Ventilator-associated pneumonia: newer definitions, controversies, and perspectives

Ventilator-associated pneumonia (VAP) is among the most common hospital-acquired infections. A multinational study including 56 centers across 11 countries revealed a VAP incidence of 15.6%. VAP may lead to adverse clinical outcomes including prolongation of ICU and hospital stay, increased antibiotic use, and add substantially to cost of care (1,2). VAP is considered to be an important measure of the quality of ICU care. However, changing definitions, lack of timely and reliable diagnostic techniques, and heterogeneity of clinical studies have besieged this topic. 

Definitions, diagnosis

In 2013, The National Healthcare Safety Network (NHSN) of the Center for Disease Control and Prevention (CDC) in the US introduced new surveillance definitions to evaluate ventilator-associated events (VAE). There are three tiers of VAEs, including ventilator associated-complications (VAC), infection-related ventilator-associated complications (IVAC), and possible or probable VAP. According to the new criteria, possible or probable VAP meets the following criteria. 

  1. An increase in daily minimum PEEP ≥ 3 cm H2O or FiO2 ≥ 0.20 sustained for at least 2 calendar days following a baseline period (2 calendar days) of stability or improvement (VAC) 
  2. Altered leukocyte count (≥ 12,000 cells/mmor ≤ 4000 cells/mm3) and/or temperature (> 38 °C or < 36 °C); a new antimicrobial prescription has been started and sustained for at least 4 calendar days (IVAC)
  3. Microbiological confirmation of a lower respiratory tract infection (possible or probable VAP)

Compared to previous definitions, the new definition does not include radiological infiltrates as a pre-requisite for the diagnosis of VAP. An increase in the FiOlevel and PEEP is considered to imply deterioration. The new design was meant primarily to identify deterioration of the respiratory status; it further aimed to reduce the subjectivity associated with previous definitions of VAP, including the development of new or progressive radiographic infiltrates and the volume and character of tracheal secretions. However, microbiological confirmation is required to diagnose possible or probable VAP. Considering the lack of certainty regarding the timing of microbiological testing, the sensitivity of these criteria may be less than optimal. Besides, several clinical conditions unrelated to pneumonia may fulfil the definition of VAE, leading to a lack of specificity. While 20–40% of all VAEs may be due to pneumonia, 30–40% of VAEs may occur from fluid overload, and 10–20% each due to collapse or acute respiratory distress syndrome (ARDS) (3). Thus, the positive predictive value of VAE as a screening tool for VAP is low, because, by definition, it includes several other conditions that result in a deterioration of the respiratory status. In a study by Klompas et al., among 597 mechanically ventilated patients, 9.3% had VAP by conventional definition compared to 23% who had VAC (4).

Conversely, other studies have revealed poor sensitivity of the VAE criteria as a screening tool. In a prospective cohort study of 8,408 mechanically ventilated patients, the VAE-VAC criteria identified less than one-third of VAPs diagnosed according to traditional criteria, using chest radiographs as the primary screening tool (5). However, VAP may often be overdiagnosed by clinicians leading to excessive antibiotic prescription (6). In an autopsy study, the accuracy of three common conventional definitions of VAP was found to be poor (7). 

Overall, the utility of VAE as a surveillance tool for VAP appears to be less than optimal and of questionable value as an ICU quality indicator, considering its poor sensitivity and low positive predictive value.  

VAP and clinical outcomes

Does VAP lead to attributable mortality in mechanically ventilated patients or could it be that sicker patients, likely to require a longer duration of ventilation, are more prone to develop VAP? Considering such confounders, the true attributable mortality due to VAP may be difficult to estimate. Fagon et al., in an early study, reported a high mortality rate of 71.4% with VAP caused by Pseudomonas or Acinetobacter species, with an attributable mortality of 42.8% (8). In contrast, Papazian et al., in a study of VAP with matched controls, revealed no excess mortality when confounding factors were eliminated (9). Bekaert et al. evaluated the attributable mortality of VAP from a multicentre database from France, including patients who underwent mechanical ventilation within 48 hours of ICU admission, and remained in the ICU for a minimum period of 2 days. The study included 4,479 patients; 685 (15.3%) developed pneumonia within 30 days of ICU admission. The authors used statistical modeling techniques to eliminate possible confounders. In contrast to previous reports, the study estimated a relatively low attributable mortality due to VAP – about 1% at 30 days, and 1.5% at 60 days (10). An epidemiological analysis evaluated the mortality of patients with ARDS who developed VAP. This epidemiological study involved the analysis of data from the ACURASYS trial that evaluated the use of cisatracurium in ARDS (11). The authors observed an increase in crude ICU mortality in patients who developed VAP compared to those who did not; however, the difference was non-significant on adjusted analysis (12).  

