Chapter 43. Ventilator-Associated Pneumonia

• The risk of nosocomial pneumonia is considerably higher in the subset of ICU patients treated with mechanical ventilation, with an incremental risk of about 1% per day of ventilation.
• Ventilator-associated pneumonia (VAP) is associated with mortality in excess of that caused by the underlying disease alone, particularly in case of infection due to high-risk pathogens, such as Pseudomonas aeruginosa and Acinetobacter spp. and when initial antibiotic therapy is inappropriate.
• The predominant organisms responsible for infection are Staphylococcus aureus, P. aeruginosa, and Enterobacteriaceae, but etiologic agents differ widely according to the population of hospital patients, duration of hospital stay, and prior antimicrobial therapy.
• Although appropriate antibiotics may improve survival in patients with VAP, use of empirical broad-spectrum antibiotics in patients without infection is potentially harmful, facilitating colonization and superinfection with multiresistant microorganisms. Any strategy designed to evaluate patients suspected of having developed VAP therefore should be able to withhold antimicrobial treatment in patients without pneumonia.
• Because even a few doses of a new antimicrobial agent can negate results of microbiologic cultures, pulmonary secretions in patients suspected of having developed VAP always should be obtained before new antibiotics are administered.
• Bronchoscopic techniques, when performed before introduction of new antibiotics, enable physicians to identify most patients who need immediate treatment and help to select optimal therapy in a manner that is safe and well tolerated.
• Empirical treatment of patients with VAP should be selected based on available epidemiologic characteristics, information provided by direct examination of pulmonary secretions, intrinsic antibacterial activities of antimicrobial agents, and their pharmacokinetic characteristics.
• Once the microbiologic data become available, antimicrobial therapy should be re-evaluated in order to avoid prolonged use of a broader spectrum of antibiotic therapy than is justified by the available information. For many patients, including those with late-onset infection, the culture data will not show the presence of highly resistant pathogens, and in these individuals, therapy can be narrowed or even reduced to a single agent in light of the susceptibility pattern of the causative pathogens without risking inappropriate treatment.
• Some very simple, no-cost measures, such as judicious use and prompt removal of a useless nasogastric tube, removal of ventilator tubing condensates with minimal exposure to patients, placement of ventilated patients in a semirecumbent position, prevention of sinusitis, and use of sucralfate instead of H2 blockers, may have an impact on the frequency of VAP.

Ventilator-associated pneumonia (VAP) remains a major cause of mortality and morbidity despite the introduction of potent broad-spectrum antimicrobial agents, major advances in the management of ventilator-dependent patients admitted to ICUs, and the use of preventive measures, including the routine use of effective procedures to disinfect respiratory equipment. Rates of pneumonia are considerably higher among patients hospitalized in ICUs compared with those in hospital wards, and the risk of pneumonia is increased three- to tenfold for the intubated patient on mechanical ventilation (MV).1–10 In contrast to infections of more frequently involved organs (e.g., urinary tract and skin), for which mortality is low, ranging from 1% to 4%, the mortality rate for VAP, defined as pneumonia occurring more than 48 hours after endotracheal intubation and initiation of MV, ranges from 24% to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens.8–18 Because several studies have shown that appropriate antimicrobial treatment of patients with VAP significantly improves outcome, more rapid identification of infected patients and accurate selection of antimicrobial agents represent important clinical goals.12,19,20 However, consensus on appropriate diagnostic, therapeutic, and preventive strategies for VAP has yet to be reached.

Accurate data on the epidemiology of VAP are limited by the lack of standardized criteria for its diagnosis. Conceptually, VAP is defined as an inflammation of the lung parenchyma caused by infectious agents not present or incubating at the time MV was started. Despite the clarity of this conception, the past three decades have witnessed the appearance of numerous operational definitions, none of which is universally accepted. Even definitions based on histopathologic findings at autopsy may fail to find consensus or provide certainty. Pneumonia in focal areas of a lobe may be missed, microbiologic studies may be negative despite the presence of inflammation in the lung, and pathologists may disagree on the findings.21–24 The absence of a “gold standard” continues to fuel controversy about the adequacy and relevance of many studies in this field. Prolonged (>48 hours) MV is the most important factor associated with nosocomial pneumonia. However, VAP may occur within the first 48 hours following intubation. Since the seminal study by Langer and colleagues,25 it is usual to distinguish early-onset VAP, which occurs during the first 4 days of MV, from late-onset VAP, which develops 5 days or more after initiation of MV. Not only are the causative pathogens commonly different, but the disease also is usually less severe and the prognosis better in early-onset than late-onset VAP.26,27

Incidence

The majority of studies have reported incidence rates of nosocomial pneumonia in general ICU populations varying between 8% and 20%. These rates are much higher than the mean annual incidence of nosocomial lower respiratory tract infection of approximately 0.6 episodes per 100 hospitalizations recorded by the National Nosocomial Infection Study (NNIS), which included all patients regardless of their location in the hospital.28

The risk of pneumonia seems to be considerably higher in the subset of ICU patients treated with mechanical ventilation. Cross and Roup5 have published specific data on overall rates of nosocomial pneumonia in relation to the use of respiratory devices. Pneumonia rates in patients with an endotracheal tube and mechanical ventilation were increased 10-fold over patients with no respiratory therapy devices. Similarly, in the Study on the Efficacy of Nosocomial Infection Control (SENIC), the pneumonia rate was 21-fold higher for patients treated with continuous ventilatory support than for patients not receiving mechanical ventilation.28

The VAP rates reported in the more recent studies evaluating homogeneous groups of patients receiving mechanical ventilation are shown in Table 43-1. In their prospective investigation on pneumonia in 23 Italian ICUs that included 724 critically ill patients who had received prolonged (>24 hour) ventilatory assistance since admission, Langer and colleagues6 found a mean rate of nosocomial pneumonia of 23%; the incidence rose from 5% in patients receiving 1 day of respiratory assistance to 68.8% in patients mechanically ventilated for more than 30 days. Using quantitative culture of specimens obtained with a protected specimen brush (PSB) during fiberoptic bronchoscopy (FOB) to define pneumonia in 567 ventilated patients, Fagon and colleagues9 reported a nosocomial pneumonia rate of 9%. Using an actuarial method, the cumulative risk of pneumonia in this context was estimated to be 6.5% at 10 days and 19% at 20 days after the onset of MV. Furthermore, the incremental risk of pneumonia was virtually constant thoughout the entire ventilation period, with a mean rate of about 1% per day. In contrast, Cook and colleagues29 demonstrated in a large series of 1014 mechanically ventilated patients that although the cumulative risk for developing VAP increased over time, the daily hazard rate decreased after day 5. The risk per day was evaluated at 3% on day 5, 2% on day 10, and 1% on day 15. Independent predictors of VAP retained by multivariable analysis were a primary admitting diagnosis of burns (risk ratio [RR] = 5.1; 95% confidence interval [CI] = 1.5−17.0), trauma (RR = 5.0; 95% CI = 1.9−13.1), central nervous system (CNS) disease (RR = 3.4; 95% CI = 1.3−8.8), respiratory disease (RR = 2.8; 95% CI = 1.1−7.5), cardiac disease (RR = 2.7; 95% CI = 1.1−7.0), MV during the previous 24 hours (RR = 2.3; 95% CI = 1.1−4.7), witnessed aspiration (RR = 3.2; 95% CI = 1.6−6.5), and paralytic agents (RR = 1.6; 95% CI = 1.1−2.4). Exposure to antibiotics conferred protection (RR = 0.4; 95% CI = 0.3−0.5), but this effect was attenuated over time. Thus the daily risk for developing VAP is highly dependent on the population being studied as well as on many other factors, particularly the number of patients in the given population who received antibiotics immediately after their admission to the ICU.

VAP is thought to be a common complication of the acute respiratory distress syndrome (ARDS) (see Table 43-1). Most clinical studies have found that pulmonary infection affects between 34% and more than 70% of patients with ARDS, often leading to the development of sepsis, multiple-organ failure, and death. When the lungs of patients who died of ARDS were examined histologically at autopsy, pneumonia could be demonstrated in as many as 73%.10,30 The diagnosis of pulmonary infection in patients with ARDS, however, is often difficult. Several studies have clearly demonstrated the inability of physicians to accurately diagnose nosocomial pneumonia in this setting based on clinical criteria alone.30 Using PSB and/or bronchoalveolar lavage (BAL) techniques at predetermined times from days 3 to 21 after the onset of the syndrome in a series of 105 patients with ARDS, Sutherland and colleagues31 concluded that VAP indeed may occur far less frequently than expected in this group of patients. Only 16 (15.2%) of their 105 patients met the quantitative criteria for pneumonia (PSB >103 colony-forming units [cfu]/mL or BAL >104 cfu/mL), and no correlations were found between total colony counts in BAL fluid or PSB cultures and severity of ARDS, as judged by PaO2/FiO2 ratios, days on MV, static lung compliance, and/or survival. Unfortunately, these results are probably not of general value because most patients included in the study were lavaged while receiving antibiotics and at predetermined times during the course of ARDS rather than at the time of clinically suspected infection. According to four other studies, the VAP rate was higher in ARDS patients than in other mechanically ventilated patients.14–16,32 In one study on 56 ARDS patients, PSB and BAL were used to define pneumonia, and the VAP rate was 55%,14 whereas it was only 28% for 187 non-ARDS patients diagnosed with the same criteria during the same period. It was specified that early-onset VAP (occurring before day 7) was relatively rare in ARDS patients: only 10% of the first VAP episodes, as opposed to 40% of non-ARDS patients. These observations were confirmed in 30 ARDS patients for whom repeated quantitative culture results of specimens obtained with a plugged catheter were available and in 94 ARDS patients with suspected VAP who underwent 172 bronchoscopies, with VAP rates of 60% (incidence density = 4.2/100 ventilator-days) and 43%, respectively.15,32 In another prospective multicentric study, VAP was confirmed bacteriologically in 49 (37%) of 134 ARDS patients versus 23% of ventilated non-ARDS patients (p <0.002).16

Mortality, Morbidity, and Cost

Crude ICU mortality rates of 24% to 76% have been reported for VAP at a variety of institutions6,9,12,13,29,33–41 (see Table 43-1). ICU ventilated patients with VAP appear to have a two- to tenfold higher risk of death compared with patients without pneumonia. In 1974, fatality rates of 50% for ICU patients with pneumonia versus 4% for patients without pneumonia were reported.42 The results of several studies conducted between 1986 and 2001 have confirmed this observation. Despite variations among studies that partly reflect the populations considered, overall mortality rates for patients with or without VAP were, respectively, 55% versus 25%,13 71% versus 28%,9 33% versus 19%,12 38% versus 9%,37 and 44% versus 19%.40 These rates correspond to increased risk ratios of mortality of VAP patients of 2.2, 2.5, 1.7, 4.4, and 2.3, respectively.

