS. (2006). Oral health status and development of ventilator-associated pneumonia: a descriptive study. Am J Crit Care, 15:453-60.

Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. (2009). Chlorhexidine, Toothbrushing, and Preventing Ventilator-Associated Pneumonia in Critically Ill Adults. Am J Crit Care, 18: 428-37.

Munro C, Grap M, Sessler C. (2007). Effect of oral care interventions on dental plaque in mechanically ventilated ICU adults [abstract]. Am J Crit Care, 16(3):309.

Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D. (2008). VAP Guidelines Committee and the Canadian Critical Care Trials Group. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: prevention. J Crit Care, 23:126-137.

Muscedere J, Rewa O, McKechnie K, Jiang X, Laporta D, Heyland DK. (2011). Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med, 39:1985-91.

Nseir S, Zerimech F, Fournier C, Lubret R, Ramon P, Durocher A, Balduyck M. (2011). Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients. Am J Respir Crit Care Med, 184:1041-7.

Ozçaka O, Basoglu OK, Buduneli N, Tasbakan MS, Bacakoglu F, Kinane DF. (2012). Chlorhexidine decreases the risk of ventilator- associated pneumonia in intensive care unit patients: a randomized clinical trial. J Periodontal Res, 47: 584-92.

Paknejad M, Jafarzadeh TS, Shamloo AM. (2006). Comparison of the efficacy of Matrica and %0.2 Chlorhexidine mouthwashes on 3-6 mm pockets in patients with chronic periodontitis. Islamic Dental Association of Iran, 18: 92-7.

Pawar M, Mehta Y, Khurana P, Chaudhary A, Kulkarni V, Trehan N. (2003). Ventilator-associated pneumonia: incidence, risk factors, outcome, and microbiology. J Cardiothorac Vasc Anesth, 17:22-8.

Perrie H, Scribante J, Windsor S. (2011). A survey of oral care practices in South African intensive care units. SAJCC 27: 42-6.

Pineda LA, Saliba RG, El Solh AA. (2006). Effect of oral decontamination with chlorhexidine on the incidence of nosocomial pneumonia: a meta-analysis. Crit Care, 10:R35.

Porzecanski I & Bowton DL. (2006). Diagnosis and treatment of ventilator-associated pneumonia. Chest 130:597-604.

Rello J, Afonso E, Lisboa T, Ricart M Balsera B Rovira A. (2012). A care bundle approach for prevention of ventilator- associated pneumonia. Clin Microbiol Infect, doi: 10.1111/j.1469-0691.2012.03808.x.

Roberts N & Moule P. (2011). Chlorhexidine and tooth- brushing as prevention strategies in reducing ventilator-associated pneumonia rates. Nurs Crit Care, 16:295-302.

Ross A & Crumpler J. (2007). The impact of an evidence- based practice education program on the role of oral care in the prevention of ventilator-associated pneumonia. Intensive Crit Care Nurs, 23:132-6.

Safdar N, Dezfulian C, Collard HR, Saint S (2005) Clinical and economic consequences of ventilator- associated pneumonia: a systematic review. Crit Care Med 33:2184-93.

Safdar N, Crnich CJ, Maki DG. (2005). The Pathogenesis of Ventilator-Associated Pneumonia: Its Relevance to Developing Effective Strategies for Prevention. Respir Care, 50:725-39.

Salehi P, Kohanteb G, Momeni Danaei Sh, Vahedi R (2005). Comparison of the Antibacterial Effects of Persica and Matrica, Two Herbal Mouthwashes with Chlohexidine Mouthwash. J Dent Shiraz Univ Med Scien, 6: 63-72.

Scannapieco FA, Wang B, Shiau HJ. (2001). Oral bacteria and respiratory infection: effects on respiratory pathogen adhesion and epithelial cell proinflammatory cytokine production. Ann periodontal, 6:78-86.

Scannapieco FA, Yu J, Raghavendran K, Vacanti A, Owens SI, Wood K. (2009). A Randomized Trial of Chlorhexidine Gluconate on Oral Bacterial Pathogens in Mechanically Ventilated Patients. Critical Care, 13:117.

