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ABSTRACT |
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ABSTRACT
CONTENTS
EPIDEMIOLOGY
DIAGNOSIS
TREATMENT
REFERENCES
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Ventilator-associated pneumonia (VAP) continues to complicate the course of 8 to 28% of patients receiving mechanical ventilation (MV). 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 ranges from 24 to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens. The predominant organisms responsible for infection are Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae, but etiologic agents widely differ according to the population of patients in an intensive care unit, duration of hospital stay, and prior antimicrobial therapy. Because 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. Our personal bias is that using bronchoscopic techniques to obtain protected brush and bronchoalveolar lavage specimens from the affected area in the lung permits physicians to devise a therapeutic strategy that is superior to one based only on clinical evaluation. When fiberoptic bronchoscopy is not available to physicians treating patients clinically suspected of having VAP, we recommend using either a simplified nonbronchoscopic diagnostic procedure or following a strategy in which decisions regarding antibiotic therapy are based on a clinical score constructed from seven variables. Selection of the initial antimicrobial therapy should be based on predominant flora responsible for VAP at each institution, clinical setting, information provided by direct examination of pulmonary secretions, and intrinsic antibacterial activities of antimicrobial agents and their pharmacokinetic characteristics. Further trials will be needed to clarify the optimal duration of treatment and the circumstances in which monotherapy can be safely used.
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CONTENTS |
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TOP
ABSTRACT
CONTENTS
EPIDEMIOLOGY
DIAGNOSIS
TREATMENT
REFERENCES
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Epidemiology
Incidence of Ventilator-associated Pneumonia
Mortality
Morbidity and Cost
Etiologic Agents
Pathogenesis
Risk Factors
Diagnosis
Clinical Evaluation Combined with Microscope Examina-
tion and Culture of Tracheal Secretions
Microbiologic Diagnosis of Ventilator-associated Pneumo-
nia Using Nonbronchoscopic Techniques
Microbiologic Diagnosis of Ventilator-associated Pneumo-
nia Using Bronchoscopic Techniques
Arguments for Bronchoscopy for the Diagnosis of Ventila-
tor-associated Pneumonia
Arguments against Bronchoscopy for the Diagnosis of Ven-
tilator-associated Pneumonia
Recommendations
Treatment
Evaluation of Current Antimicrobial Strategies
Antibiotic Treatment: General Considerations
Factors Contributing to Selection of Treatment
Monotherapy versus Combination Therapy
Duration of Antimicrobial Therapy
Antibiotic Rotation
Keywords: antimicrobial therapy; bronchoscopy; epidemiology; nosocomial infection; ventilator-associated pneumonia
Despite major advances in techniques for the management of ventilator-dependent patients and the routine use of effective procedures to disinfect respiratory equipment, ventilator-associated pneumonia (VAP) continues to complicate the course of 8 to 28% of the patients receiving mechanical ventilation (MV) (1-5). Rates of pneumonia are considerably higher among patients hospitalized in intensive care units (ICUs) compared with those in hospital wards, and the risk of pneumonia is increased 3- to 10-fold for the intubated patient receiving MV (1, 3, 6-13). 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 (2, 11-20). 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 (14, 21, 22). However, consensus on appropriate diagnostic, therapeutic, and preventive strategies for VAP has yet to be reached.
The present review is based on an evaluation of the literature, selected using a computerized MEDLINE search from 1980 through March 2001. Review articles, consensus statements, and the references cited therein were also considered in this endeavor to update our current knowledge on the epidemiology, diagnosis, and treatment of VAP. Because the Hospital Infection Control Practice Advisory Committee of the Centers for Disease Control and Prevention (CDC, Atlanta, GA) published extensive and up-to-date recommendations for the prevention of nosocomial pneumonia in 1997 (23), and other comprehensive reviews are also available (24- 26), this topic is not covered herein.
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ABSTRACT
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EPIDEMIOLOGY
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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 (27). 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 about the findings (28-31). The absence of a "gold standard" continues to fuel controversy about the adequacy and relevance of many studies in this field.
Prolonged (more than 48 hours) MV is the most important factor associated with nosocomial pneumonia. However, VAP may occur within the first 48 hours after intubation. Since the princeps study by Langer and coworkers (32), it is usual to distinguish early-onset VAP, which occurs during the first 4 days of MV, from late-onset VAP, which develops five or more days after initiation of MV. Not only are the causative pathogens commonly different but the disease is usually less severe and the prognosis better in early-onset than late-onset VAP (27, 33).
Incidence of Ventilator-associated Pneumonia
A large-scale 1-day point prevalence study of pneumonia arising in the ICU was conducted on April 29, 1992, in 1,417 ICUs (6). A total of 10,038 patients was evaluated: 2,064 (21%) had ICU-acquired infections, including pneumonia in 967 (47%) patients, for an overall nosocomial pneumonia prevalence of 10%. In that study, logistic regression analysis identified MV as one of the seven risk factors for ICU-acquired infections. Another large-scale study, conducted in 107 European ICUs, demonstrated a crude pneumonia rate of 9% (7). In that study, MV was associated with a 3-fold higher risk of developing VAP than that observed for nonventilated patients. On the basis of their analyses of overall rates of nosocomial pneumonia, Cross and Roup reported 10-fold higher frequencies for ventilated patients than for those without respiratory assistance (8). Similarly, in a nationwide American study, the pneumonia rate was 21-fold higher for patients receiving continuous ventilatory support than for those not requiring MV (34), in agreement with a multivariate analysis of 120 consecutive VAP episodes and 120 control subjects that had shown intubation to independently increase the risk of nosocomial pneumonia ~ 7-fold (11). A large prospective cohort study was conducted in 16 Canadian ICUs: of the 1,014 mechanically ventilated patients included, 177 (18%) developed VAP, as assessed by bronchoscopic sampling with bronchoalveolar lavage (BAL) or protected specimen brush (PSB) in 131 (35). These data confirmed the considerably higher risk of VAP observed in the subset of ICU patients treated with MV.