Although these statistics indicate that VAP is a severe disease, previous studies have not demonstrated clearly that pneumonia is indeed responsible for the higher mortality rate of these patients. Two independent factors make it difficult to assign responsibility unambiguously. The first is, once again, the difficulty in establishing a firm diagnosis, i.e., to clearly identify patients with VAP; thus the widely diverging VAP mortality rates reported may reflect not only differences in the populations studied but also differences in the diagnostic criteria used. Second, numerous studies have demonstrated that severe underlying illness predisposes ICU patients to the development of pneumonia, and their mortality rates are, consequently, high.3,4,8,37,43–45 Therefore, it is difficult to determine whether such patients would have survived if VAP had not occurred.

The prognosis for aerobic gram-negative bacilli (GNB) VAP is considerably worse than that for infection with gram-positive pathogens when these organisms are fully susceptible to antibiotics. Death rates associated with Pseudomonas pneumonia are particularly high, ranging from 70% to more than 80% in several studies.9,42,46–50 According to one study, mortality associated with Pseudomonas or Acinetobacter pneumonia was 87% compared with 55% for pneumonias due to other organisms.9 Similarly, Kollef and colleagues51 demonstrated that patients with VAP due to high-risk pathogens (Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia) had a significantly higher hospital mortality rate (65%) than patients with late-onset VAP due to other microbes (31%) or patients without late-onset pneumonia (37%). Concerning gram-positive pathogens, in a study comparing VAP due to methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive S. aureus (MSSA), mortality was found to be directly attributableto pneumonia for 86% of the former cases versus 12% of the latter, with a relative risk of death equal to 20.7 for MRSA pneumonia.52

Multivariate analyses conducted to evaluate the independent role played by VAP in inducing death failed to identify VAP as a variable independently associated with mortality in two studies.13,37 In contrast, the EPIC study's stepwise logistic regression analyses demonstrated that ICU-acquired pneumonia increased the risk of death with an odds ratio of 1.91 (95% CI = 1.6–2.3) independently of clinical sepsis and bloodstream infection.3 Another study based on 1978 ICU patients including 1118 patients on MV demonstrated that in addition to the severity of illness, the presence of dysfunctional organ(s); stratification according to the McCabe and Jackson criteria of underlying disease as fatal, ultimately fatal, or not fatal; and nosocomial bacteremia and nosocomial pneumonia independently contributed to the deaths of ventilated patients.38 Using the Cox model in a series of 387 patients, it was demonstrated that patients with clinically suspected pneumonia had an increased risk of mortality; however, confirmation of the diagnosis with invasive techniques added no prognostic information (respective RR = 2.1 and 1.7).39

Case-control studies have been used to assess mortality attributable to nosocomial pneumonia, i.e., the difference between the mortality rates observed for case patients (patients with pneumonia) and control subjects (patients without pneumonia). The results of matched cohort studies evaluating mortality and relative risk attributable to nosocomial pneumonia are given in Table 43-2.36,50,53–57 Of these seven studies, five concluded that VAP was associated with a significant attributable mortality. For example, it was reported that the mortality rate attributable to VAP exceeded 25%, corresponding to a relative risk of death of 2.0 (with respective values of 40% and 2.5 for cases of pneumonia caused by Pseudomonas or Acinetobacter spp.).50 These results were supported by those of other authors, who reported that the risk of mortality was almost three times higher in patients with pneumonia (RR = 2.95; 95% CI = 1.73−5.03) than those without, with a major impact being observed for patients with intermediate-grade severity.58

A recent clinical investigation to determine whether VAP is an independent risk factor for death matched 108 nonsurvivors with 108 survivors for their underlying diseases, age, admission date, severity of illness, and duration of MV59; 39 patients in each group developed VAP. This finding contrasts with those of other investigations, which identified the occurrence of VAP as an independent determinant of hospital mortality. Other factors beyond the simple development of VAP, such as the severity of the disease or the responsible pathogens, may be more important determinants of outcome for patients in whom VAP as well as other nosocomial infections develop. Indeed, it may well be that VAP increases mortality only in the subset of patients with intermediate severity58 and/or in patients with VAP caused by high-risk pathogens, as indicated earlier.9,51,52 It is probable that several case-control studies were confounded by the fact that patients with very low severity and early-onset pneumonia due to organisms such as Haemophilus influenzae or Streptococcus pneumoniae have excellent prognoses with or without VAP, whereas very ill patients with late-onset VAP occurring while they are in a quasi-terminal state would die anyway.

It is impossible to accurately evaluate the morbidity and excess costs associated with nosocomial pneumonia. However, with respect to morbidity measures, the prolonged hospital stay as a direct consequence of pneumonia has been estimated in several studies. Jimenez and colleagues45 demonstrated that nosocomial pneumonia extended the duration of MV from 10 to 32 days, and Craig and Connelly53 found that pneumonia lengthened the ICU stay threefold. Fagon and colleagues50 observed that the median length of stay in the ICU for the patients who developed VAP was 21 days versus a median of 15 days for controls (p <0.02). Recently, Baker and colleagues36 reported mean durations of MV, ICU stay, and hospital stay of 12.0, 20.5, and 43.0 days in trauma patients with pneumonia compared with 8.0, 15.0, and 34.0, respectively, in their matched controls (p <0.001). Similarly, Cunnion and colleagues54 demonstrated that the mean hospital stay after admission to the ICU was greater for cases of nosocomial pneumonia in surgical ICU patients (30.0 days versus 22.3 days in controls) and in medical and respiratory ICU patients (40.9 days versus 23.1 days in controls).

These prolonged hospitalizations underscore the considerable financial burden imposed by the development of nosocomial pneumonia. For Baker and colleagues,36 the extra hospital charges related to nosocomial pneumonia occurring in trauma patients were evaluated to be $40,000.

Etiologic Agents

Microorganisms responsible for VAP may differ according to the population of ICU patients, the durations of hospital and ICU stays, and the specific diagnostic method(s) used. The high rate of respiratory infections due to GNB in this setting has been documented repeatedly.9,12,17,60–64 Several studies have reported that more than 60% of VAPs are caused by aerobic GNB. More recently, however, some investigators have reported that gram-positive bacteria have become increasingly common in this setting, with S. aureus being the predominant gram-positive isolate. For example, S. aureus was responsible for most episodes of nosocomial pneumonia in the EPIC study, accounting for 31% of the 836 cases with identified responsible pathogens.64 The data from 24 investigations conducted on ventilated patients, for whom bacteriologic studies were restricted to uncontaminated specimens, confirmed those results: GNB represented 58% of recovered organisms9,12,14,16–19,32,36,39,65–78 (Table 43-3). The predominant GNB were P. aeruginosa and Acinetobacter spp., followed by Proteus spp., Escherichia coli, Klebsiella spp., and H. influenzae. A relatively high rate of gram-positive pneumonias also was reported in those studies, with S. aureus involved in 20% of the cases.

The high rate of polymicrobial infection in VAP has been emphasized repeatedly. In a study on 172 episodes of bacteremic nosocomial pneumonia, 13% of lung infections were caused by multiple pathogens.46 Similarly, when the PSB technique was used to identify the causative agents in 52 consecutive cases of VAP, a 40% polymicrobial infection rate was found,9 a value similar to that observed in another study conducted at the same time on a comparable population of ventilated patients.63

Underlying diseases may predispose patients to infection with specific organisms. Patients with chronic obstructive pulmonary disease (COPD) are, for example, at increased risk for H. influenzae, Moraxella catarrhalis, or S. pneumoniae infections; cystic fibrosis increases the risk of P. aeruginosa and/or S. aureus infections, whereas trauma and neurologic patients are at increased risk for S. aureus infections.26,36,52,79 Furthermore, the causative agent for pneumonia differs among ICU surgical populations,80 with 18% of the nosocomial pneumonias being due to Haemophilus or pneumococci, particularly in trauma patients but not in patients with malignancy, transplantation, or abdominal or cardiovascular surgery.