Steen et al. analyzed data of 2,720 adult patients who received mechanical ventilation within 48 hours of admission to medical and surgical ICUs. Among these patients, 210 (7.7%) developed VAP. According to this study, the hypothetical eradication of VAP would lead to a relative reduction of ICU mortality reduction by only 1.7% (95% confidence interval, −1.3 to 4.6) by Day 10 and 3.6% (95% confidence interval, 0.7 to 6.5) by day 60. The authors concluded that the attributable mortality of VAP is low, in light of the current preventive measures commonly employed (13). In patients with cancer, VAP was not associated with adverse outcomes in a retrospective study (14). Similarly, the development of VAP was not associated with mortality in patients with traumatic brain injury (15). However, VAP may be associated with an increased duration of mechanical ventilation, ICU, and hospital stay, and add to the overall cost of care (2). 

Ventilator-associated tracheobronchitis vs. VAP

Lower respiratory infection among mechanically ventilated patients without new or progressive radiological infiltrates is often referred to as ventilator-associated tracheobronchitis (VAT) (16). According to this definition, positive endotracheal aspirate cultures without corroborative radiological findings could be interpreted as either colonization or VAT. Although new-onset systemic symptoms would point towards infection, it may be difficult to distinguish pulmonary from an extrapulmonary source of infection among critically ill patients. It is debatable whether VAT requires antibiotic treatment. However, untreated VAT has the potential for progression to VAP, and an increase in the duration of mechanical ventilation or ICU stay (17,18).  Martin-Loeches et al. conducted a multicenter, prospective observational study including 114 ICUs, aiming to evaluate the incidence and impact of VAT. They observed that appropriate antibiotic therapy of patients with VAT led to a significantly lower progression to VAP compared to those who were provided with inappropriate treatment (19). Similar findings were observed in an earlier RCT that found a lower rate of progression to VAP, more ventilator-free days, and lower mortality in patients with VAT who were treated with antibiotics compared to those who were not (20). 

The universal treatment of all cases suspected of VAT may lead to excessive antibiotic usage, adding to the burden of resistant strains, especially considering the uncertainty regarding diagnosis. Hence, the decision to administer antibiotics is not always straightforward and needs to be individualized weighing the risks of treatment compared to possible benefit (21). As an alternative to intravenous administration, inhalational antibiotics have been proposed for the treatment of VAT; however, the efficacy of this modality of treatment remains unclear (22).   

Efficacy of VAP-prevention bundles 

Semi-recumbent position, sedation hold, and spontaneous breathing trials

The efficacy of several measures has been evaluated in the prevention of VAP, providing a bundled approach towards the care of mechanically ventilated patients. As VAP occurs due to the microaspiration of orogastric organisms, measures directed towards reducing the duration of mechanical ventilation are likely to be effective. These include daily interruption of sedation (23) and regular assessment for weaning and extubation with spontaneous breathing trials (24). A semi-recumbent position, with ≧ 300 head up, may reduce the incidence of VAP compared to a 0–100 position (25). A network meta-analysis of RCTs compared different body positions including lateral, prone, and semi-recumbent, among mechanically ventilated patients. In this study, the semi-recumbent and prone positions were associated with a significantly lower risk of VAP and mortality, compared to the supine position (26). However, optimal positioning of mechanically ventilated patients remains contentious, with a relative lack of high-quality evidence. 

Subglottic secretion drainage

Endotracheal tubes with the provision for subglottic drainage of accumulated secretions above the cuff is one of the commonly employed preventive interventions. A meta-analysis of 17 RCTs including 3,369 patients revealed a significantly reduced incidence of VAP (risk ratio, 0.58; 95% CI, 0.51-0.67; I= 0%). However, this study did not reveal any beneficial effect on clinical outcomes including the duration of stay in the ICU and in hospital, duration of mechanical ventilation, VAEs, or mortality (27). 

Maintenance of cuff pressure

Inadequate cuff inflation may constitute an important risk factor for microaspiration and VAP in mechanically ventilated patients. There are several devices that continuously monitor and maintain cuff pressures at pre-set threshold levels (28). Nseir et al. performed a meta-analysis of three prospective, controlled trials that assessed the efficacy of continuous control of cuff pressure on the incidence of VAP. Continuous control was compared with usual care with measurement and adjustment of cuff pressure using a conventional manometer. Continuous cuff pressure control resulted in a significantly lower incidence of VAP compared to usual care (13.6 % vs.  25.7%, HR: 0.47, 95 % CI 0.31–0.71, p < 0.001). This study did not find a significant difference in the duration of mechanical ventilation, ICU stay, or mortality (29). 