In the majority of reports, VAP frequencies varied between 8 and 28% (9, 11, 12, 14, 15, 32, 35-51) (Table 1). A prospective investigation of VAP in 23 Italian ICUs that included 724 critically ill patients who had received prolonged (more than 24 hours) ventilatory assistance after admission found a mean rate of 23%; the frequency rose from 5% for patients receiving MV for 1 day to 69% for those receiving MV for more than 30 days (9, 32). Concerning a subset of 124 trauma patients, 67% of whom were ventilated, early-onset pneumonia, defined as pneumonia occurring within the first 96 hours after admission, represented 63% of the 41 pulmonary infections complicating the course of these patients (44). In another study of 244 medical, surgical, or trauma patients treated with MV, Prod'hom and coworkers defined early-onset pneumonia as occurring during the first 4 days of MV; overall, 53 (22%) VAP episodes were observed, with early-onset pneumonia representing 45% of all pneumonia episodes (52). When quantitative cultures of specimens obtained with a PSB during fiberoptic bronchoscopy (FOB) were used to define pneumonia in 567 ventilated patients, the VAP rate was 9% (12). According to an actuarial method, the cumulative risk of pneumonia in that context was estimated to be 7% at 10 days and 19% at 20 days after the onset of MV. Furthermore, in that study, the incremental risk of pneumonia was virtually constant throughout the entire ventilation period, with a mean rate of ~ 1% per day. In contrast, Cook and coworkers demonstrated in a large series of 1,014 mechanically ventilated patients that, although the cumulative risk for developing VAP increased over time, the daily hazard rate decreased after Day 5 (35). 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 to 17.0), trauma (RR, 5.0; 95% CI, 1.9 to 13.1), central nervous system disease (RR, 3.4; 95% CI, 1.3 to 8.8), respiratory disease (RR, 2.8; 95% CI, 1.1 to 7.5), cardiac disease (RR, 2.7; 95% CI, 1.1 to 7.0), MV during the previous 24 hours (RR, 2.3; 95% CI, 1.1 to 4.7), witnessed aspiration (RR, 3.2; 95% CI, 1.6 to 6.5), and paralytic agents (RR, 1.6; 95% CI, 1.1 to 2.4). Exposure to antibiotics conferred protection (RR, 0.4; 95% CI, 0.3 to 0.5), but this effect was attenuated over time. Thus, the daily risk for developing VAP is highly dependent on the population being studied and also on many other factors, particularly the number of patients in the given population who received antibiotics immediately after their admission to the ICU.
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VAP is thought to be a common complication of the acute respiratory distress syndrome (ARDS) (Table 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% (13, 53). 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 on the basis of clinical criteria alone (53). Using PSB and/or BAL techniques at predetermined times from Day 3 to 21 after the onset of the syndrome in a series of 105 patients with ARDS, Sutherland and coworkers concluded that VAP may indeed occur far less frequently than expected in this group of patients (49). Only 16 (15.2%) of their 105 patients met the quantitative criteria for pneumonia (PSB > 103 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 (fraction of inspired oxygen) ratios, days receiving 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 patients with ARDS than in other mechanically ventilated patients (16-18, 50). In one study of 56 patients with ARDS, PSB and BAL were used to define pneumonia and the VAP rate was 55% (16), whereas it was only 28% for 187 non-ARDS patients diagnosed according to the same criteria during the same period. It was specified that early-onset VAP (occurring before Day 7) was relatively rare in patients with ARDS: only 10% of the first VAP episodes, as opposed to 40% among non-ARDS patients. Those observations were confirmed in 30 patients with ARDS 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 (17, 50). In another prospective multicenter study, VAP was bacteriologically confirmed in 49 (37%) of 134 patients with ARDS, versus 23% of ventilated non-ARDS patients (p < 0.002) (18).
The finding of a higher incidence of microbiologically provable VAP in patients with ARDS than in other populations of mechanically ventilated patients was not unexpected. Several studies have clearly shown that alveolar macrophages and neutrophils retrieved from the lungs of patients with ARDS have impaired phagocytic function and/or lower maximal activity after ex vivo stimulation by bacterial products than do corresponding cells from normal subjects, which could explain why these patients are at high risk of developing pulmonary infection (54, 55). However, the actuarial risk of pneumonia after 30 days of MV does not differ significantly between patients with and without ARDS (16). Therefore, the higher incidence of VAP observed in patients with ARDS is probably essentially the result of their need for a much longer duration of MV than that of other patients, thereby increasing the time during which they are at risk for developing VAP.
These findings emphasize (1) the major influence of underlying medical conditions on the epidemiologic characteristics of VAP, and (2) the critical role of the diagnostic techniques used to identify patients with VAP and to provide accurate epidemiologic data. As the data presented in Table 2 suggest, for the same patients, VAP was clinically diagnosed almost twice as often as it could be bacteriologically confirmed (12, 47, 56-63). Understanding this difference is crucial for the implementation of a rational and pertinent surveillance program in the ICU, with possible intra- and interunit comparisons, to evaluate new therapeutic strategies, particularly prophylactic measures, and to improve antibiotic use in this setting with accurate identification of infected patients and appropriate selection of antimicrobial agent(s). This distinction between clinically suspected versus bacteriologically confirmed VAP has now been integrated into the most recent CDC guidelines (23).