Despite somewhat different definitions of early-onset pneumonia, varying from less than 3 to less than 7 days,26,77 high rates of H. influenzae, S. pneumoniae, MSSA, or susceptible Enterobacteriaceae were constantly found in early-onset VAP, whereas P. aeruginosa,Acinetobacter spp., MRSA, and multiresistant GNB were significantly more frequent in late-onset VAP.26,76,77 This different distribution pattern of etiologic agents between early- and late-onset VAP is also linked to the frequent administration of prior antimicrobial therapy in many patients with late-onset VAP. In a prospective study that included 129 episodes of nosocomial pneumonia documented by PSB specimens, the distributions of responsible pathogens were compared according to whether or not the patients had received antimicrobial therapy before pneumonia onset.17 The most striking finding was that the rate of pneumonia caused by gram-positive cocci or H. influenzae was significantly lower (p <0.05) in patients who had received antibiotics, whereas the rate of pneumonia caused by P. aeruginosa was significantly higher (p <0.01). A stepwise logistic regression analysis retained only prior antibiotic use (odds ratio [OR] = 9.2; p <0.0001) as significantly influencing the risk of death from pneumonia.17 Very similar results were obtained when multivariate analysis was used to determine risk factors for VAP caused by potentially drug-resistant bacteria such as MRSA, P. aeruginosa, A. baumannii, and/or S. maltophilia in 135 consecutive episodes of VAP.77 Only three variables remained significant: duration of MV before VAP onset ≥7 days (OR = 6.0), prior antibiotic use (OR = 13.5), and prior use of broad-spectrum drugs (third-generation cephalosporin, fluoroquinolone, and/or imipenem) (OR = 4.1).77 Not all studies, however, have confirmed this distribution pattern. For example, one recent study found that the most common pathogens associated with early-onset VAP were P. aeruginosa (25%), MRSA (18%), and Enterobacter spp. (10%), with similar pathogens being associated with late-onset VAP.81 Their finding may be due in part to the prior hospitalization and use of antibiotics in many patients developing early-onset VAP before their transfer to the ICU.

The incidence of multiresistant pathogens is also closely linked to local factors and varies widely from one institution to another. Consequently, each ICU has to collect meticulous epidemiologic data continuously. With these aims, variations of VAP etiology among three Spanish ICUs were analyzed76 and compared with data collected in Paris.77 The authors concluded that VAP pathogens varied widely among these four treatment centers, with marked differences in all the microorganisms isolated from VAP episodes in Spanish centers as compared with the French site. Clinicians clearly must be aware of the common microorganisms associated with both early- and late-onset VAP in their own hospitals in order to avoid the administration of initial inadequate antimicrobial therapy.

Legionella spp.82,83 anaerobes,67 fungi,84 viruses,85 and even Pneumocystis carinii should be mentioned as potential causative agents but are not considered to be common in the context of pneumonia acquired during MV. However, several of these causative agents may be more common and potentially underreported because of difficulties involved with the diagnostic techniques used to identify them, including anaerobic bacteria and viruses.67,85 In a study conducted to determine the frequency of anaerobes in 130 patients with a first episode of bacteriologically documented VAP with special precautions taken to preserve anaerobic conditions during PSB transport and microbiologic procedures,67 anaerobes were involved in 23% of the total number of episodes, and the main strains isolated were Prevotella melaninogenica (36%), Fusobacterium nucleatum (17%), and Veillonella paravula (12%). The probability of recovering anaerobic bacteria was particularly high in orotracheally intubated patients and patients in whom pneumonia occurred during the 5 days after ICU admission. However, in a study conducted among 143 patients who developed 185 episodes of suspected VAP and 25 patients with aspiration pneumonia, only 1 anaerobic organism (V. paravula) was isolated from 1 patient with aspiration pneumonia, and none from patients with VAP.66 Thus, examining currently available data, the clinical significance of anaerobes in the pathogenesis and outcome of VAP remains unclear, except as etiologic agents in patients with necrotizing pneumonitis, lung abscess, or pleuropulmonary infections. Anaerobic infection and coverage with antibiotics, such as clindamycin or metronidazole, probably also should be considered for patients with Gram-stained respiratory secretions documenting numerous extra- and intracellular microorganisms in the absence of positive cultures for aerobic pathogens.

Isolation of fungi, most frequently Candida species, at significant concentrations poses interpretative problems. Invasive disease has been reported in VAP, but more frequently, yeasts are isolated from respiratory tract specimens in the apparent absence of disease. One prospective study examined the relevance of isolating Candida spp. from 25 nonneutropenic patients who had been mechanically ventilated for at least 72 hours.84 Just after death, multiple culture and biopsy specimens were obtained with bronchoscopic techniques. Although 10 patients had at least one biopsy specimen positive for Candida spp., only 2 had evidence of invasive pneumonia, as demonstrated by histologic examination. Many of the endotracheal aspirates, PSB specimens, and BAL specimens also yielded positive cultures for Candida spp., sometimes in high concentrations, but they did not contribute to diagnosing invasive disease. Based on these data, the use of the commonly available respiratory sampling methods (bronchoscopic or nonbronchoscopic) in mechanically ventilated patients appears insufficient for the diagnosis of Candida pneumonia. At present, the only sure method to establish that Candida is the primary lung pathogen is to demonstrate yeast or pseudohyphae in a lung biopsy. However, the significance of Candida isolation from the respiratory samples of mechanically ventilated patients merits being investigated in greater depth.86

A number of factors have been suspected or identified to increase the risk of pneumonia in the ICU, including those identified in the subset of mechanically ventilated patients; these factors are listed in Table 43-4. The data indicated specific high-risk populations (patients with COPD and ARDS, patients undergoing MV for more than 3 days, those requiring intracranial pressure monitoring, those with coma or impaired consciousness, and more generally, those with severe underlying medical conditions as evaluated by a high APACHE II or APACHE III score or the presence of organ failure) and specific treatment modalities or therapeutic intervention (use of H2 blockers or antacids; previous antibiotics; use of drugs that are markers for severe underlying disease such as dopamine, dobutamine, or barbiturate therapy; reintubation; and frequent changes of ventilator circuits, bronchoscopy, or nasogastric tube) as being independently associated with nosocomial pneumonia.

Surgery

Postoperative patients are at increased risk for pneumonia. In a study reported in 1981 by Garibaldi and colleagues,44 the incidence of pneumonia during the postoperative period was 17.2%. In this study, the authors stated that development of pneumonia was closely associated with preoperative markers of the severity of the underlying disease, such as low serum albumin concentration and a high score on the American Society of Anesthesiologists (ASA) preanesthesia physical status classification. A history of smoking, longer preoperative stays, longer surgical procedures, and thoracic or upper abdominal operative sites also were significant risk factors for postoperative pneumonia. In their study comparing adult critical care populations, Cunnion and colleagues54 demonstrated that surgical ICU patients were found to have consistently higher rates of nosocomial pneumonia than medical ICU patients with a risk ratio of 2.2. Multiple logistic regressions were performed to determine independent predictors for nosocomial pneumonia in the two groups; in SICU patients, mechanical ventilation (>2 days) and APACHE II score were identified by the model; in MICU patients, only mechanical ventilation (<2 days) remained significant. The relative importance of the surgical procedure itself versus intubation, prophylactic antibiotics, and/or other variables therefore remains to be clearly elucidated in surgical patients.

Antimicrobial Agents

The use of antibiotics in the hospital setting has been associated with an increased risk of nosocomial pneumonia and selection of resistant pathogens.17,37,49,64,77,79,87–89 In a cohort study of 320 patients, prior antibiotic administration was identified by logistic regression analysis to be one of the four variables independently associated with VAP along with organ failure, age greater than 60 years, and the patient's head positioning (i.e., flat on the back or supine versus head and thorax raised 30 to 40 degrees or semirecumbent).37 However, other investigators found that antibiotic administration during the first 8 days was associated with a lower risk of early-onset VAP.90,91 For example, Sirvent and colleagues92 showed that a single dose of a first-generation cephalosporin given prophylactically was associated with a lower rate of early-onset VAP in patients with structural coma. Moreover, multiple logistic regression analysis of risk factors for VAP in 358 medical ICU patients identified the absence of antimicrobial therapy as one of the factors independently associated with VAP onset.75 The same result was obtained for a particular subset of 250 patients with very early onset VAP, occurring within 48 hours of intubation, that was investigated to identify potential risk factors for developing VAP.93 Multivariate analysis selected cardiopulmonary resuscitation (OR = 5.13) and continuous sedation (OR = 4.40) as significant risk factors for pneumonia, whereas antibiotic use (OR = 0.29) had a protective effect. Finally, the results of the multicenter Canadian study on the incidence of and risk factors for VAP indicated that antibiotic treatment conferred protection against VAP.29 This apparent protective effect of antibiotics disappears after 2 to 3 weeks, suggesting that a higher risk of VAP cannot be excluded beyond this point. Thus risk factors for VAP change over time, thereby explaining why they differ from one series to another.

In contrast, prolonged antibiotic administration to ICU patients for primary infection is thought to favor selection and subsequent colonization with resistant pathogens responsible for superinfections.9,77,87,94–96 According to our data on 567 ventilated patients, those who had received antimicrobial therapy within the 15 days preceding lung infection were not at higher risk for development of VAP,9 but 65% of the lung infections that occurred in patients who had received broad-spectrum antimicrobial drugs versus only 19% of those developing in patients who had not received antibiotics were caused by Pseudomonas or Acinetobacter spp. In a 1988 investigation on mechanically ventilated baboons treated with a variety of regimens of intravenous and topical antibiotics or no antibiotics at all,94 polymicrobial pneumonia occurred in almost all untreated animals. However, baboons that had received prophylactic topical polymycin had only a slightly lower incidence of pneumonia, and the prevalence of drug-resistant microorganisms in the tracheal secretions was very high: 60% and 78% after 4 and 8 days of MV, respectively. Therefore, strong arguments suggest that the prophylactic use of antibiotics in the ICU increases the risk of superinfection with multiresistant pathogens while only delaying the occurrence of nosocomial infection.

