Because VAP is associated with increased morbidity, longer hospital stay, increased health care costs, and higher mortality rates, prevention is a major challenge for intensive care medicine.2,317,318 A number of recommendations for the prevention of VAP are empiric rather than based on controlled observations, which make evaluation of the impact of such interventions difficult in this setting for several reasons: (a) the difficulty in obtaining an accurate diagnosis of VAP, that is, to distinguish patients with true infection from patients with tracheal colonization and/or other pathologic processes as only patients who develop true VAP are likely to benefit from preventive measures; (b) the difficulty of precisely determining the impact of prophylactic measure on the overall mortality of a general ICU population, that is, to identify preventable deaths, directly attributable to VAP, among all deaths occurring in a population of ventilated ICU patients; and (c) the difficulty of evaluating the consequences of a preventive measure on a potentially pathogenic mechanism, for example, to evaluate the exact role played by prevention or reduction of tracheal colonization in modifying the development of VAP.
Conventional Infection-Control Approaches
These measures should be the first step taken in any prevention program.319 The design of the ICU has a direct effect on the potential for nosocomial infections. Adequate space and lighting, proper functioning of ventilation systems, and facilities for handwashing lead to lower infection rates.320 It should, however, be kept in mind that physical upgrading of the environment does not per se reduce the infection rate unless personnel attitude and practices are improved. In any ICU, one of the most important factors is the health care staff, including the number, quality, and motivation of medical, nursing, and ancillary members.321 The team should include a sufficient number of nurses to minimize them moving from one patient to another and to avoid having them working under constant pressure.322–325 The importance of personal cleanliness and attention to aseptic procedures must be emphasized at every possible opportunity. At the same time, unnecessarily rigid restrictions should be avoided.326 The importance of personal cleanliness and attention to aseptic procedures must be emphasized at every opportunity. It is clear that careful monitoring, decontamination, and compliance with guidelines for the use of respiratory equipment all reduce the incidence of nosocomial pneumonia.324 In particular, handwashing and handrubbing with alcohol-based solutions remain the most important components of effective infection control practices in the ICU.132,324,327
A bacterial monitoring policy facilitates the early recognition of colonization and infection and is associated with significant reductions in nosocomial infection rates.328 The focal point for infection control activities in the ICU is a surveillance system designed to establish and maintain a database that describes endemic rates of nosocomial infection. Awareness of the endemic rates enables the recognition of the onset of an epidemic when infection rates rise above a calculated threshold.
Adoption of an antibiotic policy restricting the prescription of broad-spectrum agents and useless antibiotics is of major importance.22,164,235,329 Better use of antibiotics in the ICU can be achieved by implementing strict guidelines, avoiding the treatment of patients who do not have bacterial infections, using narrow-spectrum antibiotics whenever possible, and reducing the duration of treatment. Similarly, transfusion of red blood cells and other allogenic blood products should follow a strict policy, because several studies have identified exposure to allogenic blood products as a risk factor for postoperative infection and pneumonia.330–335 Some very simple, safe, inexpensive, and logical measures may have major effects on the frequency of VAP in ventilated patients. These include avoiding nasal insertion of endotracheal and gastric tubes, maintaining the endotracheal tube cuff pressure above 20 cm H2O to prevent leakage of bacteria around the cuff into the lower respiratory tract, prompt reintubation of patients who are likely to fail extubation, removing tubing condensate, and providing adequate oral hygiene with tooth brushing.101,119,136,336,337
Specific Prophylaxis Against Ventilator-Associated Pneumonia
Specific strategies aimed at reducing the duration of mechanical ventilation (a major risk factor for VAP), such as improved methods of sedation, use of protocols to facilitate and accelerate weaning, using low tidal volume and adequate levels of positive end-expiratory pressure, and use of intensive insulin therapy to control blood glucose should be considered as integral parts of any infection-control program.338–343 All are based on the application of strict protocols. Noninvasive ventilation is an alternative approach to using artificial airways to avoid infectious complications and injury of the trachea in patients with acute respiratory failure. Many observational studies and seven randomized trials suggest that patients who tolerate noninvasive ventilation have a lower incidence of pneumonia than those tracheally intubated.338,344–352
Apart from protocols aimed at reducing the duration of mechanical ventilation, eight prophylactic approaches have been studied: semirecumbent positioning, oscillating and rotating beds, continuous or intermittent aspiration of subglottic secretions, ventilator circuits management, methods of enteral feeding, stress-ulcer prophylaxis, oral decontamination with antiseptics, and selective digestive decontamination.