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Mortality
Crude ICU mortality rates of 24 to 76% have been reported for VAP at a variety of institutions (see Table 1) (9, 12, 14, 15, 35, 40, 41, 43-47, 51, 57). ICU ventilated patients with VAP appear to have a 2- to 10-fold 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 (64). The results of several studies conducted between 1986 and 2001 have confirmed that 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% (15), 71 versus 28% (12), 33 versus 19% (14), 37 versus 9% (45), and 44 versus 19% (47). 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 clearly demonstrated 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, that is, to clearly identify patients with VAP; thus, the widely diverging VAP mortality rates reported might 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 patients in the ICU to the development of pneumonia, and their mortality rates are, consequently, high (6, 7, 11, 36, 37, 42, 45). Therefore, it is difficult to determine whether such patients would have survived if VAP had not occurred. However, nosocomial pneumonia has been recognized in several studies as an important prognostic factor for different groups of critically ill patients, including cardiac surgery patients (48, 65) or those with acute lung injury (66), and immunocompromised patients, for example those with acute leukemia (67), lung transplantation (68), or bone-marrow transplantation (69). In contrast, in patients with extremely severe medical conditions, such as those surviving cardiac arrest (70), or young patients with no underlying disease, such as those admitted after trauma (44, 71, 72), nosocomial pneumonia does not seem to significantly affect prognosis. Similarly, VAP does not appear to markedly influence overall survival of patients with ARDS, as documented by several studies (13, 16-18, 50). However, studies evaluating excess mortality attributed to VAP in patients with ARDS are difficult to interpret, because most VAP in this subset of patients occurs late in the course of the disease, whereas patients with ARDS who do not develop VAP, but who nevertheless die, do so earlier than other patients with ARDS, thus having little opportunity to develop nosocomial infection (16).
Despite these difficulties and limitations, several arguments support the notion that the presence of VAP is an important determinant of the poor prognosis of patients treated with MV. Risk factors for death of ventilated patients who developed pneumonia have been systematically investigated only by two groups (11, 14). Using multiple logistic regression analysis, Torres and coworkers demonstrated that the worsening of respiratory failure, the presence of an ultimately or rapidly fatal underlying condition, the presence of shock, inappropriate antibiotic therapy, and/or type of ICU were factors that negatively affected the prognosis of VAP. Thus, those authors emphasized the complex relationships among the severity of underlying disease leading to ICU admission and treatment with MV, the severity of pneumonia itself, and the adequacy of initial antibiotic treatment. The important prognostic role played by the adequacy of the initial empiric antimicrobial therapy was also analyzed by several other investigators and is summarized in Table 3 (19, 58, 61, 62, 73-76).
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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 (12, 64, 77-81). According to one study, mortality associated with Pseudomonas or Acinetobacter pneumonia was 87% compared with 55% for pneumonias due to other organisms (12). Similarly, Kollef and coworkers 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%) (65). 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 attributable to 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 (82).
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 (15, 45). In contrast, the EPIC (European Prevalence of Infection in Intensive Care) 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 to 2.3), independently of clinical sepsis and bloodstream infection (6). Another study based on 1,978 patients in the ICU, including 1,118 patients receiving 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 (51). 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 by invasive techniques added no prognostic information (respective relative risk of 2.1 and 1.7) (46).
Case-control studies have been used to assess mortality attributable to nosocomial pneumonia, that is, 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 4 (44, 81, 83-87). 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.) (81). 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 to 5.03) than in those without, with a major impact being observed for patients with intermediate-grade severity (88).
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Finally, only a few reports have been published on mortality as a result of nosocomial pneumonia for which autopsy material from patients who died during their hospital stay was analyzed. On the basis of the analysis of 200 consecutive hospital deaths, it was concluded that nosocomial pneumonia contributed to 60% of the fatal infections and was the leading cause of death from hospital-acquired infections (89). By matching control subjects with half of these patients who died in the hospital, the same authors found that nosocomial lower respiratory tract infection occurred in 18% of the patients but in only 4% of the control subjects. Among patients who did not have a terminal condition on admission, nosocomial infections were three times more frequent among those who died (46%) than among survivors (11%) (89). A 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 MV (90); 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 severity (88) and/or in patients with VAP caused by high-risk pathogens, as indicated above (12, 65, 82). It is probable that several case-control studies were confounded by the fact that patients with 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.
Thus, considering many different kinds of evidence, VAP seems indeed associated with a 20 to 30% higher risk of death than that due to the underlying disease alone, at least in several subgroups of patients requiring MV, which pleads for new approaches to improve the management of ventilator-dependent patients, including more effective prophylactic measures, and earlier diagnosis and treatment.
Morbidity and Cost
It is impossible to evaluate precisely the morbidity and excess costs associated with VAP. However, with respect to morbidity measures, the prolonged hospital stay as a direct consequence of VAP has been estimated in several studies (46, 51, 81, 83, 84, 91). In one study, VAP prolonged the duration of MV from 10 to 32 days (42). In another, the median length of stay in the ICU for the patients who developed VAP was 21 days versus a median of 15 days for paired control subjects (81). Furthermore, a mean prolongation of ICU stay of 20 days was noted for patients with VAP when surviving pairs were compared. Reported mean durations of MV, ICU stay, and hospital stay were, respectively, 12.0, 20.5, and 43.0 days for trauma patients with pneumonia compared with 8.0, 15.0, and 34.0 days for their matched control subjects (44). Analyzing the same variables, others found, respectively, 27.3, 32.9, and 52.5 days for case patients versus 19.7, 24.5, and 43.2 days for patients without VAP (85). Similarly, it was demonstrated that the mean hospital stay after ICU admission was longer for surgical ICU patients (30.0 versus 22.3 days for control subjects) and medical and respiratory ICU patients who developed nosocomial pneumonia (40.9 versus 23.1 days for control subjects) (84). Heyland and coworkers compared 177 VAP patients with matched patients who did not develop VAP, and showed that VAP patients stayed in the ICU 4.3 days longer than did control subjects; the attributable ICU length of stay was longer for medical than surgical patients (6.5 versus 0.7 days), and for patients infected with "high-risk" as opposed to "low-risk" organisms (9.1 versus 2.9 days) (86). In patients with ARDS, all studies clearly identified prolonged duration of MV and lengthened ICU and hospital stays for patients with VAP compared with those without (16-18, 50). Thus, summarizing available data, VAP likely extended the ICU stay by at least 4 days.
