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DIAGNOSTIC TESTING FOR VENTILATOR-ASSOCIATED PNEUMONIA
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DIAGNOSTIC TESTING FOR VENTILATOR-ASSOCIATED PNEUMONIA Miquel Gallego, MD, and Jordi Rello, MD, PhD
The diagnosis of ventilator-associated pneumonia (VAP) at the bedside is difficult, but no more so than the diagnosis of meningitis in patients with external intraventricular devices, or of urinary tract infections in patients with a bladder catheter. In VAP, somewhat surprisingly, the exceptions have been overemphasized. In addition, most investigators have neglected to evaluate the key role of the quality of the sample provided. Others have expended considerable effort on evaluating the representativity of diagnostic tools in autopsy studies, but information gathered from moribund patients receiving antibiotics for a nonrecent episode is not representative of the case of other patients in the correct clinical setting. In recent decades, much has been learned about the diagnosis of VAP, but little about the impact of diagnostic techniques on outcome. The growing number of articles about diagnosis, far from improving our understanding, have only added to the confusion. Differences in populations studied or in the timing of the performance of the technique, poor standardization of techniques, the absence of any appraisal of the quality of the samples, and the absence of a representative gold standard have made it very difficult to compare the different studies reliably, and preclude the generalization of findings. In 1999, despite almost 20 years of clinical practice with ”invasive diagnostic techniques,” only five recent investigations2,zz, 24, have focused on evaluating the impact on outcome. As the authors noted in a recent update,’6 more time has been spent on looking for “El Dorado” than on evaluating the impact on outcome of diagnostic tests.
With these precedents, and with the confusion created, it is not surprising that most clinicians have missed the real nature of the problem. In this article, the authors review the controversial topic of diagnostic testing of pneumonia in intubated patients as presented in clinical practice, based on their own experience. Specifically, they reply to the following key questions: (1) When should an etiologic investigation be performed? (2) Should an intubated patient with suspicion of pneumonia be treated? (3) How should the microbiologic findings be interpreted? (4) What is the potential impact of diagnostic techniques on outcome? SUSPICION OF PNEUMONIA
A classic histopathologic definition of pneumonia includes abscess formation or areas of accumulation of neutrophils, plus a positive quantitative culture of lung parenchyma (>lo4 microorganisms per gram of lung tissue).% The impossibility of obtaining histologic samples in clinical practice invalidates its clinical utility. VAP is indeed a special subgroup of nosocomial pneumonia that develops as a complication of an artificial airway. This, and the absence of an incubation period, mean that VAP is often developed after only a few hours of intubation, in contrast to other nosocomial infections, including pneumonia in nonventilated patients, which develops after 48 hours of admission. Pneumonia is a process that results when an invading organism overwhelms lung defenses. A local inflammatory response follows, with accumulation of neutrophils and other inflammatory cells
From the Pulmonary (MG) and Critical Care (JR) Departments, Hospital de Sabadell, Sabadell, Barcelona, Spain
CLINICS IN CHEST MEDICINE VOLUME 20 NUMBER 3 * SEPTEMBER 1999
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in peripheral bronchi and the alveolar space. This opacity, bearing in mind the aforementioned limitations, a diagnosis of pneumonia cannot be susis manifested in clinical practice by purulent respitained. No further microbiologic evaluation is reratory secretions. Although purulence is the exterquired and the patient can be observed. In nal manifestation of the inflammatory process contrast, pneumonia should be suspected in the which defines any infection (e.g., meningitis, uricase of the combination of purulent respiratory nary tract infection), purulent respiratory secresecretions and an abnormal chest radiograph tions are frequently aspirated from intubated patients because of entities other than pne~monia,'~ (which are usually accompanied by other manifestations of sepsis or progressive hypoxemia). In this reducing the positive predictive value of the test. setting, empirical antimicrobial agents should be In contrast, in the absence of purulent respiratory administered immediately. Microbiologic testing secretions, the diagnosis of VAP is highly unlikely. The only way to differentiate tracheobronchitis for causative diagnosis is recommended and should be performed as early as possible. from pneumonia in patients with purulent secretions is by the presence/absence of a compatible radiologic opacity. These two variables therefore MICROBIOLOGIC SCREENING are the major criteria required for pneumonia suspicion and microbiologictesting. Tracheobronchitis Lower respiratory airways are uniformly colois the clinical manifestation of an inflammatory nized only a few hours after intubation,'z, l9 meanprocess of the terminal bronchioli (bronchiolitis) ing that the mere recovery of a pathogen is not and may be accompanied by positive respiratory sufficient. Decisions based on qualitative techculture samples.5oRadiologic diagnosis therefore is niques are nonspecific and lead to overdiagnosis, mandatory to approach diagnosis but, in ventibringing with it an unnecessary use of broad-speclated patients, the sensitivity and specificity of trum antibiotics with the potential concerns of sechest radiographies are limited. Beydon et a17 relecting resistant organisms41and, even more imported that CT scans were more likely to detect a portantly, missed opportunities to identify other radiologic opacity than a chest radiograph. In this infectious sources or other treatable problems. study, 26%of opacities were discovered by CT, but not by chest radiograph. More frequent in clinical Blood cultures do not provide additional useful 45 The authors therefore believe that inf0rmation.4~. practice is the finding that a radiologic infiltrate semiquantitative cultures should be performed, redoes not correspond to a true diagnosis of pneugardless of whether respiratory samples are obmonia. As Meduri et a P pointed out, many other tained. entities in intubated patients can mimic the pneuThe authors have learned that finding a high monic process, including thromboembolic disease, concentration of colonies (even above the classical pulmonary edema, or atelectasis. Likewise, in 24 patients with autopsy-proven pneumonia, Wund42 by thresholds) is not diagnostic of pne~monia'~, erink et a161reported that no single radiographic itself. In the absence of radiographic opacities, these false-positives may be caused by the pressign had a diagnostic accuracy above 68%. Only the presence of air bronchograms correlated well ence of bronchiolitis,5O may be an incipient stage with pneumonia; however, in patients with adult of pneumonia', l7 or may be the result of mouth contamination. In the presence of radiographic abrespiratory distress syndrome (ARDS) this correlanormalities, they may represent just colonization' tion was extremely poor.6l At the patient's bedside, development of fever, or contaminated samples from oropharyngeal flora. The utility of semiquantitative cultures new or progressive leukocytosis, or other clinical should be limited to bacterial infection alone, besigns of sepsis oblige the physician to look for an infectious source. VAP is the most probable origin, cause they do not provide additional value for fungi." especially if tracheobronchial secretions have become purulent. Unfortunately, in autopsy studies As in urine analysis, direct staining of respiratory samples is mandatory and this information Fagon et all5 demonstrated that only 27 (30%) of should be provided within 1 hour of obtaining the 84 patients suspected of having pneumonia had sample. Because of its simplicity and value, this histopathologic confirmation. What is more, only information should be used as part of the initial 62% of predictions of pneumonia turned out to be evaluation of all patients. It provides crucial data accurate. In the presence of radiologic criteria plus on the quality of the respiratory sample and in either purulent secretions, fever, or leukocytosis, guiding an initial antibiotic choice. the sensitivity for VAP identification is very high, Decisions regarding initiation of empirical therbut specificity is poor.6, 14, 30, 49 Presence of these four criteria improves specificity, but at the cost of apy can be improved if based on direct staining of respiratory samples. The presence of intracellular a drop in sensitivity-possibly below 50% in pabacteria (ICO) or a positive Gram's stain'o,59,60 may tients with ARDS. be of great help in selecting the initial antibiotic. In spite of the aforementioned limitations, in When visualizing 5% or more ICO in direct stains clinical practice, the initial diagnosis of VAP deof bronchoalveolar lavage (BAL) material, the pends upon clinical criteria and the appearance specificity is reported to be about 95% and specific of a new pulmonary opacity or progression of a antimicrobial choices can be made with confiprevious one. Without the evidence of a radiologic
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dence. Unfortunately, concomitant antibiotic use13,M, reduces the sensitivity of the technique and false-negative results are possible. In the authors’ experience,M, one third of episodes caused by Pseudomonas aeruginosa are associated with negative direct stainings. As a result, a negative direct staining in a high-quality sample requires initial broadspectrum coverage until culture results are available. QUALITY OF SAMPLES