Supine positioning is independently associated with the development of VAP.22 Placing ventilated patients in a semirecumbent position to minimize reflux and aspiration of gastric contents is a simple measure, although some practical problems can occur in unstable patients. Only a few trials have evaluated the efficacy of semirecumbent positioning.112–114,117,353–355 In a randomized trial based on a small number of patients, Drakulovic et al observed lower rates of both clinically suspected and bacteriologically confirmed VAP, and identified supine positioning as an independent risk factor for VAP with enteral nutrition, ventilation for 7 days or longer and a Glasgow coma score of less than 9 points. The feasibility and efficacy of this intervention in a larger patient population, however, remain unknown, all the more as its efficacy was not confirmed in a subsequent trial that included 221 ventilated patients or in a recent meta-analysis.117,353 Raising the head of bed to 30 degrees or higher may also have some detrimental skin effects and may increase the incidence of pressure ulcer formation.115 Pending additional studies, most experts currently recommend maintaining the head of the bed elevated to at least 20 degrees to 30 degrees in all ventilated patients who are hemodynamically stable, particularly when they are receiving enteral nutrition.134,317,356–361
Oscillating and Rotating Bed
Immobility in critically ill patients treated with mechanical ventilation results in atelectasis, impaired secretions drainage, and potentially predisposes to pulmonary complications including VAP. Oscillating and rotating beds may help in preventing pneumonia.317 Six randomized trials, which included mostly surgical and trauma patients, ventilated or not, and summarized in a meta-analysis by Choi and Nelson,362 compared continuous lateral rotational therapy with standard beds. The meta-analysis found a significant reduction in the risk for pneumonia, principally concerning early onset (<5 days) pneumonia and a decreased duration of ICU stay. Notably, the only randomized, controlled trial—not included in the metaanalysis—conducted on a general ICU population did not show any differences in pneumonia rates but showed a significantly shorter length of ICU stay.363 Some adverse events have been described with these beds including disconnection of catheters or pressure ulceration; in addition, nursing care is potentially complicated with oscillating beds. Finally, despite the cost of such beds, cost-to-benefit analyses suggested favorable results, mainly caused by the reduction of ICU length of stay.
Oral Decontamination with Antiseptics
Topical application of chlorhexidine or other antiseptics to the oral mucosa may decrease respiratory pathogen colonization and secondary lung infection in ventilated patients. Randomized, controlled trials, however, have reported mixed results: Some showed little effect whereas others found a reduction in the incidence of VAP.364–376 Combining the results of the seven randomized controlled trials that evaluated the potential efficacy of chlorhexidine, a 30% relative reduction in the risk of VAP was observed, but no effect of chlorhexidine on reduction of mortality or duration of mechanical ventilation could be demonstated.377 The varying concentration of the chlorhexidine solutions used in these studies may have affected the results. In the study by Koeman et al,369 a 2% solution of chlorhexidine was used, a much higher concentration than in the other published studies, most of which used a 0.12% or 0.2% solution; this may partially explain the benefit of chlorhexidine for reducing VAP in this study. Reported adverse effects of oral use of chlorhexidine include staining of the teeth, which is reversible with professional cleaning, and a transient abnormality of taste.377 The optimal concentration, frequency of application, effect on promoting resistance among oropharyngeal flora, and cost-effectiveness of chlorhexidine should be addressed in future studies.
Aspiration of Subglottic Secretions and Use of Specialized Endotracheal Tubes
Repeated micro inhalations of colonized oropharyngeal (subglottic) secretions are the major mechanism of VAP. Continuous or intermittent suctioning of oropharyngeal secretions has been proposed as a means to avoid chronic aspiration of secretions through the tracheal cuff of intubated patients. Aspiration of subglottic secretions requires the use of specially designed endotracheal tube with a separate lumen that opens into the subglottic region. Thirteen randomized controlled trials have studied aspiration of subglottic secretions for the prevention of VAP for a total of 2442 randomized patients.378–386 Of the thirteen studies, twelve reported a reduction in VAP rates in the subglottic secretion drainage arm. When the results were combined in a meta-analysis, the overall risk ratio for VAP was 0.55 (95% CI, 0.46 to 0.66; p <.00001) with no heterogeneity, and the use of subglottic secretion drainage was associated with reduced ICU length of stay, decreased duration of mechanical ventilation, and increased time to first episode of VAP.386 No effect, however, on hospital or ICU mortality could be demonstrated.386 Some experimental data in sheep and ICU patients suggest the possibility of tracheal damage with the use of this type of tube.382,387,388
Bacterial aggregates in biofilm dislodged during suctioning might not be eradicated by antibiotics or effectively cleared by host immune defenses, thereby constituting dangerous inoculums for the lung. Preliminary data obtained in animal models and from small randomized human studies support the hypothesis that an endotracheal tube coated externally and internally with a potent antiseptic product such as silver could have a sustained antimicrobial effect within the proximal airways and block biofilm formation at its surface.389–394 Such a device was evaluated in a large, randomized, multicenter, single-blind trial by Kollef et al.395 The authors conclude that the new device was able to lower the VAP frequency from 7.5% for the control group to 4.8% for the group receiving the silver-coated endotracheal tube. The silver-coated tube, however, did not reduce mortality rates, the duration of intubation, hospital length of stay, or the frequency or severity of adverse effects.