These prolonged hospitalizations underscore the considerable financial burden imposed by the development of VAP. However, a precise and universal evaluation of such overcosts is difficult. Cost analysis is, indeed, dependent on a wide variety of factors that differ from one country to another, including health care system, organization of the hospital and the ICU, the possibility of patients being treated by private practitioners, cost of antibiotics, and so on. Only a few, and frequently discrepant, data are available: The average excess cost of nosocomial pneumonia was estimated to be US$1,255 in 1982 (92). In a similar study in 1985, the average extra cost was US$2,863 (93). More recently, the extra hospital charges attributed to nosocomial pneumonia occurring in trauma patients were evaluated to be US$40,000 (44).
Etiologic Agents
Microorganisms responsible for VAP may differ according to the population of patients in the ICU, 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 repeatedly documented (12, 14, 19, 34, 94-97). Several studies have reported that more than 60% of VAP is caused by aerobic GNB. More recently, however, some investigators have reported that gram-positive bacteria have become increasingly more 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 (97). The data from 24 investigations conducted with ventilated patients, for whom bacteriologic studies were restricted to uncontaminated specimens, confirmed those results: GNB represented 58% of recovered organisms (12, 14, 16, 18-21, 44, 46, 48, 50, 62, 63, 70, 98-107) (Table 5). 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 was also reported in those studies, with S. aureus involved in 20% of the cases (Table 5).
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The high rate of polymicrobial infection in VAP has been emphasized repeatedly. In a study of 172 episodes of bacteremic nosocomial pneumonia, 13% of lung infections were caused by multiple pathogens (77). 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 (12), a value similar to that observed in another study conducted at the same time on a comparable population of ventilated patients (96). Findings were also similar for patients with ARDS: 58% of the 106 VAP episodes were polymicrobial, of which 55 and 60%, respectively, occurred in patients with and without ARDS (16).
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 infection (33, 44, 72, 82). Furthermore, the causative agent for pneumonia differs among ICU surgical populations (108), 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.
Several studies tried to identify specific risk factors for infection by a given pathogen; for example, logistic regression analysis identified neurosurgery, head trauma, and large-volume aspiration as risk factors for VAP due to Acinetobacter baumannii (109). In studies of patients with ARDS compared with non-ARDS patients, there were no major differences in the distributions of pathogens responsible for VAP, with, however, a predominance of nonfermenting GNB and MRSA among the latter (16-18). Rather, the differences observed seemed primarily to reflect the duration of MV before VAP onset (16).
Despite somewhat different definitions of early-onset pneumonia, varying from < 3 to < 7 days (33, 107), 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 (33,
106, 107). 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 the patients
had received antimicrobial therapy before pneumonia onset
(19). 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 (19). 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 (107). 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) (107). Not all
studies, however, have confirmed this distribution pattern. For
example, one 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 (110). Their finding
may, in part, be due 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 must continuously collect meticulous epidemiologic data. With these aims, variations of VAP etiology among three Spanish ICUs were analyzed (106) and compared with data collected in Paris (107). The authors concluded that VAP pathogens varied widely among these four treatment centers, with marked differences in all of the microorganisms isolated from VAP episodes in Spanish centers as compared with the French site. Clinicians must clearly be aware of the common microorganisms associated with both early-onset and late-onset VAP in their own hospitals to avoid the administration of initial inadequate antimicrobial therapy.
Legionella species (111, 112), anaerobes (100), fungi (113), viruses (114), 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 (100, 114). 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 (100), anaerobes were involved in 23% of the total number of episodes and the main strains isolated were as follows: Prevotella melaninogenica (36%), Fusobacterium nucleatum (17%), and Veillonella parvula (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. parvula) was isolated from 1 patient with aspiration pneumonia, and none from patients with VAP (99).
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, should probably also be considered for patients with gram-positive 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 non-neutropenic patients who had been mechanically ventilated for at least 72 hours (113). Just after death, multiple culture and biopsy specimens were obtained by bronchoscopic techniques. Although 10 patients had at least one biopsy specimen positive for Candida spp., only two 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. On the basis of 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 (115).
In another study conducted over a 5-year period, cytomegalovirus (CMV) was identified as a possible cause of VAP in 25 of 86 patients on the basis of histologic examination of lung tissues obtained at autopsy or open-lung biopsy (114). The authors concluded that CMV should not be excluded as a pathogen potentially responsible for VAP in patients in the ICU, even those without acquired immunodeficiency syndrome, hematologic malignancy, or immunosuppressive therapy.
Pathogenesis
Pneumonia results from microbial invasion of the normally sterile lower respiratory tract and lung parenchyma caused by either a defect in host defenses, challenge by a particularly virulent microorganism, or an overwhelming inoculum. The normal human respiratory tract possesses a variety of defense mechanisms that protect the lung from infection, for example: anatomic barriers, such as the glottis and larynx; cough reflexes; tracheobronchial secretions; mucociliary lining; cell-mediated and humoral immunity; and a dual phagocytic system that involves both alveolar macrophages and neutrophils (27). When these coordinated components function properly, invading microbes are eliminated and clinical disease is avoided, but when these defenses are impaired or if they are overcome by virtue of a high inoculum of organisms or organisms of unusual virulence, pneumonitis results.