Stress Ulcer Prophylaxis

According to meta-analyses of the efficacy of stress-ulcer prophylaxis in ICU patients, respiratory tract infections were significantly less frequent in patients treated with sucralfate than in those receiving antacids or H2 blockers.97–106 However, this conclusion was not fully confirmed in a very large, multicenter, randomized, blinded, placebo-controlled trial that compared sucralfate suspension (1 g every 6 hours) with the H2-receptor antagonist ranitidine (50 mg every 8 hours) for the prevention of upper gastrointestinal bleeding in 1200 patients who required MV.107 Clinically relevant gastrointestinal bleeding developed in 10 of the 596 (1.7%) patients receiving ranitidine as compared with 23 of the 604 (3.8%) patients receiving sucralfate (RR = 0.44; 95% CI = 0.21−0.92; p = 0.02). In the ranitidine group, 114 of 596 (19.1%) patients had VAP, as diagnosed by an adjudication committee using a modified version of the Centers for Disease Control and Prevention (CDC) criteria, versus 98 of 604 (16.2%) in the sucralfate group (RR = 1.18; 95% CI = 0.92−1.51; p = 0.19). Thus, although pneumonia rates were similar for the two groups, the relative risks suggest a trend toward a lower pneumonia rate for patients receiving sucralfate. Furthermore, VAP occurred significantly less frequently in patients receiving sucralfate when the diagnosis of pneumonia was based on Memphis VAP Consensus Conference criteria (if there was radiographic evidence of abscess and a positive needle aspirate or histologic proof of pneumonia at biopsy or autopsy) (p = 0.03).107

Sucralfate appears to have a small protective effect against VAP because stress-ulcer prophylactic medications that raise the gastric pH might themselves increase the incidence of pneumonia. This contention is supported by direct comparisons of trials of H2-receptor antagonists versus no prophylaxis, which showed a trend toward higher pneumonia rates among the patients receiving H2-receptor antagonists (OR = 1.25; 95% CI = 0.78−2.00).105 Furthermore, the comparative effects of sucralfate and no prophylaxis are unclear. Among 226 patients enrolled in two randomized trials, those receiving sucralfate tended to develop pneumonia more frequently than those given no prophylaxis (OR = 2.11; 95% CI = 0.82–5.44).108,109

Endotracheal Tube—Reintubation

The presence of an endotracheal tube by itself circumvents host defenses, causes local trauma and inflammation, and increases the probability of aspirating nosocomial pathogens from the oropharynx around the cuff. Sottile and colleagues110 studied 25 endotracheal tubes by scanning electron microscopy and found that 96% had partial bacterial colonization and 84% were completely covered by bacteria in a biofilm or glycocalyx. The authors suggested that aggregates of bacteria in biofilm dislodged during suctioning may not be killed by antibiotics or cleared effectively by host immune defenses. Clearly, the type of endotracheal tube also may influence the incidence of aspiration. With low-volume, high-pressure endotracheal cuffs, an incidence of 56% was reported, which decreased to 20% with the advent of high-volume, low-pressure cuffs. In addition to the presence of endotracheal tubes, reintubation is per se a risk factor for nosocomial pneumonia, as indicated by Torres and colleagues.111 This result is probably related to an increased risk of aspiration of colonized oropharyngeal secretions into the lower airways in patients with glottic dysfunction and/or impaired consciousness after several days of intubation. Another explanation is direct aspiration of gastric contents into the lower airways, particularly when a nasogastric tube is kept in place after extubation.

Tracheostomy

The role of early tracheostomy in VAP prevention remains controversial, with only a few studies that examined this issue.112–119 While some studies found a reduction in the rate of VAP in patients with early tracheostomy,115,116,118 others could not demonstrate any benefit.112 For example, in a randomized, prospective multicenter trial on 112 patients who were thought to need prolonged MV, there were no differences, at least until day 14, among ICU length of stay, pneumonia rate, and mortality between the 53 patients who underwent early (days 3 to 5) tracheostomy and the 59 who were managed using translaryngeal intubation.112 The major problem that doomed that study was the overwhelming physician bias, which led to limited patient entry and premature arrest of the study. In the absence of any meaningful data, practice patterns are influenced and guided by strong assumptions and quasi-religious dogma. Until a properly constructed randomized trial is performed to define the timing and utility of tracheostomy in the ICU, its true impact on decreasing VAP will remain merely speculative.120

Nasogastric Tube, Enteral Feeding, and Patient Position

Nearly all patients receiving mechanical ventilation have a nasogastric tube inserted to manage gastric and enteral secretions, prevent gastric distention, or provide nutritional support. The nasogastric tube is not widely considered to be a potential risk factor for pneumonia, but it may increase oropharyngeal colonization, cause stagnation of oropharyngeal secretions, and increase reflux and the risk of aspiration. Using multivariate analysis, Joshi and colleagues43 identified the presence of a nasogastric tube as one of the three independent risk factors for nosocomial pneumonia in a series of 203 patients admitted to the ICU for 72 hours or more.

Early initiation of enteral feeding generally is regarded as beneficial in critically ill patients, but it may increase the risk of gastric colonization, gastroesophageal reflux, aspiration, and pneumonia. Pingleton and colleagues121 evaluated simultaneous daily gastric, tracheal, and oropharyngeal cultures in 18 ventilator-dependent patients not receiving antacids or H2 antagonists. After starting enteral feeding, the number of gram-negative isolates increased significantly, and 5 patients (28%) had gram-negative rods that were first recovered in the stomach and subsequently identified in the trachea.

Maintaining mechanically ventilated patients with a nasogastric tube in place in the supine position is also a risk factor for aspiration of gastric contents into the lower airways. Torres and colleagues122 injected radioactive material via a nasogastric tube directly into the stomachs of 19 mechanically ventilated patients and found that mean radioactive counts in endobronchial secretions were higher in a time-dependent fashion in samples obtained while patients were in the supine position than in those obtained while patients were in the semirecumbent position. The same microorganisms were isolated from stomach, pharynx, and endobronchial samples in 32% of the specimens taken while patients were semirecumbent and in 68% of those taken while patients were in the supine position. These results suggest that placing mechanically ventilated patients in the semirecumbent position is a simple and effective means to minimize aspiration of gastric contents into lower airways and hence constitutes a recommendable, no-cost prophylactic measure for those who can tolerate this position. Such experimental results were confirmed indirectly by Kollef,37 who demonstrated that supine patient head positioning during the first 24 hours of mechanical ventilation was an independent risk factor for acquiring VAP.

Respiratory Equipment

Respiratory equipment itself may act as a source of bacteria responsible for nosocomial pneumonia. In past years, the major risk of infection was associated with contaminated reservoir nebulizers designed to deliver small-sized particles suspended in the effluent gas. These observations led to current trends in respiratory therapy toward the use of cascade humidifiers, which do not generate microaerosols. Nevertheless, respiratory equipment continues to provide a source of bacterial contamination. For example, medication nebulizers inserted into the inspiratory-phase tube of the mechanical ventilator circuit may produce bacterial aerosols after a single use.

Mechanical ventilators with humidifying cascades often have high levels of tubing colonization and condensate formation that also may be risk factors for pneumonia. The rate of condensate formation in the ventilator circuit is linked to the temperature difference between the inspiratory-phase gas and the ambient temperature and may be as high as 20 to 40 mL/h.123 Craven and colleagues124 examined condensate colonization in 20 circuits and found a median level of 2.0 × 105 organisms/mL, and 73% of the 52 gram-negative isolates present in the patient's sputum were isolated subsequently from condensate. Since most of the tubing colonization was derived from the patient secretions, the highest bacterial counts were present near the endotracheal tube. Simple procedures such as turning the patient or raising the bed rail may accidently wash contaminated condensate directly into the patient's tracheobronchial tree. Inoculation of large amounts of fluid with high bacterial concentrations is an excellent way of overwhelming pulmonary defense mechanisms and producing pneumonia. Heating ventilator tubing markedly reduces the rate of condensate formation, but heated circuits often are nondisposable and are expensive. To date, no scientific evidence confirms that heated circuits reduce the incidence of VAP. In-line devices with one-way valves to collect condensate are probably the easiest way to handle this problem. They should be positioned correctly into disposable circuits and emptied regularly.

Sinusitis

While many studies have compared the risk of nosocomial sinusitis as a function of the intubation method used and the associated risk of VAP,125–141 only a few were powered adequately to give a clear answer. In one study on 300 patients who required MV for at least 7 days and were randomly assigned to undergo nasotracheal or orotracheal intubation, computed tomographic (CT) evidence of sinusitis was observed slightly more frequently in the nasal than oral endotracheal group (p = 0.08), but this difference disappeared when only bacteriologically confirmed sinusitis was considered.137 The rate of infectious maxillary sinusitis and its clinical relevance also were studied prospectively in 162 consecutive critically ill patients who had been intubated and mechanically ventilated for 1 hour to 12 days before enrollment.135 All had a paranasal CT scan within 48 hours of admission that was used to divide them into three groups (no, moderate, or severe sinusitis) according to the radiologic appearance of the maxillary sinuses. Patients who had no sinusitis at admission (n = 40) were randomized to receive endotracheal and gastric tubes via the nasal or oral route, and based on radiologic images, respective sinusitis rates were 96% and 23% (p <0.03), yet, no differences in the rates of infectious sinusitis were documented according to the intubation route. However, VAP was more common in patients with infectious sinusitis, with 67% of them developing lung infection in the days following the diagnosis of sinusitis.135 Therefore, whereas it seems clear that infectious sinusitis is a risk factor for VAP, no studies have yet been able to demonstrate definitively that orotracheal intubation decreases the infectious sinusitis rate compared with nasotracheal intubation, and thus no firm recommendations on the best route of intubation to prevent VAP can be advanced.

Intrahospital Patient Transport

A prospective cohort study conducted on 531 mechanically ventilated patients evaluated the impact of transporting the patient out of the ICU to other sites within the hospital.142 Results showed that 52% of the patients had to be moved at least once for a total of 993 transports and that 24% of the transported patients developed VAP compared with 4% of the patients confined to the ICU (p <0.001). Multiple logistic regression analysis confirmed that transport out of the ICU was independently associated with VAP (OR = 3.8; p <0.001).

Background and Description

The diagnosis of VAP usually is based on three components: systemic signs of infection, new or worsening infiltrates seen on the chest roentgenogram, and bacteriologic evidence of pulmonary parenchymal infection.30 The systemic signs of infection, such as fever, tachycardia, and leukocytosis, are nonspecific findings and can be caused by any condition that releases cytokines.143 In trauma and other surgical patients, fever and leukocytosis should prompt the physician to suspect infection, but during the early posttraumatic or postoperative period (i.e., during the first 72 hours), these findings usually are not conclusive. However, later, fever and leukocytosis are more likely to be caused by infection, but even then, other events associated with an inflammatory response (e.g., devascularized tissue, open wounds, pulmonary edema, and/or infarction) can be responsible for these findings.