Ventilator Circuit Management
Decreased frequency of ventilator circuit change, replacement of heated humidifiers by heat and moisture exchangers, decreased frequency of heat and moisture exchanger change, and closed suctioning systems have been tested for preventing VAP.2,317,318,396 Four randomized trials of decreased frequency of ventilator circuit changes have been published. Changes every 2 days, 7 days, and no scheduled change did not find significant difference in the rate of VAP as summarized in a recent meta-analysis.397 One meta-analysis summarized the results of five randomized, controlled trials which compared the effects of heated humidifiers and heat and moisture exchangers on the risk of VAP.318 Only one of these five studies found a significant reduction of VAP rate with the use of heat and moisture exchangers.125 Efficacy of both humidification strategies seems comparable. Two studies, however, reported increased rates of endotracheal tube occlusion with the use of heat and moisture exchangers; the increased resistive load can cause difficulties in ventilation and weaning in patients with severe acute respiratory distress syndrome—related to larger dead space. No other adverse effects were observed. No effect on mortality was reported. Finally, one study has evaluated the impact of less frequent changes (daily vs. every 5 days) in heat and moisture exchangers on the development of VAP.398 No difference in the VAP rates was observed.
To avoid hypoxia, hypotension, and contamination of suction catheters entering the tracheal tube, investigators have examined closed suctioning systems.396,399–400 They either found a nonsignificantly lower prevalence of VAP for patients managed with the closed system compared to the open system, without any adverse effect,400 or they found that its use was associated with an increased frequency of endotracheal colonization.399 Closed-suction systems also failed to reduce cross-transmission and acquisition rates of the most relevant gram-negative bacteria in ICU patients in a prospective crossover study in which 1110 patients were enrolled.396
Methods of Enteral Feeding
Nearly all ventilated patients have a nasogastric tube inserted to manage gastric and enteral secretions, prevent gastric distension, or provide nutritional support. A nasogastric tube may increase the risk for gastroesophageal reflux, aspiration, and VAP.77 Four randomized, controlled trials have evaluated methods of enteral feeding aimed at preventing VAP: postpyloric or jejunal feeding (vs. gastric feeding), the use of motility agents (metoclopramide vs. placebo), acidification of feeding (with addition of hydrochloric acid), and intermittent (vs. continuous) feeding.108,401,402 These studies did not find differences in incidence of VAP or mortality rates. Potentially serious adverse effects have been observed in patients receiving acidified feeding (gastrointestinal bleeding) or intermittent enteral feeding (increased gastric volume and lower volumes of feeding). Thus, to date, methods of enteral feeding aimed at reducing the incidence of VAP cannot be recommended for routine use.
Gastric colonization by potentially pathogenic organisms increases with decreasing gastric acidity.403 Thus, medications that decrease gastric acidity (antacids, H2 blockers, proton pump inhibitors) may increase organism counts and increase the risk of VAP. In contrast, medications that do not affect gastric acidity (sucralfate) may not increase this risk. Several meta-analyses of more than 20 randomized trials have evaluated the risk for VAP associated with the methods used to prevent gastrointestinal bleeding in critically ill patients.91,92,404 The largest randomized trial comparing ranitidine to sucralfate showed that ranitidine was superior in preventing gastrointestinal bleeding and did not increase the risk of VAP.93 Therefore, despite the potential advantage of sucralfate (potentially less VAP with more gastrointestinal-bleeding) over H2 blockers (potentially more VAP with less gastrointestinal bleeding) in preventing VAP, stress-ulcer prophylaxis with H2 blockers appears to be safe in patients who are at high risk for bleeding as well as VAP.405 Although proton pump inhibitors are now widely used for gastric bleeding prophylaxis in the ICU, based on their potentially higher efficacy, their use is associated with similar rates of nosocomial pneumonia as H2 blockers.404,406–410
Selective Digestive Decontamination
Selective decontamination of the digestive tract (SDD) includes a short course of systemic antibiotic therapy, such as cefotaxime, trimethoprim, or a fluoroquinolone, and topical administration of nonabsorbable antibiotics (usually an aminoglycoside, polymyxin B, and amphotericin) to the mouth and stomach, in order to eradicate potentially pathogenic bacteria and yeast that may cause infections.411 Since the original study published by Stoutenbeck et al in 1984,412 which demonstrated a decrease of the overall infection rate in patients receiving the SDD regimen, more than forty randomized, controlled trials, and eight meta-analyses have been published. All eight meta-analyses reported a significant reduction in the risk of VAP, and four reported a significant reduction in mortality.86,413–416 Recently, three prospective, randomized, controlled trials, all performed in ICUs with low rates of antibiotic resistance, have been published that were large enough to show a significant survival benefit in SDD-treated patients.417–419 All three were in favor of treatment with SDD, the largest and most recent one by De Smet et al demonstrating a relative decrease in 28-day mortality rate (OR 0.83,95% CI, 0.72 to 0.97) and an absolute survival benefit of 3.5%.419