As suggested by the infrequent association of VAP with bacteremia, the majority of these infections appear to result from aspiration of potential pathogens that have colonized the mucosal surfaces of the oropharyngeal airways. Intubation of the patient not only compromises the natural barrier between the oropharynx and trachea, but may also facilitate the entry of bacteria into the lung by pooling and leakage of contaminated secretions around the endotracheal tube cuff (10, 33). This phenomenon occurs in most intubated patients, whose supine position may facilitate its occurrence. In previously healthy, newly hospitalized patients, normal mouth flora or pathogens associated with community-acquired pneumonia may predominate. In sicker patients who have been hospitalized more than 5 days, GNB and S. aureus frequently colonize the upper airway (33).
Uncommonly, VAP may arise in other ways (116). Observed "macroaspirations" of gastric material initiate the process in some patients. Allowing condensates in ventilator tubing to drain into the patient's airway may have the same effect (25). FOB, tracheal suctioning, or manual ventilation with contaminated equipment may also bring pathogens to the lower respiratory tract. More recently, concerns have focused on the potential role of contaminated in-line medication nebulizers, but these devices are infrequently associated with VAP (116).
Although tracheal colonization by potentially pathogenic microorganisms occurs before lung infection in a majority of ventilated patients, its relationship with VAP development remains controversial. In 1972, Johanson and coworkers established that upper airway colonization is a frequent occurrence in ventilated patients and that it can act as a harbinger of nosocomial pneumonia in this setting (117). Those authors demonstrated that 45% of 213 patients admitted to a medical ICU became colonized with aerobic GNB by the end of 1 week in the hospital. Among the 95 colonized patients, 22 (23%) subsequently developed nosocomial pneumonia. By comparison, only four of the 118 (3.4%) noncolonized patients developed pneumonia. As determined in that study and several others, the tracheobronchial tree as well as the oropharynx of mechanically ventilated patients are frequently colonized by enteric GNB (118-121). In a study of 130 intubated patients, GNB were found in the trachea of 58% of those who had received antacids and/or H2 blockers to prevent bleeding and in 30% of those receiving sucralfate for this purpose (40). Risk factors for tracheobronchial colonization with GNB appear to be the same as those that favor pneumonia and include more severe illness, longer hospitalization, prior or concomitant use of antibiotics, malnutrition, intubation, azotemia, and underlying pulmonary disease (119). Experimental investigations have linked some of these risk factors to changes in adherence of GNB to respiratory epithelial cells. Although formerly attributed to losses of cell surface fibronectin, these changes in adherence more likely reflect alterations of cell surface carbohydrates (27). Bacterial adhesins and prior antimicrobial therapy appear to facilitate the process. Interestingly, Enterobacteriaceae usually appear in the oropharynx first, whereas P. aeruginosa more often appears first in the trachea (122, 123).
Other sources of pathogens causing VAP include the paranasal sinuses, dental plaque, and the subglottic area between the true vocal cords and the endotracheal tube cuff. The role of the gastrointestinal tract as a source of oropharyngeal and tracheal colonization by GNB is more controversial (118-120). A sequence of events leading to colonization from the stomach to the trachea, with increasing frequency in direct correlation to the gastric pH, was reported by several investigators, with 27 to 45% of patients having primary colonization of the gastric juice and subsequent colonization of the tracheobronchial tree ~ 2 days later (124-127). In addition to those microbiologic studies, other studies have clearly proven, by means of radiolabeled gastric juice or other techniques, that the gastric juice of intubated patients is aspirated into the tracheobronchial tract within a few hours (128-131). Those investigations convincingly corroborate the microbiologic studies demonstrating that tracheobronchial colonization originates in the stomach in at least 25 to 40% of patients and, therefore, lend support to the role of the gastric barrier in the pathogenesis of nosocomial pneumonia. Whether bacteria ascend from the intestines or descend from the oropharynx, the stomach may act as a reservoir in which pathogens can multiply and attain high concentrations. Alkalinization of the normally acid gastric environment seems to be a prerequisite for this mechanism to be operational.
However, not all authors agree that the gastropulmonary route of infection is truly operative in ICU patients (120, 132). Colonization from the stomach to the upper respiratory tract, eventually leading to 14 VAP episodes, could not be clearly demonstrated in one study (132). The same group, in another study conducted with 141 patients (117), reported that intragastric acidity influenced gastric colonization but not colonization of the upper respiratory tract or the incidence of VAP, suggesting therefore that it is unlikely that the gastropulmonary route contributes importantly to VAP development. Similarly, de Latorre and coworkers demonstrated that only 19 of 72 patients developed tracheal colonization after pharyngeal or gastric colonization by the same organisms; moreover, among the 12 patients who developed VAP, the microorganism(s) responsible had already colonized the trachea in 10 of them, but only 10 of the 21 responsible microorganisms isolated from VAP had previously colonized the pharynx or stomach (133). Last, efforts to eliminate the gastric reservoir by antimicrobial therapy without decontaminating the oropharyngeal cavity have generally failed to prevent VAP (134, 135). In fact, there is more than one potential pathway for colonization of the oropharynx and trachea in such a setting, including fecal-oral cross-infection on the hands of health care personnel, and contaminated respiratory therapy equipment. Patient care activities, such as bathing, oral care, tracheal suctioning, enteral feeding, and tube manipulations, provide ample opportunities for transmission of pathogens when infection control practices are substandard (136).