Modified tube surface, coated endotracheal tubes

Coating the endotracheal tube surface with different types of material, including silver, to prevent the development of biofilms has been studied; however, there is no firm evidence to support this practice (30). Another approach has been the creation of grooves or roughness on the inner surface of endotracheal tubes, thereby, reducing bacterial adhesion (31). 

Hand hygiene, oral care

Hand hygiene of healthcare workers is an important facet of the VAP prevention bundle. However, questions remain regarding the optimal hand-hygiene technique, dose and strength of alcohol-based hand rubs, and their dry times for optimal efficacy (32). Chlorhexidine-based oral care has been in widespread practice as a VAP prevention technique. However, most studies have included postoperative cardiac surgical patients who generally undergo less than a day of mechanical ventilation. It is unclear if these findings are extrapolatable to general critically ill patients. Besides, the use of chlorhexidine, an antiseptic, might result in negative cultures from endotracheal aspirates; however, the incidence of pneumonia may remain unchanged. Furthermore, a meta-analysis suggested a possible increase in mortality among non-cardiac surgical patients with chlorhexidine-based oral care (33). Adverse outcomes may be related to respiratory complications arising from the microaspiration of chlorhexidine (34).  

Selective digestive decontamination

Selective digestive decontamination (SDD) uses a combination of non-absorbable enteral antibiotics and parenteral antibiotics as a technique to prevent the growth of pathogenic organisms in the oropharynx and intestines. Although the efficacy of this technique has been demonstrated in the prevention of VAP, the ICUs involved had a low incidence of resistant organisms (35). Excessive use of antibiotics with SDD regimes may also potentially lead to increased antibiotic resistance with the modification of ICU flora. 

Duration of therapy 

The diagnosis of VAP may often be presumptive, and antibiotics may be commenced early based on signs of clinical worsening. Deterioration of respiratory function may not always be due to VAP; hence, in some patients, continued antibiotic treatment may not be required once the non-infective origin is apparent (36). Clearly, a shorter duration of antibiotic treatment would have favorable effects on the bacterial ecology and reduce the emergence of resistant strains (37). If antibiotics are commenced initially on clinical suspicion of VAP, it may be appropriate to cease therapy if the probability of an infective etiology appears low on later evaluation. This was demonstrated in a retrospective study, with an ultra-short antibiotic course of 1–3 days compared with >3 days of treatment in patients with suspected VAP (38). On sensitivity analyses using propensity scores to match patients in both cohorts, the hospital mortality, duration of mechanical ventilation, and hospital length-of-stay were not significantly different between the two groups of patients. This study underlines the importance of early cessation of antibiotics in patients who are initially suspected to have VAP, but may have an alternate, non-infective etiology for the deterioration of respiratory status. 

In a landmark RCT, Chastre et al. compared 8 vs. 15 days of antibiotic treatment in patients with VAP (39). The 28-day mortality, incidence of recurrent infection, mechanical ventilation-free days, organ failure-free days, and duration of ICU stay were similar between the two groups. A French study compared an 8-day compared to a 15-day antibiotic therapy in early-onset VAP (40). The rate of clinical cure was similar between the two groups; the 21-day mortality was also not significantly different between both patient cohorts. Robust evidence supports a shorter duration of antibiotic therapy in VAP.

Key points

  • VAP is the most common nosocomial infection in critically ill, mechanically ventilated patients
  • The attributable mortality of VAP has been low in recent studies, probably related to the implementation of preventive bundles. However, it may lead to prolonged duration of mechanical ventilation, ICU stay, and increase the overall cost of care 
  • Newer definitions were introduced as a surveillance technique for VAP. Although the new definitions improve objectivity, they have poor positive predictive value and sensitivity for the diagnosis of VAP
  • VAT may often be the harbinger of VAP and may require antibiotic treatment. However, treatment should be individualized; universal treatment of suspected VAT leads to excessive antibiotic usage and the emergence of resistant strains
  • Preventive bundles have been introduced to reduce the incidence of VAP. The interventions that may be useful include meticulous hand hygiene of healthcare personnel, daily interruption of sedation combined with spontaneous breathing trials, adoption of a semi-recumbent position of >300, subglottic secretion drainage, and maintenance of tracheal cuff pressures to prevent microaspiration
  • Oropharyngeal decontamination with chlorhexidine and SDD are unlikely to be effective in the prevention of VAP
  • A shorter duration of antibiotic therapy of 7 days is as effective compared with longer durations of therapy in VAP. Longer duration of antibiotic usage results in an increase in the resistance burden. Ultra-short duration of antibiotic administration for 1–3 days may be appropriate when empirical treatment is commenced based on clinical suspicion alone, and later turns out to be non-infective deterioration of the respiratory status


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