Segers P, Speekenbrink RGH, Ubbink DT, van Ogtrop ML, Bas A. (2006). Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx and oropharynx with chlorhexidine gluconate: a randomized controlled trial. JAMA, 296:2460- 66.

Seymour RA & Whitworth JM. (2002). Antibiotic prophylaxis for endocarditis, prosthetic joints and surgery. Dent Clin North Am, 46:635-51.

Shorr AF, Zilberberg MD, Kollef M. (2009). Cost- effectiveness analysis of a silver-coated endotracheal tube to reduce the incidence of ventilator-associated pneumonia. Infect Control Hosp Epidemiol, 30:759-63.

Snyders O, Khondowe O, Bell J. (2011). Oral chlorhexidine in the prevention of ventilator- associated pneumonia in critically ill adults in the ICU: A systematic review. SAJCC, 27: 48-56.

Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. (2004). Guidelines for preventing health- care- associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep, 53:1-36.

Taraghi Z, Darvishi Khezri H, Gholipour Baradari, Heidari Gorji MA, Sharifpour A, Ahanjan M. (2011). Evaluation of the Antibacterial Effect of Persica ® Mouthwash in Mechanically Ventilated ICU Patients: A Double Blind Randomized Clinical Trial. Middle- East Journal of Scientific Research, 10: 631-637.

Terragni PP, Antonelli M, Fumagalli R, Faggiano CH, Berardino M, Pallavicini FB, Miletto A, Mangione S, Sinardi AU, Pastorelli M. (2010). Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA 303:1483-89.

Tsai HC, Lin FC, Chen YC, Chang SC (2012) The role of total bile acid in oral secretions in ventilator- associated pneumonia. J Crit Care, 27: 1-6.

Veksler AE, Kayrouz GA, Newman MG. (1998). Reduction of salivary bacteria by pre-procedural rinses with chlorhexidine 0.12%. Critical Care Medicine, 26: 301-308.

Vianna ME, Gomes BPFA, Berder VB, Zaia AA, Feraz CCR, SouzaFilho FJ. (2004). In vitro evaluation of the antimicrobial activity of chlorhexidine and sodium hypochlorite. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 97:79-84.

Warren DK, Shukla SJ, Olsen MA, Kollef MH, CHS, Cox MJ, Cohen MM, Fraser VJ. (2003). Outcome and attributable cost of ventilator-associated pneumonia among intensive care unit patients in a suburban medical center. Crit Care Med, 31:1312-17.

Westwell S. (2008). Implementing a ventilator care bundle in an adult intensive care unit. Nurs Crit Care, 13:203- 7.

Wiegand D & Carlson K. (2005). AACN Procedure Manual for Critical Care. 2th ed. St. Louis: Elsevier Saunders.

Wunderink RG. (1999). Prevention of ventilator- associated pneumonia: does one size fit all? Chest, 116:1155-56.

Yao LY, Chang CK, Maa SH, Wang C, Chen CC. (2011). Brushing teeth with purified water to reduce ventilator- associated pneumonia. J Nurs Res, 19:289-97.

Zack JE, Garrison T, Trovillion E, Clinkscale D, Coopersmith CM, Fraser VJ, Kollef MH. (2002). Effect of an education program aimed at reducing the occurrence of ventilator-associated pneumonia. Crit Care Med, 30: 2407-12.

Zamora F. (2011). Effectiveness of oral care in the prevention of ventilator-associated pneumonia. systematic review and meta-analysis of randomised clinical trials. Enferm Clin, 21:308-19.

Zanella A, Scaravilli V, Isgrò S, Milan M, Cressoni M, Patroniti N, Fumagalli R, Pesenti A. (2011.) Fluid leakage across tracheal tube cuff, effect of different cuff material, shape, and positive expiratory pressure: a bench-top study. Intensive Care Med, 37:343-47.

Zurmehly J. (2013). Oral care education in the prevention of ventilator-associated pneumonia: quality patient outcomes in the intensive care unit. J Contin Educ Nurs, 44:67-75.