In summary, the relationship between VAP and tracheal, pharyngeal, and/or gastric colonizations remains to be elucidated for patients with an endotracheal tube. To date, these findings lead to the following conclusions: (1) tracheal colonization precedes VAP in most, but not all, patients; (2) only a minority of patients with tracheal colonization develop VAP; (3) the stomach can be a reservoir for pneumonia pathogens, although this is not the case in many ICU patients requiring MV.
Risk Factors
Risk factors provide information about the probability of lung infection developing in individuals and populations. Thus, they may contribute to the elaboration of effective preventive strategies by indicating which patients might be most likely to benefit from prophylaxis against pneumonia. Independent factors for VAP that were identified by multivariate analyses in selected studies are summarized in Table 6 (7, 11, 14, 15, 19, 35, 36, 45, 72, 84, 137).
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Surgery. Postsurgical patients are at high risk for VAP, which accounts for nearly one-third of the pulmonary infiltrates in these ICU patients (11, 45, 108, 138). In a 1981 report, the pneumonia rate during the postoperative period was 17% (37). Those authors stated that the development of pneumonia was closely associated with preoperative markers of severity of the underlying disease, such as low serum albumin concentration and high American Society of Anesthesiologists preanesthesia physical status classification score (37). A history of smoking, longer preoperative stays, longer surgical procedures, and thoracic or upper abdominal surgery were also significant risk factors for postsurgical pneumonia. Another study comparing adult ICU populations demonstrated that postoperative patients had consistently higher rates of nosocomial pneumonia than did medical ICU patients, with a RR of 2.2 (84). Multiple regression analysis was performed to identify independent predictors of nosocomial pneumonia in the two groups; for surgical ICU patients, MV (> 2 days) and acute physiology and chronic health evaluation score were retained by the model; for the medical ICU population, only MV (> 2 days) remained significant. It has been suggested that different surgical ICU patient populations may have different risks for nosocomial pneumonia: cardiothoracic surgery (139) and trauma (particularly the head) patients were more likely to develop VAP than medical or other types of surgical patients (35).
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 (19, 45, 72, 80, 97, 107, 117, 140, 141). 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 > 60 years, and the patient's head positioning (i.e., flat on his back or supine versus head and thorax raised 30 to 40° or semirecumbent) (45). However, other investigators found that antibiotic administration during the first 8 days was associated with a lower risk of early-onset VAP (142, 143). For example, Sirvent and coworkers 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 (144). 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 (105). 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 (145). 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 multicentric Canadian study on the incidence of and risk factors for VAP indicated that antibiotic treatment conferred protection against VAP (35). 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 (12, 107, 140, 146-148). 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 (12), 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 of mechanically ventilated baboons treated with a variety of regimens of intravenous and topical antibiotics or no antibiotics at all (146), 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 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. In theory, patients receiving stress ulcer prophylaxis that does not change gastric acidity should have lower rates of gastric bacterial colonization and, consequently, a lower risk for nosocomial pneumonia. A direct relationship between alkaline gastric pH and gastric bacterial colonization has been demonstrated in several studies (124-127). For example, 86% of 28 postoperative patients had sterile gastric juice at ICU admission; 2 days later, the gastric secretions were colonized in 61% of the patients and the pH was more than 4 in 43% of them (125). These findings were fully confirmed by an analysis of 153 ICU patients receiving antacid or cimetidine: Total gastric colonization, particularly with GNB, was highly significantly increased (p < 0.001) (127). When the pH was less than 2, the gastric juice was sterile in 65% of the cases, but when it rose above 4, gastric juice GNB colonization was documented in at least 60% of the patients.
The results of several studies have indicated lower rates of pneumonia for patients given a gastroprotective agent (sucralfate) rather than agents that neutralize gastric secretions (antacids) or block gastric acid secretion (H2 blockers) (40, 52, 137, 149, 150). In a well-designed, randomized study of 244 mechanically ventilated patients that compared stress ulcer prophylaxis with antacids, ranitidine, or sucralfate, the potential benefit of using sucralfate was confirmed (52). Although no differences in the incidence of macroscopic gastric bleeding and early-onset (within 4 days of ICU entry) VAP were found among the three groups, late-onset VAP was observed in only 5% of the patients who had received sucralfate compared with 16 and 21% of the patients who had received antacids or ranitidine, respectively (p < 0.02). Sucralfate-treated patients also had a lower median gastric pH and less frequent gastric colonization compared with the other groups. Molecular typing showed that 84% of the patients with late-onset GNB pneumonia had gastric colonization with the same strain before pneumonia developed. 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 (150-159). However, this conclusion was not fully confirmed in a 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 1,200 patients who required MV (160). Clinically relevant gastrointestinal bleeding developed in 10 of the 596 (1.7%) patients receiving ranitidine, as compared with 23 of the 604 (3.8%) receiving sucralfate (RR, 0.44; 95% CI, 0.21 to 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 CDC criteria, versus 98 of 604 (16.2%) in the sucralfate group (RR, 1.18; 95% CI, 0.92 to 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) (160). 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 to 2.00) (158). 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 to 5.44) (161, 162).Endotracheal tube, reintubation, and tracheotomy. The presence of an endotracheal tube by itself circumvents host defenses, causes local trauma and inflammation, and increases the probability of aspiration of nosocomial pathogens from the oropharynx around the cuff. Scanning electron microscopy of 25 endotracheal tubes revealed that 96% had partial bacterial colonization and 84% were completely coated with bacteria in a biofilm or glycocalyx (163). The authors hypothesized that bacterial aggregates in biofilm dislodged during suctioning might not be killed by antibiotics or effectively cleared by host immune defenses (163, 164). Clearly, the type of endotracheal tube may also influence the likelihood of aspiration. Use of low-volume, high-pressure endotracheal cuffs reduced the rate to 56% and the advent of high-volume, low-pressure cuffs further lowered it to 20% (131). Leakage around the cuff allows secretions pooled above the cuff to enter the trachea; this mechanism, recently confirmed, underlines the importance of maintaining adequate intracuff pressure for preventing VAP (145). The relationship between tracheal colonization and VAP occurrence was confirmed in a study of 100 patients with head trauma and Glasgow Coma Scale scores less than 12 (165): within 24 hours of intubation, 68% of the patients who required intubation and MV for coma had tracheal S. aureus, H. influenzae, or S. pneumoniae colonization, which was identified as an independent risk factor for developing early-onset (less than 5 days) VAP.