In spite of these benefits, widespread use of SDD in ICU patients remains controversial. The major concern with use of SDD is that it probably needs to be used in nearly all patients in a given ICU, and this widespread use has been shown in some studies to promote the emergence of resistant bacteria, particularly gram-positives such as MRSA.420–424 This is likely to be even a greater problem in ICUs with a high baseline rate of resistance.317,318,425 In contrast to what was expected, however, most studies that have evaluated this issue showed a lower incidence of colonization with (multi)resistant bacteria in SDD-treated patients than in control patients.418,426 In a single-center observational study from Germany, 5-year use of SDD was not associated with an increase of MRSA or aminoglycoside and β-lactam resistance in gram-negative bacteria.427 Putative explanations why colonization with resistant microorganisms is lower after treatment with SDD include the almost invariable sensibility of gram-negative aerobic bacteria for the commonly used combination of polymyxin E and tobramycin, the fact that treatment with polymyxin E rarely induces resistance, the very high local concentrations in the bowel of the used antibiotics, and the lower rate of use of systemic antibiotics in SDD-treated patients.428
Implementing a Structured Prevention Policy
The application of consistent evidence-based interventions to prevent VAP has been highly variable from one ICU to another and often suboptimal.429–430 Moreover, no single preventive measure can succeed alone, emphasizing the need to use multifaceted and multidisciplinary programs to prevent VAP. Such programs are frequently referred to as “care bundles.” A care bundle is a set of readily implementable interventions that are required to be undertaken for each patient on a regular basis.431 The key goal is that every intervention must be implemented for every patient on every day of his or her stay in the ICU. Compliance is assessed for the bundle as a whole, so failure to complete even a single intervention means failure of the whole bundle at a particular assessment. The interventions need to be packaged in such a way that they are easy to assess for compliance, which usually means that no more than five interventions are included in each care bundle. The performance goal is to routinely achieve more than 95% compliance. Care bundles make it possible to introduce evidence-based preventive measures, including appropriate nurse staffing levels, hand hygiene with alcohol-based formulations, standardized weaning protocols and daily interruption of sedation, oral care with chlorhexidine, and keeping patients who receive enteral nutrition in a semirecumbent position.252 All of these measures can be consistently applied to all patients in a coordinated way. The aim of care bundles is therefore only to facilitate and promote changes in patient care and encourage compliance with guidelines. Several studies using quasi-experimental designs confirmed the usefulness of this strategy for preventing VAP in the ICU.134,355,432–444
The lack of methodologic rigor of the reported studies, however, precludes any conclusive statements about “bundle care” effectiveness or cost-effectiveness. The exact set of key interventions that should be part of the “VAP-prevention bundle” is also not currently known as well as the optimal way for implementing it.134,445–447 Successful VAP prevention requires an interdisciplinary team, educational interventions, system innovations, process indicator evaluation, and feedback to health care workers. As shown by a recent study, simply having a checklist available for reference without consideration of a robust implementation and adherence strategy is unlikely to maximize patient outcomes.444 Whether this organization and data collection can be generalized to all ICUs remains to be determined, as well as the selection of the “optimal” bundle. In the meantime, clinical practice quality indicators must be developed in parallel with guidelines to check the adequacy between the two and to find solutions to improve guideline compliance.
In the United States, the Centers for Medicare and Medicaid Services has proposed stopping hospital reimbursements for care made necessary by preventable complications, including nosocomial infections, aiming for a zero-VAP rate.448 Although this plan may have the desirable consequences of improving the quality of care, it also may penalize hospitals that admit high-risk patients and inadvertently encourage institutions to underreport VAP or to overuse antibiotics, thereby favoring dissemination of multidrug-resistant microorganisms. This possibility further underscores the need to carefully evaluate all new strategies potentially aimed at preventing VAP against what represents best clinical practices.