Although the plain (usually portable) chest roentgenogram remains an important component in the evaluation of hospitalized patients with suspected pneumonia, it is most helpful when it is normal and rules out pneumonia. When infiltrates are evident, the particular pattern is of limited value for differentiating among cardiogenic pulmonary edema, noncardiogenic pulmonary edema, pulmonary contusion, atelectasis (or collapse), and pneumonia. Because atelectasis is common in ICU patients, the contribution of repeating the chest x-ray after vigorous pulmonary physiotherapy was emphasized to differentiate infiltrates caused by atelectasis from those due to infection.144 Few studies have examined the accuracy of the portable chest radiograph in the ICU.30,145–150 In a review of 24 patients with autopsy-proven pneumonia who were receiving MV, no single radiographic sign had a diagnostic accuracy of more than 68%.145 The presence of air bronchograms was the only sign that corresponded well to pneumonia, correctly predicting 64% of pneumonias in the entire group. When the group was divided into patients with and without ARDS, however, a significant difference was noted. The presence of air bronchograms or alveolar opacities in patients without ARDS correlated with pneumonia, whereas no such correlation was found for patients with ARDS. A number of causes other than pneumonia can explain asymmetric consolidation in patients with ARDS, e.g., atelectasis, emphysema, pulmonary edema, and thromboembolic disease. Marked asymmetry of radiographic abnormalities also has been reported in patients with uncomplicated ARDS.151

Microscopic evaluation and nonquantitative culture of tracheal secretions and/or expectorated sputum also frequently are inconclusive for patients clinically suspected of having pneumonia because the upper respiratory tract of most ICU patients is colonized with potential pulmonary pathogens whether or not parenchymal pulmonary infection is present.63,89,152–154 Based on specimens obtained simultaneously from the deep trachea and lung for culture from 48 patients with respiratory failure undergoing open-lung biopsy, culture results agreed for only 40% of these paired samples.155 For patients with histologically documented pneumonia, endotracheal aspirate sensitivity was 82%, but its specificity was only 27%.

Ideally, any diagnostic strategy intended to be used in patients suspected clinically of having developed VAP should be able to reach the three following objectives: (1) to accurately identify patients with true pulmonary infection and, in case of infection, to isolate the causative microorganisms (in order to initiate immediate appropriate antimicrobial treatment and then to optimize therapy based on susceptibility patterns), (2) to identify patients with extrapulmonary sites of infection, and (3) to withhold and/or withdraw antibiotics in patients without infection.

Two diagnostic algorithms can be used in case of VAP suspicion. One option is to treat every patient suspected clinically of having a pulmonary infection with new antibiotics, even when the likelihood of infection is low, arguing that several studies showed that immediate initiation of appropriate antibiotics was associated with reduced mortality.19,156–158 In this option, the selection of appropriate empirical therapy is based on risk factors and local resistance patterns and involves qualitative testing to identify possible pathogens, antimicrobial therapy being adjusted according to culture results or clinical response (Fig. 43-1). This “clinical” approach has two potential advantages: First, no specialized microbiologic techniques are requested, and second, the risk of missing a patient who needs antimicrobial treatment is minimal, at least when all suspected patients are treated with new antibiotics. However, such a strategy leads to overestimation of the incidence of VAP because tracheobronchial colonization and noninfectious processes mimicking it are included. Qualitative endotracheal aspirate cultures contribute indisputably to the diagnosis of VAP only when they are completely negative for a patient with no modification of prior antimicrobial treatment. In such a case, the negative-predictive value is very high, and the probability of the patient having pneumonia is close to null.24

Concern about the inaccuracy of clinical approaches to VAP recognition had led numerous investigators to postulate that “specialized” diagnostic methods, including quantitative cultures of endotracheal aspirates or specimens obtained with bronchoscopic or nonbronchoscopic techniques such as BAL and/or PSB, could improve identification of patients with true VAP and facilitate decisions about whether or not to treat and thus clinical outcome.19,27,74,159,160 Using such a strategy, the decision algorithm is similar to the one described in Figure 43-1, except that therapeutic decisions are taken based on results of direct examination of distal pulmonary samples and results of quantitative cultures (Fig. 43-2).

Summary of the Evidence

Other than decision-analysis studies161,162 and one retrospective study,163 only four trials have so far assessed the impact of a diagnostic strategy on antibiotic use and outcome of patients suspected of having VAP using a randomized scheme.72–74,164 No differences in mortality and morbidity were found when either invasive (PSB and/or BAL) or noninvasive (quantitative endotracheal aspirate cultures) techniques were used to diagnose VAP in three Spanish randomized studies.72,73,164 However, those studies were based on relatively few patients (51, 76, and 88, respectively), and antibiotics were continued in all patients despite negative cultures, thereby neutralizing one of the potential advantages of any diagnostic test in patients clinically suspected of having VAP. Concerning the latter, several prospective studies have concluded that antibiotics indeed can be stopped in patients with negative quantitative cultures with no adverse effects on the recurrence of VAP and mortality.19,70,163,165,166 One of the first studies to clearly demonstrate a benefit in favor of invasive techniques was a prospective, randomized trial that compared the two strategies in 413 patients suspected of having VAP.74 Compared with patients managed clinically, those receiving invasive management had a lower mortality rate on day 14 (16% and 25%; p = 0.02) and lower mean sepsis-related organ failure assessment scores on days 3 and 7 (p = 0.04). At 28 days, the invasive-management group had significantly more antibiotic-free days (11 ± 9 versus 7 ± 7; p <0.001), and only multivariate analysis showed a significant difference in mortality (hazards ratio [HR] = 1.54; 95% CI = 1.10–2.16; p = 0.01).74 Thus implementation of bronchoscopic techniques for the diagnosis of VAP may reduce antibiotic use and improve patient outcome.

Because VAP in the ICU has substantial attributable mortality, there is justification,albeit unwarranted at times, to use antibiotics for patients withpulmonary infiltrates despite a low likelihood of infection. A recent randomized study proposed to minimize excessive use of antibacterial agents but still allow clinicians flexibility in managing patients with a perceived treatable infection.167 Patients with a clinical pulmonary infection score (CPIS) of 6 or less (implying low likelihood of pneumonia) were randomized to receive either standard therapy (choice and duration of antibiotics at the discretion of physicians) or ciprofloxacin monotherapy with re-evaluation on day 3; ciprofloxacin was discontinued when CPIS remained 6 or less. Antibiotics were continued beyond 3 days for 90% (38 of 42) of the patients receiving standard therapy compared with 28% (11 of 39) in the ciprofloxacin group (p = 0.0001). Mortality and length of ICU stay did not differ despite the shorter duration (p = 0.0001) and lower cost (p = 0.003) of antimicrobial therapy in the monotherapy than in the standard-therapy arm. Antimicrobial resistance, superinfections, or both developed in 15% of the patients in the ciprofloxacin versus 35% of the patients in the standard-therapy group (p = 0.017). Such an approach thus may lead to significantly lower antimicrobial therapy costs, antimicrobial resistance, and superinfections without adversely affecting the length of stay or mortality and merits prospective analysis in a large study sample. However, it should be emphasized that this strategy was tested in relatively few patients (n = 81) and that only 42% of patients included in the study did not require MV. Thus it remains to be precisely determined whether this strategy can perform as well when it is applied to mechanically ventilated patients.

Operating characteristics of nonbronchoscopic techniques for diagnosing VAP are probably very similar to those based on bronchoscopy, with only small differences in their sensitivities, specificities, positive predictive values, and likelihood ratios.168 Therefore, the choice of procedure(s) eventually may depend on the preferences and experiences of individual physicians and the patient's underlying disease(s). Despite broad clinical experience with the PSB and BAL techniques, it remains, nonetheless, unclear which one should be used in clinical practice. Most investigators prefer to use BAL rather than PSB to diagnose bacterial pneumonia because BAL (1) has a slightly higher sensitivity to identify VAP-causative microorganisms, (2) enables better selection of an empirical antimicrobial treatment before culture results are available, (3) is less dangereous for many critically ill patients, (4) is less costly, and (5) may provide useful clues for the diagnosis of other types of infections.27 However, it must be acknowledged that a very small return on BAL may contain only diluted material from the bronchial rather than alveolar level and thus give rise to false-negative results, particularly for patients with very severe COPD. In these patients, the diagnostic value of BAL techniques is greatly diminished, and the PSB technique should be preferred.169

Cultures of pulmonary secretions for diagnostic purposes after initiation of new antibiotic therapy in patients suspected of having developed VAP clearly can lead to a high number of false-negative results regardless of the way in which these secretions are obtained. Using a lower threshold to define a positive quantitative result in such a setting may be inaccurate because follow-up cultures can be completely negative in at least 40% of true cases of VAP.65,170,171 Pulmonary secretions therefore need to be obtained before new antibiotics are administered, as is the case for all microbiologic samples.

Conclusions and Recommendations

Available evidence suggests that reliance on clinical signs and endotracheal aspirate culture results leads to overdiagnosis of VAP. When performed before introduction of new antibiotics, the use of quantitative culture techiques after having obtained PSB and/or BAL specimens from the lung of patients with signs suggestive of VAP allows definition of a therapeutic strategy that is superior to that based exclusively on clinical evaluation, minimizing the use of unnecessary antibiotics with no adverse effects on patient outcome (see Fig. 43-2). In patients with clinical evidence of severe sepsis or patients with a very high pretest probability of the disease, the initiation of antibiotic therapy should not be delayed, and patients should be treated immediately with broad-spectrum antibiotics, even when no bacteria are detected using microscopic examination of pulmonary secretions. Although the true impact of this decision tree on patient outcome remains controversial, being able to withhold antimicrobial treatment from some patients without infection may constitute a distinct advantage in the long term by minimizing the emergence of resistant microorganisms in the ICU and redirecting the search for another (the true) infection site.