Continuous or intermittent suction of oropharyngeal secretions has been proposed to avoid chronic aspiration of secretions through the tracheal cuff of intubated patients (Table 7) (166- 169). Among 145 ventilated patients, pneumonia occurred less frequently (13%) in those whose endotracheal tube had a separate dorsal lumen for hourly suctioning of stagnant secretions above the cuff than the others (29%; p < 0.05) and VAP developed later (16.2 versus 8.3 days for the control group) (166). Similarly, in a 3-year prospective, randomized, controlled study, a lower VAP rate was documented when continuous subglottic suction was applied (18 versus 33% of the control subjects, NS; corresponding to an incidence density of 19.9 versus 39.6 episodes per 1,000 ventilator days, p < 0.03) (168). However, this difference was fully explained by the VAP occurring during the first week (3 of 76 versus 21 of 77, p < 0.009), whereas late-onset pneumonias were more frequent in the continuous subglottic-suctioning group (11 of 76 versus only 4 of 77) than the control 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 and mortality rates did not differ between the two groups (168). On the basis of 343 patients who had undergone cardiac surgery, continuous subglottic suction significantly delayed VAP occurrence but did not modify the overall VAP frequency (5 versus 8%; p = 0.24) (169).
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Nasogastric tube, enteral feeding, and position of the patient. Almost all patients receiving MV have a nasogastric tube inserted to evacuate gastric and enteral secretions, prevent gastric distention, and/or provide nutritional support. The nasogastric tube is not generally considered to be a potential risk factor for VAP, but it may increase oropharyngeal colonization, cause stagnation of oropharyngeal secretions, and increase reflux and the risk of aspiration. A multivariate analysis retained the presence of a nasogastric tube as one of the three independent risk factors for nosocomial pneumonia based on a series of 203 patients admitted to the ICU for 72 hours or more (36). The case-control study cited above also identified a nasogastric tube as one of the four independent risk factors for VAP in postcardiac surgery patients (48).
Early initiation of enteral feeding is generally regarded as beneficial in critically ill patients, but it may increase the risk of gastric colonization, gastroesophageal reflux, aspiration, and pneumonia (179, 180). Cultures of simultaneously sampled daily gastric, tracheal, and oropharyngeal specimens from 18 MV-dependent patients not receiving antacids or H2 antagonists (181) showed that, after enteral feeding was started, the number of gram-negative isolates increased significantly, and 5 (28%) patients had gram-negative rods that were first recovered in the stomach and subsequently isolated from the trachea. The mechanism of transfer of gastric organisms into the trachea appears to have been aspiration. Among enterally fed, critically ill patients with small-bore nasogastric tubes, aspiration was reported in 38%, even though the bolus technique was used to feed all patients (130). Other observations suggested that aspiration is infrequent when small-bore feeding tubes and continuous infusion are used (182-186), but the real benefit of using small-bore tube is still unclear. To determine whether gastroesophageal reflux and microaspiration in intubated patients can be reduced by the use of a small-bore nasogastric tube, 17 patients intubated for more than 72 hours were assigned, after instillation of radioactive technetium colloid in each patient's stomach, to receive in randomized order one of two different types of nasogastric tubes (one with a 6.0-mm external bore and the other with a 2.85-mm external bore) (187). No differences were found between tube types when the time course and cumulative counts of pharyngeal and tracheal samples were compared, suggesting that small-bore nasogastric tubes do not reduce gastroesophageal reflux or microaspiration in intubated patients. The aspiration rate generally varies as a function of differences in the patient population, neurologic function, type of feeding tube, location of the feeding port, and method of evaluating aspiration (182, 188). Clinical impressions and preliminary data suggest that postpyloric or jejunal feeding entails less risk of aspiration and may therefore be associated with fewer infectious complications than gastric feeding, although this point remains controversial (129, 189). Nonetheless, aspiration can easily occur should the feeding tube be inadvertently dislodged. A retrospective study of noncritically ill adult patients showed a 40% rate of accidental feeding-tube dislodgment, but all the patients whose tube was dislodged were confused, disoriented, or had altered awareness, as is frequently observed in patients in ICUs (190). Maintaining mechanically ventilated patients with a nasogastric tube in place in a supine position is also a risk factor for aspiration of gastric contents into the lower airways. When radioactive material was injected through a nasogastric tube directly into the stomach of 19 mechanically ventilated patients, the mean radioactive counts in endobronchial secretions were higher in a time-dependent fashion in samples obtained from patients in a supine position than in those obtained from patients in a semirecumbent position (128). The same microorganisms were isolated from the stomach, pharynx, and endobronchial samples of 32% of the specimens taken while patients were lying supine. However, the results of a subsequent study published by the same group from Barcelona were disappointing, as they demonstrated that gastroesophageal reflux in mechanically ventilated patients with a nasogastric tube occurs irrespective of body position (191). The same investigators then conducted a randomized trial comparing semirecumbent and supine positions (192). The trial, which included 86 intubated and mechanically ventilated patients, was stopped after the planned interim analysis because the frequency and the risk of VAP were significantly lower for the semirecumbent group. These findings were indirectly confirmed by the demonstration that the head position of the supine patient during the first 24 hours of MV was an independent risk factor for acquiring VAP (45).Respiratory equipment. Respiratory equipment itself may be a source of bacteria responsible for VAP. In the 1980s, the major risk of infection was associated with contaminated reservoir nebulizers, designed to deliver small-sized particles suspended in the effluent gas (15). Those observations led to the current practices in respiratory therapy, for example, the use of cascade humidifiers, which do not generate microaerosols. Nevertheless, respiratory equipment continues to be a source of bacterial contamination. For example, medication nebulizers inserted into the inspiratory-phase tube of the mechanical ventilator circuit may inadvertently be responsible for bacterial aerosols after a single use (193).