Before making therapeutic decisions or performing cultures, the authors look at the cellular product of the sample to evaluate its quality. This is crucial because if the sample is contaminated by epithelial cells, further cultures uniformly will be followed by growing nonpathogenic mouth flora. Coagulase-negative Staphylococcus, Neisseria spp, viridans group Streptococcus, anaerobic flora, and Candida spp are not usually considered the cause of pneumonia unless the patient has received a large bolus of organisms and a large-volume aspiration event has been documented. This strategy does not differ from the standard approach used to look at urine samples to diagnose a urinary tract infection. The importance of this strategy should be emphasized, because most investigations do not report information regarding the quality of the sample, which is a major problem in interpretating the findings. In the authors’ experience, even if adherence to protocol is good, sample contamination frequently occurs. The presence of more than 1% of epithelial cells in bronchoscopic samples suggests heavy oropharyngeal contamination, and the interpretation of cultures is therefore unreliable.51This is true of all kinds of respiratory samples, except for tracheobronchial aspirates, in which some authors” suggest that the level may rise to 10 squamous epithelial cells per low-power field (magnification, x 100). These authors reported that only 15%of endotracheal suction aspirate specimens contained fewer than 10 squamous epithelial cells per low-power field.34The remaining specimens should be rejected for analysis. Indirectly, this is an acknowledgment of the difficulty in obtaining samples free of oropharyngeal contamination if the analysis is based on samples collected by nonbronchoscopic techniques. In addition, in the presence of pneumonia, analysis of the cellular product of an invasive sample must not show fewer than 10% neutrophils. With endotracheal aspirates, on the other hand, the number of polymorphonuclear leukocytes has no discriminant value and is not predictive of an interpretable specimen for pneumonia.34 Neutrophilia in BAL samples is a uniform finding in patients with pneumonia,M,but is not diagnostic because other inflammatory processes of the lung, such as ARDS, are also associated with these findings. In contrast, a low percentage makes pneumo-
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nia unlikely,’* and the presence or absence of epithelial cells provides information regarding management of the sample and an evaluation of an individual patient. A good example of the importance of this information is provided by a study reported by Mertens et a1,3l indicating that fewer than 10% inflammatory cells in protected specimen brush (PSB) samples is uniformly associated with negative cultures. In the presence of more than 1% epithelial cells and fewer than 10% neutrophils, therefore, samples should not be processed for etiologic investigation of VAP and further samples should be provided for appropriate analysis. On the other hand, presence of fewer than 10% neutrophils in an appropriate sample (4% epithelial cells) of a ventilated patient with suspicion of pneumonia should be followed by a careful search for alternative diagnoses. INTERPRETATION OF CULTURE FINDINGS
As already noted, semiquantitative cultures are necessary to interpret bacterial cultures in respiratory samples, but this should not be done independently of the adequate clinical context. Consequently, the authors are reluctant to use the concept ”positive” or ”negative” culture samples based on a previously established cutoff. Interpretation of microbial results requires good communication between clinicians and the microbiology laboratory and should not be done without taking into account the clinical setting. Information regarding the exact number of cfu per milliliter should be provided to the clinician for individual interpretation. Semiquantitative cultures in high-quality samples remain the key to understanding the significance of the pathogen. The bacterial burden should be interpreted, however, considering the specific clinical setting of each patient and the potential interference of antimicrobial regimens on the culture. Indeed, bacterial proliferation in airways from ventilated patients represents a dynamic process, going from asymptomatic colonization through manifest pulmonary infection. In the presence of low bacterial counts, pneumonia is unlikely and the isolated organism probably indicates airway colonization. An increasing bacterial burden is associated with a progressive inflammatory reaction, which defines the development of pneumonia. Special populations may have relatively high bacterial counts, as is the case in patients with chronic obstructive pulmonary disease% without significant inflammatory changes. This should be borne in mind when evaluating organism counts in certain subpopulations. In spite of these exceptions, classically recommended cutoffs select patients with a high probability of pneumonia: Higher bacterial counts are correlated with higher probability of disease. Figure 1 summarizes the probability of having pneumonia according to the
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Figure 1. Probability of having presence/absence of pneumonia across the range of colony counts in cultures of protected specimen brush diluent. (Adapted from Baker AM, Bowton DL, Haponik EF: Decision making in nosocomial pneumonia. Chest 107:85-95,1995; with permission.)
bacterial concentration in respiratory samples in ventilated patients. The overall specificity of classical cutoffs for diagnosing pneumonia in alive, ventilated patients is up to 90% in most series. In an individual sample, the exact concentration of organisms does not depend solely on the patient's comorbidities. Several other factors, such as the timing of the pneumonia, exposure to antibiotics, the skill of the physician performing the bronchoscopy and processing of the sample may be associated with lower bacterial counts, which should not be wrongly interpreted as absence of pneumonia. All these factors must be borne in mind when interpreting semiquantitative cultures and making therapeutic decisions. Marquette et alZ7reported that repeated brushing of the same area of lung demonstrated a 13.6% variance at 1000 cfu/mL, the recommended cutoff for the PSB technique. Other investigators,= using blind procedures, found that the yield may also decrease when the sample was not obtained from the affected lobe. Brush specimens must be introduced into 1 mL of saline solution or Ringer's lactate solution; variations in this volume can produce a dilutional effect that could alter the total number of colonies. Regarding BAL specimens, initial studies were performed with a volume of instillation of 140 mL. The questions of whether lower instillation volumes affect the counts, and the impact of dilutional effects, depending on the percentage of fluid recovered, are not known. Overall, returns of less than 10% of the instilled fluid are probably not representative of the lower respiratory tract. In tracheal aspirates, the effects of the volume of secretions obtained, the frequency of prior tracheal aspirations, and homogenization in the laboratory on the reproducibility of bacterial counts are also unknown. Certain technical aspects may also be associated with lower counts and should be considered when
interpreting samples. Delays in transport of up to 60 minutes have been associated with lower counts of microorganisms, especially Streptococcus pneumoniae and Haernuphilus infl~enzae.~,On the other hand, a delayed culture may be associated with overgrowth and overdiagnosis. One elegant study suggested that the sample should be refrigerated at 4°C if immediate culture is not available, but taking into account that H. infuenzae counts can be Finally, exposure to antibiotics is the variable that most frequently reduces the bacterial concentration of organisms. Some researchers have suggested withholding antibiotics for between 24 and 48 hours in patients with suspicion of pneumonia to improve the microbiologic yield. This approach should be strongly discouraged because it exposes critically ill patients to increased risk of mortality because of delayed antimicrobial treatment?, 24, In addition, recent studies have reported that the sensitivity and specificity of PSB or BAL are unaffected in patients receiving a long course of antibiotics for a prior infection.53,56 This is because the overwhelming majority of organisms responsible for VAP in this setting are resistant to previously administered agents, because of the selective pressure of these antimicrobial^^^; their growth is only minimally affected by prior antimicrobial regimens. In contrast, both in patients without treatment or under prior antibiotic regimens, efforts must be made to obtain respiratory samples before institution of a new antibiotic regimen. Many investigators", 37 have described a decrease in the diagnostic sensitivity of samples because of the recent introduction of a new antimicrobial. Souweine et a153demonstrated that there was a significant decrease in the number of colonies recovered in patients who were started on-a new antibiotic in the 24 hours prior to collection of the specimen. With some pathogens, such as H . infuenzae, a sin-
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gle dose of antibiotics can sterilize the culture sample! In contrast, with nonfermentative gram-negative bacilli, this effect is less marked.39 At the bedside, pathogens recovered in counts above the classical cutoffs in samples with an appropriate inflammatory response should be considered as highly specific and the definite cause of pneumonia. Likewise, isolates with a lower count, particularly if the patient has received a new antibiotic-ven a single dose-in the previous 48 hours should be considered as probable pathogens in the appropriate clinical setting. Longer exposure to antibiotics is unlikely to be the cause of falsenegatives. The percentage of neutrophils or the identification of ICO are useful complementary tools in interpreting individual cases. BRONCHOSCOPIC VERSUS NONINVASIVE SAMPLING