When quantitative culture techniques are not available to physicians treating patients clinically suspected of having VAP, we recommend following a clinical strategy, emphasizing that antimicrobial treatment should be re-evaluated on day 3, when susceptibility patterns of the microorganism(s) considered to be causative are available, in order to select treatment with a narrower spectrum or even to stop antimicrobial therapy if the clinical outcome is barely compatible with a diagnosis of pneumonia.167

Evaluation of Current Antimicrobial Strategies

Despite many advances in antimicrobial therapy, successful treatment of patients with nosocomial pneumonia remains a difficult and complex undertaking. No consensus has been reached concerning issues as basic as the optimal antimicrobial regimen for therapy or duration of treatment. Although some investigators have recommended two-drug parenteral therapy for most cases, recent data have demonstrated the efficacy of newer β-lactam antibiotics as monotherapy for some patients. Similarly, the efficacy of endotracheal or aerosolized antibiotics as either the sole or adjunctive therapy for gram-negative pneumonia remains controversial. In fact, to date, evaluation of various antimicrobial strategies for the treatment of bacterial pneumonia in mechanically ventilated patients has been difficult for several reasons.

First, as indicated earlier, obtaining a definitive diagnosis of pneumonia in critically ill patients is far from easy. Although clinically distinguishing between bacterial colonization of the tracheobronchial tree and true nosocomial pneumonia is difficult, nearly all previous therapeutic investigations have relied solely on clinical diagnostic criteria and therefore probably have included patients who did not have pneumonia. Second, most of these studies used cultures of tracheal secretions as the major source of samples for microbiologic analysis despite the fact that the upper respiratory tract of most ventilated patients usually is colonized with multiple potential pathogens. Finally, the lack of an adequate technique to directly sample the infection site in the lung has hampered study of both the ability or inability of antibiotics to eradicate the causative pathogens from the lower respiratory tract and therefore the ability to predict their bacteriologic efficacy.

Recently, Montravers and colleagues65 evaluated the bacteriologic and clinical efficacy of antimicrobial therapies selected on the basis of the etiologic microorganisms identified by cultures of PSB samples obtained during bronchoscopy for the treatment of nosocomial bacterial pneumonia in 76 patients receiving MV. Using follow-up PSB sample culture to assess the infection site in the lung directly, their results demonstrated that the administration of an antimicrobial therapy combining, in most cases, two effective agents was able to sterilize or contain the lower respiratory tract infection after only 3 days of treatment in 67 (88%) of the patients included in the study. The only two bacteriologic failures were observed in patients who did not receive adequate treatment because of errors in the selection of antimicrobial drugs. Early superinfection caused by bacteria resistant to the initial antibiotics was, however, documented in 7 (9%) patients, emphasizing the need to monitor carefully the impact of treatment on the initial microbial flora for optimal management of such patients when the clinical response is suboptimal. Furthermore, results of cultures of follow-up PSB samples were well correlated with the clinical outcome noted during the 15-day observation period, making this test a good prognostic indicator in patients with nosocomial bacterial pneumonia. Whereas the percentage of patients with clinical improvement was 96% and 82% in those with sterilized or persistent low-grade infection, respectively, it was only 44% in those with persistent high-grade infection.65 Using such techniques to sample the infection site in the lung directly therefore may provide a more rigorous evaluation of different antimicrobial strategies.

Factors Contributing to Selection of Initial Treatment

The important prognostic role played by the adequacy of the initial empirical antimicrobial therapy was analyzed by several investigators and is summarized in Table 43-5.19,73,158,164,172–174 Factors to be considered for the optimal selection of initial antibiotic therapy include (1) putative causative pathogens and their patterns of antibiotic susceptibilities, based on the clinical setting and previous epidemiologic studies, (2) data obtained by surveillance cultures in the same patient, (3) information given by direct microscopic examination of pulmonary secretions, and (4) intrinsic antibacterial activities of antimicrobial agents and their pharmacokinetic characteristics.

Clinical Setting

Underlying diseases and specific risk factors may predispose patients to infection with specific organisms, as well as some intrinsic factors linked to each hospital or ICU.26 Therefore, selection of initial antimicrobial therapy needs to be tailored to each institution's local patterns of antimicrobial resistance.76 Patients with COPD, for example, are at increased risk of H. influenzae infection, whereas cystic fibrosis would increase the risk of P. aeruginosa and S. aureus infection. On the other hand, trauma and neurosurgical patients are at increased risk of S. aureus infection. Based on the results of a French prospective study in which the responsible microorganisms for infection in 135 consecutive episodes of VAP observed in the ICU were documented using bronchoscopic specimens, the distribution of infecting pathogens was influenced markedly by prior duration of MV and prior antibiotic use.77 While early-onset pneumonias in patients who had not received prior antimicrobial treatment were caused mainly by susceptible Enterobacteriaceae, Haemophilus spp., MSSA, or S. pneumoniae, early-onset pneumonias in patients who had received prior antibiotics commonly were caused by nonfermenting GNB such as P. aeruginosa, in addition to streptococci and Haemophilus spp. On the other hand, late-onset pneumonias that occurred without antibiotics during the 15 days preceding the onset of infection largely were caused by streptococci, MSSA, or Enterobacteriaceae; however, some of these GNBs were class I cephalosporinase producers, which may require treatment with a new cephalosporin, such as cefepime or cefpirome, for optimal therapy. Late-onset pneumonias in patients having recently received antibiotics were caused by multiresistant pathogens such as P. aeruginosa, A. baumannii, or MRSA in more than 40% of cases. Taking these epidemiologic characteristics into account allowed the authors to devise a rational decision tree for selecting initial treatment in this setting that prevents resorting to broad-spectrum drug coverage in all patients (Table 43-6). A computerized decision-support program linked to computer-based patient records can facilitate the dissemination of such information to physicians for immediate use in therapy decision making and improve the quality of care.175

Routine Surveillance Culture Results

Several investigators have recommended routine surveillance cultures of ICU patients because they may be predictive of patients who are at high risk of invasive disease, and furthermore, should invasive disease develop, empirical therapy can be selected based on the predominant pathogens identified in these cultures.15 However, the accuracy of this approach for selecting initial antimicrobial treatment for ICU patients requiring new antibiotics for VAP has not yet been established. This hypothesis was retested recently in a prospective study conducted on 125 patients who required MV for more than 48 hours and for whom strict bronchoscopic criteria were applied to diagnose pneumonia and identify the causative pathogens.176 Although a large number of various prior microbiologic specimen culture results (mean = 45 ± 43 per episode) were obtained before FOB for each VAP episode, only 73 (33%) of the 220 VAP-causative microorganisms were isolated by these routine analyses and their susceptibility patterns available to guide initial antimicrobial treatment. When the analysis focused on VAP episodes for which prior (within 72 hours) respiratory secretion culture results were available, hypothesizing that this microbiologic information might be particularly useful for identifying the responsible organisms in the case of subsequent pneumonia, results were better but still disappointing because all causative pathogens were recovered for less than 60% of them. Such a strategy also may increase the workload of the microbiology laboratory considerably without having any positive impact on patient management.

Colonization with potentially drug-resistant pathogens, such as MRSA or extended-spectrum β-lactamase-producing strains of Klebsiella pneumoniae or other Enterobacteriaceae, is associated with an increased risk of infection caused by the corresponding microorganism. These results were confirmed in the study by Hayon and colleagues,176 with positive predictive values of recovering such a microorganism from a specimen of 62%, 52%, or 24% for VAP caused by MRSA, P. aeruginosa, or A. baumannii, respectively. However, because the sensitivity of prior microbiologic culture results for identifying bacteria causing VAP do not exceed 70%, selection of initial antimicrobial therapy for patients with VAP hardly can be based only on these results, especially for deciding to use (or not) vancomycin and/or a broad-spectrum β-lactam, which are effective against P. aeruginosa and/or A. baumannii. However, when one of the three microorganisms (or any pathogen) is isolated from respiratory secretions within 72 hours of VAP, it probably should be covered by the antimicrobial regimen selected, even though predictive values do not exceed 50% to 60%.

Information Given by Direct Examination of Pulmonary Secretions

Direct microscopy of pulmonary secretions is extremely important not only to identify patients with true VAP but also to select appropriate treatment, especially when BAL specimens are used to prepare cytocentrifuged Gram-stained smears. In patients with pneumonia, the morphology and Gram staining of bacteria are closely correlated with the results of bacterial cultures, enabling early formulation of a specific antimicrobial regimen before the culture results are available. In a study of 94 mechanically ventilated patients with suspected VAP who underwent FOB with BAL and PSB, direct BAL fluid examination results were available within 2 hours, BAL and PSB culture results were available after 24 hours, and antibiotic susceptibility was available after 48 hours.71 At each step in the strategy, the senior physician and the resident in charge of the patient were asked their diagnoses and their therapeutic plans based on the available data. Using a threshold of 1% infected cells, direct BAL examination discriminated well between patients with and without VAP (sensitivity 94%, specificity 92%, area under the receiver operating characteristic curve 0.95). In contrast, the senior clinical judgment before FOB was correct for only 71% of the patients compared with the definitive diagnosis and final antibiotic susceptibility test results. In addition, the therapeutic prediction was correct for 65% using clinical judgment (15 untreated patients, 3 ineffective treatments, and 15 unnecessary treatments), 66% using airway visualization (14 untreated VAP patients, 4 ineffective treatments, and 14 unnecessary treatments), and 88% using direct BAL examination results (1 untreated patient, 6 ineffective treatments, and 4 unnecessary treatments). Therefore, a strategy based on bronchoscopy and direct examination of BAL fluid may lead to more rapid and appropriate treatment of VAP than a strategy based only on clinical evaluation.