To avoid hypoxia, hypotension, and contamination of suction catheters entering the tracheal tube, investigators have examined closed suctioning systems (Table 7) (194-196). Closed versus open suctioning systems were compared for 104 mechanically ventilated patients and a nonsignificantly lower prevalence rate of VAP was found for patients managed with the closed system compared with those with the open system (7.3 versus 15.9 per 1,000 patient-days; p = 0.07) without demonstrating any adverse effect (196). In an earlier study, not only did the investigators not show a statistically significant protective effect of the closed system on the incidence of VAP (26 versus 29%), they observed a higher frequency of endotracheal colonization associated with the closed device (67 versus 39%; p < 0.02) (194). Mechanical ventilators with humidifying cascades often have high levels of tubing colonization and condensate formation that may also 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 (197- 199). Examination of condensate colonization in 20 circuits detected a median level of 2.0 × 105 organisms/ml, and 73% of the 52 gram-negative isolates present in the patients' sputum samples were subsequently isolated from condensates (198). Because most of the tubing colonization was derived from the patients' secretions, the highest bacterial counts were present near the endotracheal tube. Simple procedures, such as turning the patient or raising the bed rail, may accidentally spill contaminated condensate directly into the patient's tracheobronchial tree. Inoculation of large amounts of fluid with high bacterial concentrations is an excellent way to overwhelm pulmonary defense mechanisms and cause pneumonia. Heating ventilator tubing markedly lowers the rate of condensate formation, but heated circuits are often nondisposable and are expensive. In-line devices with one-way valves to collect the condensate are probably the easiest way to handle this problem; they must be correctly positioned into disposable circuits and emptied regularly. Furthermore, to date, no scientific evidence has confirmed that heated circuits reduce the rate of VAP (199). To decrease condensation and moisture accumulation in ventilator circuits, several studies have investigated the use of heat-moisture exchangers (HMEs) in place of conventional heated-water humidification systems. Slightly lower VAP rates were observed in four studies and a significant difference was observed in a fifth study, suggesting that HMEs are at least comparable to heated humidifiers and may be associated with lower VAP rates than heated humidifiers (Table 7) (200-204). Changing the HME every 48 hours did not affect ventilator circuit colonization, and the authors concluded that the cost of MV might be substantially reduced without any detriment to the patient by prolonging the time between HME changes from 24 to 48 hours (205). Furthermore, using HMEs may decrease the nurses' workload (no need to refill cascades, to void water traps on circuits, etc.), decrease the number of septic procedures (it was clearly shown that respiratory tubing condensates must be handled as an infectious waste), and reduce the cost of MV, especially when used for prolonged periods without change. However, because some observational studies have documented an increased resistive load and a larger dead space associated with exchangers (206, 207), their use should be discouraged in patients with ARDS ventilated with a low tidal volume and in patients with COPD during the weaning period, when pressure support, and not T-piece trials, are used. There is no apparent advantage to changing ventilator circuits frequently for VAP prevention. This holds true whether circuits are changed every 2 days or every 7 days compared with no change at all and whether they are changed weekly as opposed to three times per week (208-210). A policy of no circuit changes or infrequent circuit changes is simple to implement and the costs are likely lower than those generated by regular, frequent circuit changes; thus, such a policy is strongly recommended by the 1997 CDC guidelines (23).Sinusitis. Whereas many studies have compared the risk of nosocomial sinusitis as a function of the intubation method used and the associated risk of VAP (211-227), only a few were adequately powered to give a clear answer. In 1 study of 300 patients who required MV for at least 7 days and were randomly assigned to undergo nasotracheal or orotracheal intubation, computed tomographic evidence of sinusitis was observed slightly more frequently in the nasotracheal group than in the oral endotracheal group (p = 0.08), but this difference disappeared when only bacteriologically confirmed sinusitis was considered (223). The rate of infectious maxillary sinusitis and its clinical relevance were also prospectively studied in 162 consecutive critically ill patients, who had been intubated and mechanically ventilated for 1 hour to 12 days before enrollment (221). All had a paranasal computed tomography scan within 48 hours of admission, which 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, on the basis of 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 (221). Therefore, whereas it seems clear that infectious sinusitis is a risk factor for VAP, no studies have yet been able to definitively demonstrate 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 with 531 mechanically ventilated patients evaluated the impact of transporting the patient out of the ICU to other sites within the hospital (171). 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).
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ABSTRACT
CONTENTS
EPIDEMIOLOGY
DIAGNOSIS
TREATMENT
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Unlike community-acquired pneumonia, it may be difficult to determine whether pneumonia has developed in a hospitalized ventilator-dependent patient.
Clinical Evaluation Combined with Microscope Examination and Culture of Tracheal Secretions
The diagnosis of VAP is usually based on three components: systemic signs of infection, new or worsening infiltrates seen on the chest roentgenogram, and bacteriologic evidence of pulmonary parenchymal infection (53). The systemic signs of infection, such as fever, tachycardia, and leukocytosis, are nonspecific findings and can be caused by any condition that releases cytokines (228). 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) che