Lower respiratory sampling includes PSB and BAL performed either under bronchoscopic guidance or blindly. Other authors have suggested that tracheal aspirate provides similar information and is more cost-effective. Hundreds of studies have debated the right method for collecting specimens, and a complete discussion is beyond the objectives of this article. The main techniques investigated for diagnostic sampling in intubated patients include: 1. Blood cultures 2. Tracheal aspirates 3. Blind procedures 3.1. Protected specimen brush 3.2. Protected bronchoalveolar lavage 4. Bronchoscopic techniques 4.1. Bronchoalveolar lavage 4.2. Protected bronchoalveolar lavage 4.3. Protected specimen brush
Only a few researchers have used an histologic gold standard9,25, "; most have used bronchoscopic methods. As indicated previously, the studies using. a histologic gold standard did not provide valuable information on live patients. Because most patients have been taking antibiotics before death, they represent a very late evaluation of the event; the study population is biased to moribund patients, and some of the histologic findings may, indeed, be terminal events. Defenders of bronchoscopic techniques argue that visualization of the tracheobronchial tree is useful for differential diagnosis and even for definitive diagnosis. In a well-conducted trial, Timsit et a155reported that visualization of the tracheobronchial tree can accurately predict pneumonia. In this study, three independent factors were associated with the development of pneumonia-a decrease of the partial oxygen pressure-to-fractional inspired oxygen ratio (Pao2/FIo2)greater than 50 mm Hg, presence of distal purulent secretions, and persistence of secretions emerging from distal
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bronchi during exhalation. Furthermore, direct visualization permits the correct selection of the segment affected radiologi~ally.2~ Detractors of bronchoscopic techniques point to autopsy studiesw,58 to argue that selection of an adequate bronchial segment is not necessary, because bronchopneumonia affects all parts of both lungs. Marquette et a1,28in a study comparing bronchoscopic PSB and blinded PSB, for example, concluded that correlation between the two techniques was good. In contrast, in a similar study comparing the same techniques, Jorda et alZoreported that the correlation decreased when opacities affected upper lobes or when solely the left lung was involved. LealNova1 et al,23comparing the yield for right versus left localized pneumonias, demonstrated that the yield for blind brushing was 85% for right lower lobe pneumonia, but only 28% for left lower lobe pneumonia. The cost-effectiveness relationship, and the unavailability in some institutions of highly skilled personnel to perform invasive methods over 24 hours, have been other arguments against their use. For these reasons, the interest in noninvasive samples such as tracheobronchial aspirates (EA) has increased in the late 1990s. Some researchers=, 26 suggested that quantitative culture of tracheal aspirates, with a cutoff of lo6 organisms/mL was more sensitive than PSB, and no less specific. In contrast, in a population with no recent changes in antibiotherapy, Jourdain et aP1 reported a lower sensitivity and specificity (68% and 84%)than PSB; moreover, they reported that the microorganisms cultured from EA correlated weakly with those obtained using PSB specimens. These authors concluded that the main drawback of performing EA is the possibility of overtreating many false-positive cultures, with the risk of increasing bacterial resistance and superinfections, as well as missing opportunities to identify the real problem of the patient. As discussed previously, information regarding the quality of the sample or whether secretions were previously cleared is rarely reported, making it impossible to compare different studies. As already mentioned, in immunocompetent intubated patients, it is necessary to differentiate infection from colonization or contamination. This supports the use of the diagnostic technique that yields the highest specificity and positive predictive values for causative diagnosis in intubated patients. On the other hand, interest should focus on the more sensitive techniques when assessing specific subgroups of immunocompromised populations. ADVERSE EFFECTS OF DIAGNOSTIC TESTING
There are some potential risks involved in performing bronchoscopies in ventilated patients, including temporary alterations in lung mechanics and gas exchange, barotrauma, increase in intra-
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cranial pressure, or cross-transmission of pathogens. Other reported complications have included arrhythmias, transient worsening in pulmonary infiltrates, and fever. There is some additional risk with specific procedures, including bleeding from the brush procedure or severe hypoxemia from the BAL procedure. These risks are also present for blind procedures and the risk of hypoxemia is even present in collecting EA. End-expiratory volume and positive end-expiratory pressure are reduced, facilitating alveolar closure and venous admixture. These changes slowly wear off after the procedure. In spite of this, to the best of the authors' knowledge, no deaths have been reported in relation to these procedures in ventilated patients, provided that transbronchial biopsies are not performed. The avoidance of complications is highly dependent on the expertise of the physician in ventilating patients and the skill of the operator of the procedure. Strict adherence to formal contraindications and careful management of the ventilatory setting are associated with a marginal incidence of adverse events. In general, for adult patients, the endotracheal tube size should be equal to or greater than 1.5 mm larger than the external diameter of the flexible bronchoscope. All intubated patients should be adequately sedated and should receive a short-acting paralytic agent to prevent coughing during the procedure. Secondary hypotension should be anticipated and appropriate intravenous fluids should be available for immediate administration. During the procedure, close monitoring is recommended, including exhaled tidal volume and peak inspiratory pressure, single-channel electrocardiography, and continuous oximetry. Platelet transfusion before the procedure should be administeredZ9if a PSB sample is to be obtained and the platelet count is under 20,000/mm3. Regarding the ventilator setting, the FIO, should be set at loo%, respiratory rate at 20 breaths/ minute, and peak inspiratory flow at less than or equal to 60 L/minute. The peak pressure alarm should be increased to a level that allows adequate ventilation. Other ventilator settings should be individually titrated to maximize exhaled tidal volume. Finally, patients with severe hypoxemia need to receive continuous positive airway pressure as previously administered. In patients with severe head injury, the procedure may raise intracranial pressure, but median arterial pressure also rises, and cerebral perfusion pressure is maintained within acceptable levels. The intracranial pressure returns to basal levels after the procedure. When properly performed, these procedures do not affect neurologic status in patients with severe head injury.36 IMPACT ON OUTCOME
Three factors are related to the resolution of an episode of pneumonia-host defenses, pathogen
virulence, and bacterial burden. The antibiotic therapy works by preventing bacterial replication and reducing the bacterial inoculum. Adequate antibiotic therapy therefore is crucial in immunocompromised patients and also of great importance in critically ill patients developing pneumonia. In 1990, using multivariate statistical analysis, Torres et a157were the first to report that inappropriate antimicrobial therapy was an independent factor for increase of mortality (fivefold of odds ratio). Other researchers5 have questioned whether episodes of VAP were associated with excess mortality in critically ill patients. Indeed, the excess of mortality is questionable in some clinical settings, such as trauma patients or episodes caused by primary endogenous pathogens (such as methicillin-sensitive Staphylococcus aureus, S. pneumoniae, or H. influenzae). Consequently, there is some doubt about the potential ability of microbiologic testing to reduce mortality in these subgroups. We know that most patients who die of pneumonia were infected with nonfermentative gram-negative bacilli or methicillin-resistant S. a ~ r e u s . ~Now, ' there is clearcut evidence that episodes caused by P. aeruginosa, A. baumannii, or MRSA cause an excess of mortality compared with predictions made on the basis of severity of illness on ICU admission.M,46,47 The clinical setting in which these microorganisms appear therefore is likely to benefit from an appropriate antimicrobial regimen and systematic microbiologic testing. Obviously, the impact of microbiologic tests on outcome is also dependent on the adequacy of the initial antibiotic choice. It can be hypothesized that if everybody received appropriate therapeutic regimens, the benefit of microbiologic investigation on outcome would be marginal. As mentioned previously, screening can adjust the initial choice in some cases, but sensitivity of direct staining for nonfermentative pathogens is not optimal. Indeed, the more frequent the wrong initial choices, the greater the potential benefit of diagnostic testing. Using bronchoscopic techniques in patients with severe pneumonia, Rodriguez de Castro et a14sconcluded that in up to 30% of cases there was a change in antibiotics, either to reduce the spectrum or to adjust therapy because an initially resistant organism was found. Unfortunately, the impact on outcome was not assessed. Luna et alZ4found that the percentage of patients receiving inappropriate therapy was as high as 68%. Likewise, the authors' groupa evaluated that 23.9% of patients with VAP were at risk of a wrong initial antibiotic choice when diagnosed using bronchoscopic methods. A multicenter study of VAP with causative diagnosis based on tracheal aspirates*reported that 43.7%of patients with VAP required a change of the empiric initial treatment because of isolates of resistant pathogens. This evidence suggests that adjustment of therapy based on microbiologic testing would be of benefit. In spite of this, whether bronchoscopic techniques are really useful has been the topic of nu-