Intrinsic Antibacterial Activities of Antimicrobial Agents

Intrinsic antibacterial activities of antimicrobial agents used for the treatment of nosocomial pneumonia, based on frequently reported pathogens associated with this type of infection, are indicated in Table 43-7. Effective antibiotic treatment of bacterial pneumonia depends on adequate delivery of antibacterial agents to the infection site, and therefore, scrupulous attention must be given to optimal doses, route of administration, and pharmacodynamic characteristics of each agent used to treat this infection. Owing to major methodologic problems, published data concerning the penetration of most antibiotics into the lung probably should be viewed with caution, and only general trends concerning concentrations achievable at the infected site in lung tissue can be derived from those studies.177

For penicillins and cephalosporins, the bronchial secretion-to-serum-drug-concentration ratios range between 0.05 and 0.25. Fluoroquinolones have better penetration characteristics, and bronchial secretion concentrations are between 0.8 and 2 times those in serum. Aminoglycosides and tetracyclines have ratios of 0.2 to 0.6. Host-related as well as drug-related factors may, however, influence the penetration of antimicrobial drugs across the blood-bronchus and alveolar-capillary barriers. Thus, for those drugs, such as the β-lactams and the glycopeptides, which do not cross membranes readily, penetration may increase in the presence of inflammation because of enhanced membrane permeability.178

Several published reports have demonstrated a relationship among serum concentrations of β-lactams or other antibiotics, the in vitro minimal inhibitory concentration (MIC) of the infecting organism, and the rate of bacterial eradication from respiratory secretions in patients with lung infection, thereby emphasizing that clinical and bacteriologic outcomes can be improved by optimizing the therapeutic regimen according to pharmacokinetic properties of the agent(s) selected for treatment.179–182 Most investigators distinguish between antimicrobial agents that kill by a concentration-dependent mechanism (e.g., aminoglycosides and fluoroquinolones) and those that kill by a time-dependent mechanism (e.g., β-lactams and vancomycin).

Development of a priori dosing algorithms based on MIC, patient creatinine clearance and weight, and a clinician-specified pharmacokinetic-pharmacodynamic variable, such as the 24-hour area under the concentration-time curve divided by the MIC (AUIC), therefore may be a valid way to improve treatment of these patients, leading to a more precise approach than current guidelines for optimal use of antimicrobial agents.

De-Escalation

Once the microbiologic data become available, it is necessary to de-escalate therapy to avoid prolonged use of a broader spectrum of antibiotic therapy than is justified by the available information.183 For many patients, including those with late-onset infection, the culture data will not show the presence of highly resistant pathogens, and in these individuals, therapy can be narrowed or even reduced to a single agent in light of the susceptibility pattern of the causative pathogens without risking inappropriate treatment. While a de-escalating approach to antibiotic therapy (i.e., culture-guided treatment) may not help individual patients, it could benefit the ICU as a whole by reducing the selection pressure for resistance. Every possible effort therefore should be made to obtain, before new antibiotics are administered, reliable pulmonary specimens for direct microscope examination and cultures from each patient clinically suspected of having developed VAP.

Monotherapy versus Combination Therapy

Several studies have examined the use of a single antibiotic, e.g., a third-generation cephalosporin, imipenem-cilastatin, or a fluoroquinolone, to treat VAP.27,184 In general, monotherapy has proven to be a useful alternative to combination therapy, with the same success rate and no more superinfections or colonizations by multiresistant pathogens.185 Because these studies included nonhomogeneous populations of patients with different types of infections, and given the potential inaccuracy of using only clinical criteria to diagnose lung infection, further trials are needed to clarify all these uncertainties. Furthermore, for patients with severe infection due to P. aeruginosa or other multiresistant bacteria, such as Klebsiella spp. or Acinetobacter spp., combining an antipseudomonal β-lactam with an aminoglycoside or ciprofloxacin is likely to obtain a much better outcome than monotherapy, as shown previously. In a prospective clinical study of 200 patients with P. aeruginosa bacteremia, mortality rates for patients with pneumonia receiving monotherapy or combination therapy as the initial empirical treatment were 88% (7 of 8 patients) and 35% (7 of 20 patients), respectively (p = 0.03).186 Similarly, for the subgroup of 55 patients who experienced hypotension within 72 hours prior to or on the day of the positive blood culture in a prospective observational study on 230 Klebsiella bacteremias, the mortality rate was significantly lower for patients who received combination therapy (24%) than for those given monotherapy (50%).187 It should be noted, however, that the β-lactam agents used in these studies were older agents with less potent activity than the advanced cephalosporins or carbapenems available today.

Based on these data, it is probably safer to use a β-lactam antibiotic in combination with an aminoglycoside or a quinolone for patients with severe VAP, at least for the first days of therapy while culture results of pulmonary secretions are pending. It may be that monodrug therapies for nosocomial pneumonia would best be reserved for infections in which P. aeruginosa or other multiresistant microorganisms, such as Klebsiella, Enterobacter, Citrobacter, Serratia, or Acinetobacter spp. have been excluded as the etiologic agents.

Duration of Antimicrobial Therapy

The optimal antimicrobial regimen and duration of therapy for patients who develop pneumonia have not been established. Most experts recommend that the duration be adapted to the severity of the disease, the time to clinical response, and the microorganism(s) responsible.26 A “long” treatment, i.e., a minimum of 14 to 21 days, is prescribed for the following situations: multilobular involvement, malnutrition, cavitation, gram-negative necrotizing pneumonia, and isolation of P. aeruginosa or Acinetobacter spp., which correspond to the majority of pulmonary infections occurring in patients requiring mechanical ventilation. This duration is essentially justified by the high theoretical risk of relapse, especially in case of infection caused with P. aeruginosa, which is particularly difficult to eradicate from the respiratory tract.188 Thus, at present, a short-term regimen is rarely prescribed in patients who develop VAP, despite the potential major advantages it could have in terms of bacterial ecology and the prevention of emergence of multiresistant bacteria. Lowering the amount of antibiotics administered to patients hospitalized in ICUs is indeed a primary objective of every strategy aimed at reducing the emergence and dissemination of such bacteria.189

Because VAP has been associated with increased morbidity, longer hospital stays, increased health care costs, and higher mortality rates, prevention of this infection is a major challenge for intensive care medicine. A number of preventive strategies have been tested, and a number of recommendations have been published.120,190–194 However, evaluation of the impact of such interventions is a complex issue. Three methodologic difficulties make the measurement of potential efficacy of prevention strategies for VAP of limited value: (1) the difficulty of obtaining an accurate diagnosis of VAP (in fact, only patients who develop true VAP are likely to benefit from preventive measures), (2) the difficulty of precisely determining the impact of prophylactic measures on the overall mortality of a general ICU population (i.e., to identify preventable deaths directly attributable to VAP among all deaths occurring in a population of ventilated ICU patients), and (3) the difficulty of assessing the consequences of a preventive measure on a potentially pathogenic mechanism—a surrogate outcome (e.g., to determine the exact role played by prevention or reduction or modulation 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.195 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 adequate facilities for hand washing lead to lower infection rates.196 However, it should 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 probably the team that staffs it: the number, quality, and motivation of its medical, nursing, and ancillary members. The team should include a sufficient number of nurses to avoid having them move from one patient to another and to avoid working under constant pressure.197 The importance of personal cleanliness (education and awareness programs) and attention to aseptic procedures (simple barrier isolation methods based on the use of disposable gowns and nonsterile gloves) must be emphasized at every possible opportunity. It is clear that careful monitoring, decontamination, and compliance with the usage guidelines of respiratory equipment decrease the incidence of nosocomial pneumonia.198 In any case, hand washing or hand rubbing with alcohol-based solutions remains uncontested as the most important infection control practice.197,199

A bacterial monitoring policy facilitates the early recognition of colonization and infection and has been associated with statistically significant reductions in nosocomial infection rates.200 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 recognition of the onset of an epidemic when infection rates rise above a calculated threshold.

Preventing infection by modifying host risk has focused on treatment of underlying diseases and complications and control of antibiotic use. Adoption of an antibiotic policy restricting the prescription of broad-spectrum agents and useless antibiotics is of major importance.201 Simple, safe, inexpensive, logical, but unproven measures, including the use of physiotherapy,202 the judicious use and prompt removal of nasogastric tubes,43 and removal of tubing condensate, may have tremendous impact on the frequency of nosocomial pneumonia in mechanically ventilated patients.124

Specific Prophylaxis Against VAP

Since invasive MV is a risk factor for VAP, strategies that reduce its duration may reduce its incidence. Optimization of weaning protocols is a first way to reduce the duration of exposure to risk.203,204 Noninvasive ventilation is an alternative approach to the use of artificial airways to avoid infectious complications and injury of the trachea in patients with acute respiratory failure. Many observations and studies, unfortunately small and not blinded, suggest that patients who tolerate noninvasive ventilation have a lower incidence of pneumonia than those intubated tracheally, whatever the possible explanations: noninvasive ventilation itself or differences in disease severity, in the distribution of risk factors for VAP, or in the duration of exposure to each of the two ventilation methods.205–208 However, although seven randomized trials have compared noninvasive ventilation with conventional MV for prevention of pneumonia, only one could demonstrate a statistically significant benefit in favor of noninvasive ventilation.204,209–214

Apart from these protocols aiming at reducing the duration of mechanical ventilation, seven 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, and antibiotic use, including selective digestive decontamination.

Semirecumbent Positioning

Supine patient positioning has been shown to be independently associated with the development of VAP.37 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. Three trials have evaluated the potential efficacy of semirecumbent positioning,122,215,216 but only one measured the incidence of VAP.215 This trial, which included 86 intubated and mechanically ventilated patients, was stopped after the planned interim analysis because the frequency and risk of VAP were significantly lower for the semirecumbent group. These findings were confirmed indirectly by demonstration that the head position of the supine patient during the first 24 hours of MV was an independent risk factor for acquiring VAP.215 No adverse effects were observed in patients assigned to semirecumbent positioning.