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merous pro-con debates between experts. In a pilot study comparing bronchoscopy against tracheal aspirates, Sanchez-Nieto et a152concluded that management using the results of bronchoscopic studies led to more frequent antibiotic changes but did not influence outcome. Unfortunately, as with most of the studies already mentioned, the authors failed to evaluate the quality of the samples. In addition, the lack of randomization according to a severity-of-illness score meant that the group with bronchoscopies had higher Acute Physiology and Chronic Health Evaluation I1 scores; the percentage of patients with P. aeruginosa isolates was higher in the group with bronchoscopy, which raises doubts about the validity of the conclusions. Recently, French researchers conducted a large, multicenter, randomized, prospective study comparing bronchoscopic testing as part of the initial evaluation with a strategy based on empiric therapy alone. Interestingly, a statistically significant difference in crude mortality was found at 15-days follow-up, favoring the group with microbiologic testing (Fagon J, personal communication). Although mortality is the most important indicator of outcome, other variables are also relevant. Antibiotic resistance is spawned in large measure by the selective pressure of antibiotic use. Several lines of evidence, including the authors' own experience,4l suggest that there is an association between antimicrobial use in hospitals and antimicrobial resistance, an association that is in all probability causal. The possibility of reducing the use of broad-spectrum antimicrobials is of great interest in the efforts to contain the problem. The authors and others43, 48 have reported that reducing the spectrum of the selected regimen is possible in some patients on the basis of microbiologic tests, and the interest in this possibility should not be undervalued because of the increase in mortality of episodes of pneumonia caused by multiresistant pathogens.4l Some authors have postulated that empiric therapy alone is more cost-effective than an approach based on empiric therapy plus microbiologic investigation. They advocate reserving microbiologic investigation for the subgroup of patients with nonresolving pneumonia. This approach contrasts with the classic management of other infections in patients at risk of death, such as cases of meningitis or urinary tract infections. Moreoever, recent evidence suggests the importance of the timing of testing on its impact on the microbiologic findings and outcome. In patients with a wrong initial antibiotic choice and late rescue treatment, it is not possible to modify the case fatality whereas modification of the antimicrobial regimen based on early diagnostic testing (i.e. within 12 hours of pneumonia suspicion) permits resolution of 63% of episodes.43 In addition to prompt timing, other variables may increase the efficacy of the microbiologic investigation. Decision analysis- has shown that antibiotic treatment of VAP based on any diagnostic
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technique, the positive predictive value of which reliably exceeds 28%, would be associated with improved survival. In general, these arguments favor the use of techniques with high positive predictive value whenever possible. Patients at risk of mortality attributable to pneumonia are the target population that might obtain significant benefit on outcome of an early investigation-patients at risk for multiresistant organisms with an intermediate degree of severity-of-illness, usually represented by late episodes of pneumonia in patients who received prior antimicrobial therapy. CONCLUSIONS
Diagnosis of VAP is based on the presence of a pulmonary inflammatory reaction of bacterial origin in patients ventilated through an artificial airway. This is recognized at the bedside by the development of purulent respiratory secretions in ventilated patients with new or progressive radiographic opacities. Other systemic signs of sepsis or progressive hypoxemia are often documented. If pneumonia is suspected, antimicrobial agents are administered because delaying appropriate therapy is correlated with higher mortality. As in other infectious processes, microbiologic testing for causative diagnosis is recommended and should be performed as early as possible. Direct staining is mandatory to evaluate the quality of the respiratory sample and to guide initial antibiotic choice. An analysis of the cellular product showing greater than 1% epithelial cells is suggestive of oropharyngeal contamination and should be rejected for culture, because it will be followed by growing nonpathogenic mouth flora. Presence of fewer than 10% neutrophils in an appropriate sample of a patient with pneumonia suspicion should suggest an alternative diagnosis. Whereas visualizing greater than 5% ICO in direct stains of BAL material guides the initial antibiotic choice, a negative direct stain requires initial broad-spectrum coverage because one third of episodes caused by l? aeruginosa are associated with negative direct satn is@ . -' The simple recovery of an organism in a sample of good quality is not sufficient, because lower airway colonization is uniformly present only a few hours after intubation. Semiquantitative culture results provide information on the relative burden of pathogens. Whereas concentrations above classical cutoffs are associated with high specificity, lower concentrations may be clinically significant in certain settings, such as patients who received a dose of a new antibiotic after pneumonia suspicion. As in urine analysis, respiratory culture samples should be interpreted after screening the quality of the sample and evaluating the bacterial burden, the potential interference of new antibiotic regimens, and the specific clinical setting. The authors have learned that microbiologic findings should not be used to decide whether a
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ventilated patient has a pneumonia or not, but are definitely important in improving the use of antimicrobial agents. The authors believe that current evidence justifies performing routine diagnostic tests whenever possible in all patients with VAP. The microbiologic findings may make it possible to reduce the antibiotic spectrum in some patients, which can contribute to reducing the selection and spread of resistant pathogens. Moreover, recent reports have shown that early microbiologic testing improves outcome of patients with VAP. Although it is not possible to mod* the case fatality ratez4in patients with a wrong initial antibiotic choice and late rescue treatment, modification of the antimicrobial regimen based on early diagnostic testing (within the 12 hours immediately after pneumonia suspicion) permits resolution in 63% of epis0des.4~
References 1. A'Court CHD, Garrard CS, Crook D, et al: Microbiological surveillance in mechanically ventilated patients, using non-directed bronchial lavage and quantitative culture. QJh486:635-648,1993 2. Alvarez-Lerma F and ICU-Acquired Pneumonia Study Group: Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. Intensive Care Medicine 22387394, 1996 3. Baker AM, Bowton DL, Haponik EF Decision making in nosocomial pneumonia: An analytic approach to the interpretation of quantitative bronchoscopic cultures. Chest 1078595,1995 Haponik EF Pneumonia in 4. Baker AM, Meredith JW, intubated trauma patients. Microbiology and outcomes. Am J Respir Crit Care Med 153:343-349,1996 5. Baselski VS, El-Torky M, Coalson JJ, et ak The standardization of criteria for processing and interpreting laboratory specimens in patients with suspected ventilatorassociated pneumonia. Chest 102571-579S, 1992 6. Baughman RP, Thorpe JE, Stanek J, et a1 Use of the protected specimen brush in patients with endotracheal or tracheostomy tubes. Chest 91:223-235, 1987 7. Beydon 1, Saada M, Liu N, et al: Can portable chest x-ray examination accurately diagnose lung consodilation after major surgery? A comparison with computed tomography scan. Chest 1021698-1703,1992 8. Blavia R, Dorca J, Verdaguer R, et a1 Bacteriological follow-up of nosocomial pneumonia by successive protected specimen brush [Abstr]. Eur Respir J 4A823, 1991 9. Chastre J, Fagon JY, Bomet-Lecso M, et al: Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 152~231-240,1995 10. Chastre J, Fagon JY, Soler E', et al: Diagnosis of nosocomial bacterial pneumonia in intubated patients undergoing ventilation: Comparison of the usefulness of bronchoalveolar lavage and the protected specimen brush. Am J Med M499-506,1988 11. Chastre J, Viau F, Brun P, et al: Prospective evaluation of the protected specimen brush for the diagnosis of pulmonary infections in ventilated patients. Am Rev Respir Dis 130924-929, 1984 12. Correa H, Marini F, Franca G: Infecci6n pulmonar en el paciente con asistencia respiratoria. Arch Med Int 4191-205, 1982
13. Dotson RG, Pingleton SK The effect of antibiotic therapy on recovery of intracellular bacteria from bronchoalveolar lavage in suspected ventilator-associated pneumonia. Chest 103541-546, 1993 14. Fagon JY, Chastre J, Hance AJ, et al: Detection of nosocomial lung infection in ventilated patients: Use of protected specimen brush and quantitative culture techniques in 147 patients. Am Rev Respir Dis 138:llO-116, 1988 15. Fagon JY, Chastre J, Hance AJ, et al: Evaluation of clinical judgment in the identification and treatment of nosocomial pneumonia in ventilated patients. Chest 103:547-553, 1993 16. Gallego M, Valles J, Rello J: New perspectives in the diagnosis of nosocomial pneumonia. Curr Opin Pulm Med 23116-119, 1997 17. Garrard CHS, A'Court C D The diagnosis of pneumonia in the critically ill. Chest 108(suppl):17-25, 1995 18. Grey SW, Wunderink RG, Jones CB, et a1 Correlation of bronchoalveolar lavage neutrophilia with quantitatives cultures in the diagnosis of ventilator-associated pneumonia. Am Rev Respir Dis 149:970,1994 19. Johanson W, Pierce A, Sanford JE', et a1 Nosocomial respiratory infections with gram-negative bacilli. Ann Intern Med 77701-706, 1972 20. Jorda R, Parras F, Ibaiiez J, et a1 Diagnosis of nosocomial pneumonia in mechanically ventilated patients by the blind protected telescoping catheter. Intensive Care Medicine 19:337-382, 1993 21. Jourdain B, Novara A, Joly-Guillou ML: Role of quantitative cultures of endotracheal aspirates in the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 152241-246, 1995 22. Kollef MH, Ward S The influence of mini-BAL cultures on patient outcome: Implications for the antibiotic management of ventilator-associated pneumonia. Chest 113:412-420, 1998 23. Leal-Nova1 SR, Alfaro-Rodriguez E, Murillo-Cabeza F, et al: Diagnostic value of the blind brush in mechanically ventilated patients with nosocomial pneumonia. Intensive Care Med 18:410-414, 1992 24. Luna CM, Vujacich P, Niederman M, et al: Impact of BAL data on the therapy and outcome of ventilatorassociated pneumonia. Chest 111:676485, 1997 25. Marquette CH, Copin MC, Wallet F, et al: Diagnostic test for pneumonia in ventilated patients: Prospective evaluation of diagnostic accuracy using histologic gold standard. Am J Respir Crit Care Med 151:18781888,1995 26. Marquette CH, Georges F, Wallet P, et al: Diagnostic efficiency of endotracheal aspirates with quantitative bacterial cultures in intubated patients with suspected pneumonia: Comparison with PSB. Am Rev Respir Dis 148138-144,1993 27. Marquette CH, Herengt F, Mathieu D, et al: Diagnosis of pneumonia in mechanically ventilated patients: Repeatability of protected specimen brush. Am Rev Respir Dis 147211-214,1993 28. Marquette CH, Herengt F, Saulnier F, et a1 Protected specimen brush in the assessment of ventilator-associated pneumonia: Selection of a certain lung segment for bronchoscopic sampling is unnecessary. Chest 103:243-247, 1993 29. Meduri GU, Chastre J: The standardization of bronchoscopic techniques for ventilator-associated pneumonia. Chest 1023557-5648, 1992 30. Meduri GU, Mauldin GL, Wunderink RG, et al: Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia. Chest 106221-235,1994 31. Mertens AH, Nagler JM, Galdermans DI, et al: Qual-
DIAGNOSTIC TESTING FOR VENTILATOR-ASSOCIATED PNEUMONIA ity assessment of protected specimen brush samples by microscopic cell count. Am J Respir Crit Care Med 1571240-1243, 1998 32. Middlelton Rh4 111, Huff MW, Brickey CDA, et a1 Comparison of quantitative cultures to semiquantitative loop cultures of bronchoscopic protected specimen brush samples. Chest 109:1204-1208, 1996 33. Monso E, Ruiz A, Rose11 J, et a 1 Bacterial infection in chronic obstructive pulmonary disease: A study of stable and exacerbated outpatients using the protected specimen brush. Am J Respir Crit Care Med 152:1316-1320,1995 34. Moms AJ, David CT, Reller LB: Rejection criteria for endotracheal aspirates from adults. J Clin Microbiol 31~1027-1029,1993 35. Papazian L, Bregeon F, Thirion X, et a 1 Effect of ventilator-associated pneumonia on mortality and morbidity. Am J Respir Crit Care Med 154:91-97, 1996 36. Peerless JR, Snow N, Likavec MJ, et a1 The effect of fiberoptic bronchoscopy on cerebral hemodynamics in patients with severe head injury. Chest 108:962965,1995 37. Pham LH, Brun-Buisson C, Legrand P,et al: Diagnosis of nosocomial pneumonia in mechanically ventilated patients: Comparison of a plugged telescoping catheter with the protected specimen brush. Am Rev Respir Dis 1431055-1061,1991 38. Pingleton SK, Fagon JY, Leeper KV: Patients selection for clinical investigation of ventilator-associated pneumonia: Criteria for evaluating diagnostic techniques. Chest 102553-558S, 1992 39. Frats E, Dorca J, Irigaray R, et a1 Bacteriological follow-up of ventilator-associated pneumonia during the first 24 hours of antibiotic treatment [Abstr]. Am J Respir Crit Care Med 151:A791,1995 40. Rein MF, Mandell G L Bacterial killing by bacteriostatic saline solutions-potential for diagnostic error. N Engl J Med 2983794795,1973 41. Rello J, Ausina V, Ricart M, et a1 Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest 10412301235, 1993 42. Rello J, Esandi ME, Diaz E, et al: The role of Candida sp isolated from bronchoscopic samples in nonneutropenic patients. Chest 114:146-149,1998 43. Rello J, Gallego M, Mariscal D, et a1 The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 156196200,1997 44. Rello J, Jubert P, Vall6s J, et a1 Evaluation of outcome for intubated patients with pneumonia due to Pseudomonas aeruginosa. Clin Infect Dis 23:97>978, 1996 45. Rello J, Mirelis B, Alonso C, et a1 Lack of usefulness of blood cultures to diagnose ventilator-associated pneumonia. Eur Respir J 4:1020, 1991 46. Rello J, Rue M, Jubert P, et a1 Survival in patients with nosocomial pneumonia: Impact of the severity of illness and the etiologic agent. Crit Care Med 25:1862-1867, 1997 47. Rello J, Torres A, Ricart M, et al: Ventilator-associated
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pneumonia by Staphylococcus aureus: Comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1501545-1549, 1994 48. Rodriguez de Castro F, Sole-Violin J, Aranda LA, et al: Do quantitative cultures of protected brush specimens modify the initial empirical therapy in ventilated patients with suspected pneumonia? Eur Respir J 9:3741, 1996 49. Rodriguez De Castro FR, Sole-Violin J, Capuz BL, et al: Reliability of the bronchoscopic protected catheter brush in the diagnosis of pneumonia in mechanically ventilated patients. Crit Care Med 19:171-175, 1991 50. Rouby JJ, de Lassale EM, Poete P, et a1 Nosocomial bronchopneumonia in the critical ill Histologic and bacteriologic aspects. Am Rev Respir Dis 14630591066,1992 51. Salata RA, Lederman MM, Shlaes DM, et a1 Diagnosis of nosocomial pneumonia in intubated intensive care patients. Am Rev Respir Dis 135:426-432,1987 52. Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, et al: Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: A pilot study. Am J Respir Crit Care Med 157371-376, 1998 53. Souweine B, Veber B, Bedos JP, et al: Diagnostic accuracy of protected specimen brush and bronchoalveolar lavage in nosocomial pneumonia: Impact of previous antimicrobial treatments. Crit Care Med 26:236-244, 1998 54. Sterling TR, Ho EJ, Brehm WT, et a 1 Diagnosis and treatment of ventilator-associated pneumonia: Impact on survival. A decision analysis. Chest 110:10251034, 1996 55. Timsit JE, Misset B, Azoulay E, et al: Usefulness of airway visualization in the diagnosis of nosocomial pneumonia in ventilated patients. Chest 110:172179, 1996 56. Timsit JF, Misset B, Renaud B, et al: Effect of previous antimicrobial therapy on accuracy of the main procedures used to diagnose nosocomial pneumonia in ventilated patients. Chest 1081036-1040, 1995 57. Torres A, Aznar R, Gatell JM, et al: Incidence, risk, and prognosis factors of nosocomial pneumonia in ventilated patients. Am Rev Respir Dis 142523-528, 1990 58. Torres A, El-Elbiary M, Padro L, et al: Validation of different techniques for the diagnosis of ventilatorassociated pneumonia. Am J Respir Crit Care Med 149324-331, 1994 59. Torres A, El-Elbiary M, Fibregas N, et al: Value of intracellular bacteria detection in the diagnosis of ventilator-associated pneumonia. Thorax 51:378-384, 1996 60. Vall6s J, Rello J, Fernindez R, et a1 Role of bronchoalveolar lavage in mechanically ventilated patients with suspected pneumonia. Eur J Clin Microbiol Infect Dis 13:549-558, 1994 61. Wunderink RG, Woldenberg LS, Zeiss J, et al: The radiologic diagnosis of autopsy-proven ventilator-associated pneumonia. Chest 101:45%463, 1992
Address reprint requests to Jordi Rello, MD, PhD Critical Care Department Hospital de Sabadell Parc Tauli s/n E08208 Sabadell, Barcelona, Spain e-mail: [email protected]
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DIAGNOSTIC TESTING FOR VENTILATOR-ASSOCIATED PNEUMONIA Miquel Gallego, MD, and Jordi Rello, MD, PhD
The diagnosis of ventilator-associated pneumonia (VAP) at the bedside is difficult, but no more so than the diagnosis of meningitis in patients with external intraventricular devices, or of urinary tract infections in patients with a bladder catheter. In VAP, somewhat surprisingly, the exceptions have been overemphasized. In addition, most investigators have neglected to evaluate the key role of the quality of the sample provided. Others have expended considerable effort on evaluating the representativity of diagnostic tools in autopsy studies, but information gathered from moribund patients receiving antibiotics for a nonrecent episode is not representative of the case of other patients in the correct clinical setting. In recent decades, much has been learned about the diagnosis of VAP, but little about the impact of diagnostic techniques on outcome. The growing number of articles about diagnosis, far from improving our understanding, have only added to the confusion. Differences in populations studied or in the timing of the performance of the technique, poor standardization of techniques, the absence of any appraisal of the quality of the samples, and the absence of a representative gold standard have made it very difficult to compare the different studies reliably, and preclude the generalization of findings. In 1999, despite almost 20 years of clinical practice with ”invasive diagnostic techniques,” only five recent investigations2,zz, 24, have focused on evaluating the impact on outcome. As the authors noted in a recent update,’6 more time has been spent on looking for “El Dorado” than on evaluating the impact on outcome of diagnostic tests.