Semirecumbent positioning is a low-cost, low-risk preventive approach that merits being considered in all ventilated patients, whenever feasible.

Oscillating and Rotating Beds

Immobility in critically ill patients treated with MV results in atelectasis and impaired secretions drainage and potentially predisposes to pulmonary complications, including VAP. Oscillating and rotating beds may help in preventing pneumonia.217–224 Six randomized trials, including mostly surgical and trauma patients, ventilated or not, summarized in a meta-analysis by Choi and Nelson225 have compared continuous lateral rotational therapy with standard beds for the prevention of nosocomial pneumonia. The meta-analysis found a statistically significant reduction in the risk for pneumonia, principally concerning early-onset (<5 days) pneumonia, and a decreased duration of ICU stay. However, five of these studies were limited to surgical patients or those with neurologic impairment. The sixth study, which included primarily medical patients, found no significant benefit.219 A recent randomized, controlled trial of medical and surgical patients not included in the meta-analysis also found no benefit to oscillating beds.226 Some adverse events have been described with these beds, including disconnection of catheters or pressure ulceration; in addition, nursing care potentially is complicated with oscillating beds. Despite the cost of such beds, cost-benefit analyses performed in those studies seem favorable, mainly due to the shorter duration of the ICU stay.

Although oscillating or rotating beds have no apparent benefit in general populations of medical patients, there is reasonably good evidence that this practice may be effective in surgical patients or patients with neurologic problems. Use of these beds in these select patient populations therefore should be considered.

Aspiration of Subglottic Secretions

Continuous or intermittent aspiration of oropharyngeal secretions has been proposed to avoid chronic aspiration of secretions through the tracheal cuff of intubated patients. Aspiration of subglottic secretions requires the use of a specially designed endotracheal tube with a separate lumen that opens into the subglottic region. Three randomized, controlled trials have studied aspiration of subglottic secretions for the prevention of VAP.227–229 Mahul and colleagues227 found that pneumonia was significantly less frequent in patients with endotracheal tubes having a separate dorsal lumen for hourly suctioning of stagnant secretions above the cuff than in others and that VAP development was delayed. Similarly, in a 3-year prospective, randomized, controlled study, Valles and colleagues228 documented a lower VAP rate when continuous subglottic aspiration was performed. However, this difference was fully explained by the VAP occurring during the first week, whereas late-onset pneumonias were more frequent in the aspiration group. Furthermore, detailed microbiologic analysis demonstrated that this reduction concerned only pneumonia due to H. influenzae or gram-positive cocci. The incidence of VAP due to P. aeruginosa or Enterobacteriaceae did not differ between the two groups.228 Kollef and colleagues229 performed a randomized trial on 343 post–cardiac surgery patients to compare continuous subglottic aspiration and standard postoperative medical care. Although those authors found similar rates of VAP in both groups, VAP episodes occurred significantly later in patients receiving subglottic aspiration than in those treated conventionally. No difference in mortality rates was observed in these three studies. Whereas no adverse events were reported with aspiration of subglottic secretions in the three studies just reported, experimental data have suggested the possibility of tracheal damage in sheeps intubated with this type of tube.230

Aspiration of subglottic secretions is a promising strategy for the prevention of early-onset VAP but cannot be recommended for general use because of the mixed results in the literature. Further study of this approach is warranted.

Ventilator Circuit Management

Decreased frequency of ventilator circuit changes, replacement of heated humidifiers by heat and moisture exchangers, decreased frequency of heat and moisture exchanger changes, and closed suctioning systems all have been tested for preventing VAP. Four randomized trials of decreased frequency of ventilator circuit changes have been published231–234 comparing changes every 2 days, 7 days, and no scheduled change and did not find any significant differences in the rate of VAP, as summarized in a recent meta-analysis.235 One meta-analysis summarized the results of five randomized, controlled trials that compared the effects of heated humidifiers and heat and moisture exchangers on the risk of VAP.194 Only one out of these five studies found a significant reduction of VAP rate with the use of heat and moisture exchangers.236 The efficacy of both humidification strategies seems comparable; however, two studies reported increased rates of endotracheal tube occlusion with the use of heat and moisture exchangers.194 Another potential caveat of these devices includes an increased resistive load resulting in difficulties in the ventilation and weaning process of patients with severe ARDS.237 Finally, one study evaluated the impact of less frequent changes (daily versus every 5 days) of heat and moisture exchangers on the development of VAP.238 No differences in the VAP rates were observed.

A policy of no circuit changes or infrequent circuit changes is simple to implement, does not lead to increased development of VAP, and costs less than frequent, regular circuit changes. Such a policy should be considered in all mechanically ventilated patients. The favorable impact of the use of heat and moisture exchangers on the risk of VAP has to be confirmed before being recommended for general use.

To avoid hypoxia, hypotension, and contamination of suction catheters entering the tracheal tube, investigators have examined closed suctioning systems.239–241 While some found a nonsignificantly lower prevalence rate of VAP for patients managed with the closed system compared with those with the open system,241 others not only failed to show a statistically significant protective effect of the closed system on the incidence of VAP but also observed an increased frequency of endotracheal colonization associated with the closed device.239 At the present time, use of theses devices cannot be recommended for preventing VAP.

Methods of Enteral Feeding

Nearly all patients receiving mechanical ventilation have a nasogastric tube inserted to manage gastric and enteral secretions, prevent gastric distention, or provide nutritional support. The nasogastric tube may increase the risk for gastroesophageal reflux, aspiration, and VAP.43 Four randomized, controlled trials have evaluated various methods of enteral feeding aimed at preventing VAP: postpyloric or jejunal feeding (versus gastric feeding), the use of motility agents (metoclopramide versus placebo), acidification of feeding (with addition of hydrochloric acid), and intermittent (versus continuous) feeding.242–245 These studies did not find differences in the incidence of VAP and/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 to reduce the incidence of VAP cannot be recommended for routine use.

Stress Ulcer Prophylaxis

Gastric colonization by potentially pathogenic organisms has been shown to increase with decreasing gastric acidity.246 Thus medications that decrease gastric acidity (antacids, H2 blockers) may increase organism counts and increase the risk for VAP. In contrast, medications that do not affect gastric acidity, such as sucralfate, may not increase this risk.

Seven 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.97,98,100,105,106,247,248 Four of these seven meta-analyses reported a significant reduction in VAP incidence with sucralfate therapy compared with H2 blockers97,100,106 and three a statistically significant mortality benefit.98,100,105

However, the relationships between prophylaxis of stress ulcer and prophylaxis of VAP are complex: (1) VAP is a possible indirect consequence of the use of drugs that raise the stomach pH, (2) gastrointestinal bleeding is a serious complication in critically ill patients at high risk for stress ulcer (e.g., patients with coagulopathy or the need for prolonged mechanical ventilation) but is extremely rare in patients at low to moderate risk, (3) the largest randomized trial comparing ranitidine with sucralfate showed that ranitidine was superior in preventing gastrointestinal bleeding and did not increase the risk of VAP,107 and (4) the risk of VAP is unknown when accurate methods of enteral feeding or other preventive measures are used in combination with stress ulcer prophylaxis.

Clinicians must weigh the potential benefit of sucralfate (with potentially less VAP and more gastrointestinal bleeding) versus H2 blockers (with potentially more VAP and less gastrointestinal bleeding) and probably limit stress ulcer prophylaxis to high-risk patients.

Selective Digestive Decontamination

There is theoretical interest in using topical antibiotics to sterilize the oropharynx and stomach in mechanically ventilated patients, with the goal of reducing the incidence of VAP.249 Several groups have used topical prophylactic antibiotics for selective decontamination of the oropharynx and digestive tract (SDD) in patients at high risk for nosocomial pneumonia. The SDD regimen usually includes a short course of systemic antibiotic therapy, such as cefotaxime, trimethoprim, or a fluoroquinolone, and nonabsorbable local antibiotic prophylaxis consisting of a combination of an aminoglycoside, polymyxin B, and amphotericin.249 Since the original studies published by Stoutenbeck and colleagues250,251 in 1984, which demonstrated a decrease of the overall infection rate in patients receiving the SDD regimen, more than 40 randomized, controlled trials and 7 meta-analyses have been published.91,252–258 All seven meta-analyses reported a significant reduction in the risk of VAP, and four reported a significant reduction in mortality.91,254,255,257 No mortality benefit occurred with topical prophylaxis alone.91,252,254,257 However, a clear consensus as to the effectiveness of SDD has not been established owing to limitations and methodologic deficiencies of the studies analyzed.104,259 Furthermore, the impact of SDD on the emergence of resistant organisms is currently unknown but potentially important.260,261

Conclusions drawn based on meta-analyses of SDD studies may be summarized as follows: (1) SDD reduces the incidence of VAP and, when a combined topical and systemic regimen is used, may reduce mortality, (2) an inverse relationship has been described between methodologic quality of the studies and benefit, questioning the overall value of results reported in the meta-analyses, (3) the long-term effects of SDD on emergence of resistance and risk of superinfections currently are unknown, and finally, (4) the impact of SDD on the duration of MV, ICU stay, and hospital stay appears to be limited. Thus, at present, this approach cannot be recommended for overall populations of ICU patients treated with MV, although SDD may be effective for specific populations, particularly surgical or trauma patients.

Early attempts at systemic prophylaxis with parenteral antibiotics alone against pneumonia clearly were unsuccessful.262,263 In contrast, recent studies showed that a short-course antibiotic regimen in patients with structural coma or severe burns was an effective prophylactic strategy to decrease the VAP rate.92 The influence of rotating of antibiotics (generally associated with restrictive use) in the ICU on VAP prevalence was investigated recently by comparing successive periods during which one antibiotic was used in place of another for the empirical treatment of suspected gram-negative bacterial infections. Some investigators found that VAP occurred significantly less frequently during the after period compared with the before period.264–266