With these precedents, and with the confusion created, it is not surprising that most clinicians have missed the real nature of the problem. In this article, the authors review the controversial topic of diagnostic testing of pneumonia in intubated patients as presented in clinical practice, based on their own experience. Specifically, they reply to the following key questions: (1) When should an etiologic investigation be performed? (2) Should an intubated patient with suspicion of pneumonia be treated? (3) How should the microbiologic findings be interpreted? (4) What is the potential impact of diagnostic techniques on outcome? SUSPICION OF PNEUMONIA
A classic histopathologic definition of pneumonia includes abscess formation or areas of accumulation of neutrophils, plus a positive quantitative culture of lung parenchyma (>lo4 microorganisms per gram of lung tissue).% The impossibility of obtaining histologic samples in clinical practice invalidates its clinical utility. VAP is indeed a special subgroup of nosocomial pneumonia that develops as a complication of an artificial airway. This, and the absence of an incubation period, mean that VAP is often developed after only a few hours of intubation, in contrast to other nosocomial infections, including pneumonia in nonventilated patients, which develops after 48 hours of admission. Pneumonia is a process that results when an invading organism overwhelms lung defenses. A local inflammatory response follows, with accumulation of neutrophils and other inflammatory cells
From the Pulmonary (MG) and Critical Care (JR) Departments, Hospital de Sabadell, Sabadell, Barcelona, Spain
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in peripheral bronchi and the alveolar space. This opacity, bearing in mind the aforementioned limitations, a diagnosis of pneumonia cannot be susis manifested in clinical practice by purulent respitained. No further microbiologic evaluation is reratory secretions. Although purulence is the exterquired and the patient can be observed. In nal manifestation of the inflammatory process contrast, pneumonia should be suspected in the which defines any infection (e.g., meningitis, uricase of the combination of purulent respiratory nary tract infection), purulent respiratory secresecretions and an abnormal chest radiograph tions are frequently aspirated from intubated patients because of entities other than pne~monia,'~ (which are usually accompanied by other manifestations of sepsis or progressive hypoxemia). In this reducing the positive predictive value of the test. setting, empirical antimicrobial agents should be In contrast, in the absence of purulent respiratory administered immediately. Microbiologic testing secretions, the diagnosis of VAP is highly unlikely. The only way to differentiate tracheobronchitis for causative diagnosis is recommended and should be performed as early as possible. from pneumonia in patients with purulent secretions is by the presence/absence of a compatible radiologic opacity. These two variables therefore MICROBIOLOGIC SCREENING are the major criteria required for pneumonia suspicion and microbiologictesting. Tracheobronchitis Lower respiratory airways are uniformly colois the clinical manifestation of an inflammatory nized only a few hours after intubation,'z, l9 meanprocess of the terminal bronchioli (bronchiolitis) ing that the mere recovery of a pathogen is not and may be accompanied by positive respiratory sufficient. Decisions based on qualitative techculture samples.5oRadiologic diagnosis therefore is niques are nonspecific and lead to overdiagnosis, mandatory to approach diagnosis but, in ventibringing with it an unnecessary use of broad-speclated patients, the sensitivity and specificity of trum antibiotics with the potential concerns of sechest radiographies are limited. Beydon et a17 relecting resistant organisms41and, even more imported that CT scans were more likely to detect a portantly, missed opportunities to identify other radiologic opacity than a chest radiograph. In this infectious sources or other treatable problems. study, 26%of opacities were discovered by CT, but not by chest radiograph. More frequent in clinical Blood cultures do not provide additional useful 45 The authors therefore believe that inf0rmation.4~. practice is the finding that a radiologic infiltrate semiquantitative cultures should be performed, redoes not correspond to a true diagnosis of pneugardless of whether respiratory samples are obmonia. As Meduri et a P pointed out, many other tained. entities in intubated patients can mimic the pneuThe authors have learned that finding a high monic process, including thromboembolic disease, concentration of colonies (even above the classical pulmonary edema, or atelectasis. Likewise, in 24 patients with autopsy-proven pneumonia, Wund42 by thresholds) is not diagnostic of pne~monia'~, erink et a161reported that no single radiographic itself. In the absence of radiographic opacities, these false-positives may be caused by the pressign had a diagnostic accuracy above 68%. Only the presence of air bronchograms correlated well ence of bronchiolitis,5O may be an incipient stage with pneumonia; however, in patients with adult of pneumonia', l7 or may be the result of mouth contamination. In the presence of radiographic abrespiratory distress syndrome (ARDS) this correlanormalities, they may represent just colonization' tion was extremely poor.6l At the patient's bedside, development of fever, or contaminated samples from oropharyngeal flora. The utility of semiquantitative cultures new or progressive leukocytosis, or other clinical should be limited to bacterial infection alone, besigns of sepsis oblige the physician to look for an infectious source. VAP is the most probable origin, cause they do not provide additional value for fungi." especially if tracheobronchial secretions have become purulent. Unfortunately, in autopsy studies As in urine analysis, direct staining of respiratory samples is mandatory and this information Fagon et all5 demonstrated that only 27 (30%) of should be provided within 1 hour of obtaining the 84 patients suspected of having pneumonia had sample. Because of its simplicity and value, this histopathologic confirmation. What is more, only information should be used as part of the initial 62% of predictions of pneumonia turned out to be evaluation of all patients. It provides crucial data accurate. In the presence of radiologic criteria plus on the quality of the respiratory sample and in either purulent secretions, fever, or leukocytosis, guiding an initial antibiotic choice. the sensitivity for VAP identification is very high, Decisions regarding initiation of empirical therbut specificity is poor.6, 14, 30, 49 Presence of these four criteria improves specificity, but at the cost of apy can be improved if based on direct staining of respiratory samples. The presence of intracellular a drop in sensitivity-possibly below 50% in pabacteria (ICO) or a positive Gram's stain'o,59,60 may tients with ARDS. be of great help in selecting the initial antibiotic. In spite of the aforementioned limitations, in When visualizing 5% or more ICO in direct stains clinical practice, the initial diagnosis of VAP deof bronchoalveolar lavage (BAL) material, the pends upon clinical criteria and the appearance specificity is reported to be about 95% and specific of a new pulmonary opacity or progression of a antimicrobial choices can be made with confiprevious one. Without the evidence of a radiologic
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dence. Unfortunately, concomitant antibiotic use13,M, reduces the sensitivity of the technique and false-negative results are possible. In the authors’ experience,M, one third of episodes caused by Pseudomonas aeruginosa are associated with negative direct stainings. As a result, a negative direct staining in a high-quality sample requires initial broadspectrum coverage until culture results are available. QUALITY OF SAMPLES
Before making therapeutic decisions or performing cultures, the authors look at the cellular product of the sample to evaluate its quality. This is crucial because if the sample is contaminated by epithelial cells, further cultures uniformly will be followed by growing nonpathogenic mouth flora. Coagulase-negative Staphylococcus, Neisseria spp, viridans group Streptococcus, anaerobic flora, and Candida spp are not usually considered the cause of pneumonia unless the patient has received a large bolus of organisms and a large-volume aspiration event has been documented. This strategy does not differ from the standard approach used to look at urine samples to diagnose a urinary tract infection. The importance of this strategy should be emphasized, because most investigations do not report information regarding the quality of the sample, which is a major problem in interpretating the findings. In the authors’ experience, even if adherence to protocol is good, sample contamination frequently occurs. The presence of more than 1% of epithelial cells in bronchoscopic samples suggests heavy oropharyngeal contamination, and the interpretation of cultures is therefore unreliable.51This is true of all kinds of respiratory samples, except for tracheobronchial aspirates, in which some authors” suggest that the level may rise to 10 squamous epithelial cells per low-power field (magnification, x 100). These authors reported that only 15%of endotracheal suction aspirate specimens contained fewer than 10 squamous epithelial cells per low-power field.34The remaining specimens should be rejected for analysis. Indirectly, this is an acknowledgment of the difficulty in obtaining samples free of oropharyngeal contamination if the analysis is based on samples collected by nonbronchoscopic techniques. In addition, in the presence of pneumonia, analysis of the cellular product of an invasive sample must not show fewer than 10% neutrophils. With endotracheal aspirates, on the other hand, the number of polymorphonuclear leukocytes has no discriminant value and is not predictive of an interpretable specimen for pneumonia.34 Neutrophilia in BAL samples is a uniform finding in patients with pneumonia,M,but is not diagnostic because other inflammatory processes of the lung, such as ARDS, are also associated with these findings. In contrast, a low percentage makes pneumo-
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nia unlikely,’* and the presence or absence of epithelial cells provides information regarding management of the sample and an evaluation of an individual patient. A good example of the importance of this information is provided by a study reported by Mertens et a1,3l indicating that fewer than 10% inflammatory cells in protected specimen brush (PSB) samples is uniformly associated with negative cultures. In the presence of more than 1% epithelial cells and fewer than 10% neutrophils, therefore, samples should not be processed for etiologic investigation of VAP and further samples should be provided for appropriate analysis. On the other hand, presence of fewer than 10% neutrophils in an appropriate sample (4% epithelial cells) of a ventilated patient with suspicion of pneumonia should be followed by a careful search for alternative diagnoses. INTERPRETATION OF CULTURE FINDINGS
As already noted, semiquantitative cultures are necessary to interpret bacterial cultures in respiratory samples, but this should not be done independently of the adequate clinical context. Consequently, the authors are reluctant to use the concept ”positive” or ”negative” culture samples based on a previously established cutoff. Interpretation of microbial results requires good communication between clinicians and the microbiology laboratory and should not be done without taking into account the clinical setting. Information regarding the exact number of cfu per milliliter should be provided to the clinician for individual interpretation. Semiquantitative cultures in high-quality samples remain the key to understanding the significance of the pathogen. The bacterial burden should be interpreted, however, considering the specific clinical setting of each patient and the potential interference of antimicrobial regimens on the culture. Indeed, bacterial proliferation in airways from ventilated patients represents a dynamic process, going from asymptomatic colonization through manifest pulmonary infection. In the presence of low bacterial counts, pneumonia is unlikely and the isolated organism probably indicates airway colonization. An increasing bacterial burden is associated with a progressive inflammatory reaction, which defines the development of pneumonia. Special populations may have relatively high bacterial counts, as is the case in patients with chronic obstructive pulmonary disease% without significant inflammatory changes. This should be borne in mind when evaluating organism counts in certain subpopulations. In spite of these exceptions, classically recommended cutoffs select patients with a high probability of pneumonia: Higher bacterial counts are correlated with higher probability of disease. Figure 1 summarizes the probability of having pneumonia according to the
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Figure 1. Probability of having presence/absence of pneumonia across the range of colony counts in cultures of protected specimen brush diluent. (Adapted from Baker AM, Bowton DL, Haponik EF: Decision making in nosocomial pneumonia. Chest 107:85-95,1995; with permission.)
bacterial concentration in respiratory samples in ventilated patients. The overall specificity of classical cutoffs for diagnosing pneumonia in alive, ventilated patients is up to 90% in most series. In an individual sample, the exact concentration of organisms does not depend solely on the patient's comorbidities. Several other factors, such as the timing of the pneumonia, exposure to antibiotics, the skill of the physician performing the bronchoscopy and processing of the sample may be associated with lower bacterial counts, which should not be wrongly interpreted as absence of pneumonia. All these factors must be borne in mind when interpreting semiquantitative cultures and making therapeutic decisions. Marquette et alZ7reported that repeated brushing of the same area of lung demonstrated a 13.6% variance at 1000 cfu/mL, the recommended cutoff for the PSB technique. Other investigators,= using blind procedures, found that the yield may also decrease when the sample was not obtained from the affected lobe. Brush specimens must be introduced into 1 mL of saline solution or Ringer's lactate solution; variations in this volume can produce a dilutional effect that could alter the total number of colonies. Regarding BAL specimens, initial studies were performed with a volume of instillation of 140 mL. The questions of whether lower instillation volumes affect the counts, and the impact of dilutional effects, depending on the percentage of fluid recovered, are not known. Overall, returns of less than 10% of the instilled fluid are probably not representative of the lower respiratory tract. In tracheal aspirates, the effects of the volume of secretions obtained, the frequency of prior tracheal aspirations, and homogenization in the laboratory on the reproducibility of bacterial counts are also unknown. Certain technical aspects may also be associated with lower counts and should be considered when
interpreting samples. Delays in transport of up to 60 minutes have been associated with lower counts of microorganisms, especially Streptococcus pneumoniae and Haernuphilus infl~enzae.~,On the other hand, a delayed culture may be associated with overgrowth and overdiagnosis. One elegant study suggested that the sample should be refrigerated at 4°C if immediate culture is not available, but taking into account that H. infuenzae counts can be Finally, exposure to antibiotics is the variable that most frequently reduces the bacterial concentration of organisms. Some researchers have suggested withholding antibiotics for between 24 and 48 hours in patients with suspicion of pneumonia to improve the microbiologic yield. This approach should be strongly discouraged because it exposes critically ill patients to increased risk of mortality because of delayed antimicrobial treatment?, 24, In addition, recent studies have reported that the sensitivity and specificity of PSB or BAL are unaffected in patients receiving a long course of antibiotics for a prior infection.53,56 This is because the overwhelming majority of organisms responsible for VAP in this setting are resistant to previously administered agents, because of the selective pressure of these antimicrobial^^^; their growth is only minimally affected by prior antimicrobial regimens. In contrast, both in patients without treatment or under prior antibiotic regimens, efforts must be made to obtain respiratory samples before institution of a new antibiotic regimen. Many investigators", 37 have described a decrease in the diagnostic sensitivity of samples because of the recent introduction of a new antimicrobial. Souweine et a153demonstrated that there was a significant decrease in the number of colonies recovered in patients who were started on-a new antibiotic in the 24 hours prior to collection of the specimen. With some pathogens, such as H . infuenzae, a sin-
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gle dose of antibiotics can sterilize the culture sample! In contrast, with nonfermentative gram-negative bacilli, this effect is less marked.39 At the bedside, pathogens recovered in counts above the classical cutoffs in samples with an appropriate inflammatory response should be considered as highly specific and the definite cause of pneumonia. Likewise, isolates with a lower count, particularly if the patient has received a new antibiotic-ven a single dose-in the previous 48 hours should be considered as probable pathogens in the appropriate clinical setting. Longer exposure to antibiotics is unlikely to be the cause of falsenegatives. The percentage of neutrophils or the identification of ICO are useful complementary tools in interpreting individual cases. BRONCHOSCOPIC VERSUS NONINVASIVE SAMPLING
Lower respiratory sampling includes PSB and BAL performed either under bronchoscopic guidance or blindly. Other authors have suggested that tracheal aspirate provides similar information and is more cost-effective. Hundreds of studies have debated the right method for collecting specimens, and a complete discussion is beyond the objectives of this article. The main techniques investigated for diagnostic sampling in intubated patients include: 1. Blood cultures 2. Tracheal aspirates 3. Blind procedures 3.1. Protected specimen brush 3.2. Protected bronchoalveolar lavage 4. Bronchoscopic techniques 4.1. Bronchoalveolar lavage 4.2. Protected bronchoalveolar lavage 4.3. Protected specimen brush
Only a few researchers have used an histologic gold standard9,25, "; most have used bronchoscopic methods. As indicated previously, the studies using. a histologic gold standard did not provide valuable information on live patients. Because most patients have been taking antibiotics before death, they represent a very late evaluation of the event; the study population is biased to moribund patients, and some of the histologic findings may, indeed, be terminal events. Defenders of bronchoscopic techniques argue that visualization of the tracheobronchial tree is useful for differential diagnosis and even for definitive diagnosis. In a well-conducted trial, Timsit et a155reported that visualization of the tracheobronchial tree can accurately predict pneumonia. In this study, three independent factors were associated with the development of pneumonia-a decrease of the partial oxygen pressure-to-fractional inspired oxygen ratio (Pao2/FIo2)greater than 50 mm Hg, presence of distal purulent secretions, and persistence of secretions emerging from distal
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bronchi during exhalation. Furthermore, direct visualization permits the correct selection of the segment affected radiologi~ally.2~ Detractors of bronchoscopic techniques point to autopsy studiesw,58 to argue that selection of an adequate bronchial segment is not necessary, because bronchopneumonia affects all parts of both lungs. Marquette et a1,28in a study comparing bronchoscopic PSB and blinded PSB, for example, concluded that correlation between the two techniques was good. In contrast, in a similar study comparing the same techniques, Jorda et alZoreported that the correlation decreased when opacities affected upper lobes or when solely the left lung was involved. LealNova1 et al,23comparing the yield for right versus left localized pneumonias, demonstrated that the yield for blind brushing was 85% for right lower lobe pneumonia, but only 28% for left lower lobe pneumonia. The cost-effectiveness relationship, and the unavailability in some institutions of highly skilled personnel to perform invasive methods over 24 hours, have been other arguments against their use. For these reasons, the interest in noninvasive samples such as tracheobronchial aspirates (EA) has increased in the late 1990s. Some researchers=, 26 suggested that quantitative culture of tracheal aspirates, with a cutoff of lo6 organisms/mL was more sensitive than PSB, and no less specific. In contrast, in a population with no recent changes in antibiotherapy, Jourdain et aP1 reported a lower sensitivity and specificity (68% and 84%)than PSB; moreover, they reported that the microorganisms cultured from EA correlated weakly with those obtained using PSB specimens. These authors concluded that the main drawback of performing EA is the possibility of overtreating many false-positive cultures, with the risk of increasing bacterial resistance and superinfections, as well as missing opportunities to identify the real problem of the patient. As discussed previously, information regarding the quality of the sample or whether secretions were previously cleared is rarely reported, making it impossible to compare different studies. As already mentioned, in immunocompetent intubated patients, it is necessary to differentiate infection from colonization or contamination. This supports the use of the diagnostic technique that yields the highest specificity and positive predictive values for causative diagnosis in intubated patients. On the other hand, interest should focus on the more sensitive techniques when assessing specific subgroups of immunocompromised populations. ADVERSE EFFECTS OF DIAGNOSTIC TESTING
There are some potential risks involved in performing bronchoscopies in ventilated patients, including temporary alterations in lung mechanics and gas exchange, barotrauma, increase in intra-
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cranial pressure, or cross-transmission of pathogens. Other reported complications have included arrhythmias, transient worsening in pulmonary infiltrates, and fever. There is some additional risk with specific procedures, including bleeding from the brush procedure or severe hypoxemia from the BAL procedure. These risks are also present for blind procedures and the risk of hypoxemia is even present in collecting EA. End-expiratory volume and positive end-expiratory pressure are reduced, facilitating alveolar closure and venous admixture. These changes slowly wear off after the procedure. In spite of this, to the best of the authors' knowledge, no deaths have been reported in relation to these procedures in ventilated patients, provided that transbronchial biopsies are not performed. The avoidance of complications is highly dependent on the expertise of the physician in ventilating patients and the skill of the operator of the procedure. Strict adherence to formal contraindications and careful management of the ventilatory setting are associated with a marginal incidence of adverse events. In general, for adult patients, the endotracheal tube size should be equal to or greater than 1.5 mm larger than the external diameter of the flexible bronchoscope. All intubated patients should be adequately sedated and should receive a short-acting paralytic agent to prevent coughing during the procedure. Secondary hypotension should be anticipated and appropriate intravenous fluids should be available for immediate administration. During the procedure, close monitoring is recommended, including exhaled tidal volume and peak inspiratory pressure, single-channel electrocardiography, and continuous oximetry. Platelet transfusion before the procedure should be administeredZ9if a PSB sample is to be obtained and the platelet count is under 20,000/mm3. Regarding the ventilator setting, the FIO, should be set at loo%, respiratory rate at 20 breaths/ minute, and peak inspiratory flow at less than or equal to 60 L/minute. The peak pressure alarm should be increased to a level that allows adequate ventilation. Other ventilator settings should be individually titrated to maximize exhaled tidal volume. Finally, patients with severe hypoxemia need to receive continuous positive airway pressure as previously administered. In patients with severe head injury, the procedure may raise intracranial pressure, but median arterial pressure also rises, and cerebral perfusion pressure is maintained within acceptable levels. The intracranial pressure returns to basal levels after the procedure. When properly performed, these procedures do not affect neurologic status in patients with severe head injury.36 IMPACT ON OUTCOME
Three factors are related to the resolution of an episode of pneumonia-host defenses, pathogen
virulence, and bacterial burden. The antibiotic therapy works by preventing bacterial replication and reducing the bacterial inoculum. Adequate antibiotic therapy therefore is crucial in immunocompromised patients and also of great importance in critically ill patients developing pneumonia. In 1990, using multivariate statistical analysis, Torres et a157were the first to report that inappropriate antimicrobial therapy was an independent factor for increase of mortality (fivefold of odds ratio). Other researchers5 have questioned whether episodes of VAP were associated with excess mortality in critically ill patients. Indeed, the excess of mortality is questionable in some clinical settings, such as trauma patients or episodes caused by primary endogenous pathogens (such as methicillin-sensitive Staphylococcus aureus, S. pneumoniae, or H. influenzae). Consequently, there is some doubt about the potential ability of microbiologic testing to reduce mortality in these subgroups. We know that most patients who die of pneumonia were infected with nonfermentative gram-negative bacilli or methicillin-resistant S. a ~ r e u s . ~Now, ' there is clearcut evidence that episodes caused by P. aeruginosa, A. baumannii, or MRSA cause an excess of mortality compared with predictions made on the basis of severity of illness on ICU admission.M,46,47 The clinical setting in which these microorganisms appear therefore is likely to benefit from an appropriate antimicrobial regimen and systematic microbiologic testing. Obviously, the impact of microbiologic tests on outcome is also dependent on the adequacy of the initial antibiotic choice. It can be hypothesized that if everybody received appropriate therapeutic regimens, the benefit of microbiologic investigation on outcome would be marginal. As mentioned previously, screening can adjust the initial choice in some cases, but sensitivity of direct staining for nonfermentative pathogens is not optimal. Indeed, the more frequent the wrong initial choices, the greater the potential benefit of diagnostic testing. Using bronchoscopic techniques in patients with severe pneumonia, Rodriguez de Castro et a14sconcluded that in up to 30% of cases there was a change in antibiotics, either to reduce the spectrum or to adjust therapy because an initially resistant organism was found. Unfortunately, the impact on outcome was not assessed. Luna et alZ4found that the percentage of patients receiving inappropriate therapy was as high as 68%. Likewise, the authors' groupa evaluated that 23.9% of patients with VAP were at risk of a wrong initial antibiotic choice when diagnosed using bronchoscopic methods. A multicenter study of VAP with causative diagnosis based on tracheal aspirates*reported that 43.7%of patients with VAP required a change of the empiric initial treatment because of isolates of resistant pathogens. This evidence suggests that adjustment of therapy based on microbiologic testing would be of benefit. In spite of this, whether bronchoscopic techniques are really useful has been the topic of nu-
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merous pro-con debates between experts. In a pilot study comparing bronchoscopy against tracheal aspirates, Sanchez-Nieto et a152concluded that management using the results of bronchoscopic studies led to more frequent antibiotic changes but did not influence outcome. Unfortunately, as with most of the studies already mentioned, the authors failed to evaluate the quality of the samples. In addition, the lack of randomization according to a severity-of-illness score meant that the group with bronchoscopies had higher Acute Physiology and Chronic Health Evaluation I1 scores; the percentage of patients with P. aeruginosa isolates was higher in the group with bronchoscopy, which raises doubts about the validity of the conclusions. Recently, French researchers conducted a large, multicenter, randomized, prospective study comparing bronchoscopic testing as part of the initial evaluation with a strategy based on empiric therapy alone. Interestingly, a statistically significant difference in crude mortality was found at 15-days follow-up, favoring the group with microbiologic testing (Fagon J, personal communication). Although mortality is the most important indicator of outcome, other variables are also relevant. Antibiotic resistance is spawned in large measure by the selective pressure of antibiotic use. Several lines of evidence, including the authors' own experience,4l suggest that there is an association between antimicrobial use in hospitals and antimicrobial resistance, an association that is in all probability causal. The possibility of reducing the use of broad-spectrum antimicrobials is of great interest in the efforts to contain the problem. The authors and others43, 48 have reported that reducing the spectrum of the selected regimen is possible in some patients on the basis of microbiologic tests, and the interest in this possibility should not be undervalued because of the increase in mortality of episodes of pneumonia caused by multiresistant pathogens.4l Some authors have postulated that empiric therapy alone is more cost-effective than an approach based on empiric therapy plus microbiologic investigation. They advocate reserving microbiologic investigation for the subgroup of patients with nonresolving pneumonia. This approach contrasts with the classic management of other infections in patients at risk of death, such as cases of meningitis or urinary tract infections. Moreoever, recent evidence suggests the importance of the timing of testing on its impact on the microbiologic findings and outcome. In patients with a wrong initial antibiotic choice and late rescue treatment, it is not possible to modify the case fatality whereas modification of the antimicrobial regimen based on early diagnostic testing (i.e. within 12 hours of pneumonia suspicion) permits resolution of 63% of episodes.43 In addition to prompt timing, other variables may increase the efficacy of the microbiologic investigation. Decision analysis- has shown that antibiotic treatment of VAP based on any diagnostic
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technique, the positive predictive value of which reliably exceeds 28%, would be associated with improved survival. In general, these arguments favor the use of techniques with high positive predictive value whenever possible. Patients at risk of mortality attributable to pneumonia are the target population that might obtain significant benefit on outcome of an early investigation-patients at risk for multiresistant organisms with an intermediate degree of severity-of-illness, usually represented by late episodes of pneumonia in patients who received prior antimicrobial therapy. CONCLUSIONS
Diagnosis of VAP is based on the presence of a pulmonary inflammatory reaction of bacterial origin in patients ventilated through an artificial airway. This is recognized at the bedside by the development of purulent respiratory secretions in ventilated patients with new or progressive radiographic opacities. Other systemic signs of sepsis or progressive hypoxemia are often documented. If pneumonia is suspected, antimicrobial agents are administered because delaying appropriate therapy is correlated with higher mortality. As in other infectious processes, microbiologic testing for causative diagnosis is recommended and should be performed as early as possible. Direct staining is mandatory to evaluate the quality of the respiratory sample and to guide initial antibiotic choice. An analysis of the cellular product showing greater than 1% epithelial cells is suggestive of oropharyngeal contamination and should be rejected for culture, because it will be followed by growing nonpathogenic mouth flora. Presence of fewer than 10% neutrophils in an appropriate sample of a patient with pneumonia suspicion should suggest an alternative diagnosis. Whereas visualizing greater than 5% ICO in direct stains of BAL material guides the initial antibiotic choice, a negative direct stain requires initial broad-spectrum coverage because one third of episodes caused by l? aeruginosa are associated with negative direct satn is@ . -' The simple recovery of an organism in a sample of good quality is not sufficient, because lower airway colonization is uniformly present only a few hours after intubation. Semiquantitative culture results provide information on the relative burden of pathogens. Whereas concentrations above classical cutoffs are associated with high specificity, lower concentrations may be clinically significant in certain settings, such as patients who received a dose of a new antibiotic after pneumonia suspicion. As in urine analysis, respiratory culture samples should be interpreted after screening the quality of the sample and evaluating the bacterial burden, the potential interference of new antibiotic regimens, and the specific clinical setting. The authors have learned that microbiologic findings should not be used to decide whether a
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ventilated patient has a pneumonia or not, but are definitely important in improving the use of antimicrobial agents. The authors believe that current evidence justifies performing routine diagnostic tests whenever possible in all patients with VAP. The microbiologic findings may make it possible to reduce the antibiotic spectrum in some patients, which can contribute to reducing the selection and spread of resistant pathogens. Moreover, recent reports have shown that early microbiologic testing improves outcome of patients with VAP. Although it is not possible to mod* the case fatality ratez4in patients with a wrong initial antibiotic choice and late rescue treatment, modification of the antimicrobial regimen based on early diagnostic testing (within the 12 hours immediately after pneumonia suspicion) permits resolution in 63% of epis0des.4~
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Address reprint requests to Jordi Rello, MD, PhD Critical Care Department Hospital de Sabadell Parc Tauli s/n E08208 Sabadell, Barcelona, Spain e-mail: [email protected]