Diagnosis of ventilator-associated pneumonia

Journal of Critical Care (2009) 24, 473.e1–473.e6

Diagnosis of ventilator-associated pneumonia☆ Andrew R.L. Medford MD, MRCP a,⁎, Syed A. Husain MRCP c , Hesham M. Turki MB, BCh b , Ann B. Millar MD, FRCP d a

North Bristol Lung Centre, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom Pilgrim Hospital, Sibsey Road, Boston, Lincolnshire PE21 9QS, United Kingdom c Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, United Kingdom d Lung Research Group, Clinical Science at North Bristol, University of Bristol, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom b

Keywords: Bronchoalveolar lavage; Ventilator-associated pneumonia; Endotracheal aspirate; Quantitative culture

Abstract Introduction: Ventilator-associated pneumonia (VAP) is difficult to diagnose. Recent data suggest quantitative endotracheal aspirate (ETA) may be noninferior diagnostically to quantitative bronchoalveolar lavage (BAL). We hypothesized this would be the case. Methods: Blind quantitative ETA and BAL were performed on 150 consecutive ventilated patients with suspected VAP in a prospective single-centre medical intensive care unit study over a 2-year inclusion period. Patients were either antibiotic-naive or antibiotic-free for 72 hours. Diagnostic yield, Gram stain and culture results, and impact on antibiotic therapy were assessed. The independent impact of a positive BAL or ETA result on ventilator settings and 28-day mortality was calculated. The BAL/ETA safety was assessed hemodynamically. Results: Bronchoalveolar lavage had significantly higher diagnostic yield (49.3% vs 34.0%, P = .01), more frequent impact on antibiotic therapy (usually de-escalation) (48.0% vs 32.7%, P = .01), and greater sensitivity (64.1% vs 42.6%, P = .0003) than ETA. There was moderate intertest agreement and no difference in specificity and positive and negative predictive values. A positive BAL or ETA result did not independently alter the frequency of ventilator changes or 28-day mortality. Both procedures were well tolerated. Conclusion: Quantitative BAL is safe and has greater diagnostic utility than ETA for VAP facilitates deescalation. This study provides support for quantitative BAL in VAP diagnosis. © 2009 Elsevier Inc. All rights reserved.

1. Introduction ☆

Institution where work performed: Lung Research Group, Clinical Science at North Bristol, University of Bristol, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. ⁎ Corresponding author. Tel.: +44 117 9595348; fax: +44 117 9595018. E-mail addresses: [email protected] (A.R.L. Medford), [email protected] (S.A. Husain), [email protected] (H.M. Turki), [email protected] (A.B. Millar). 0883-9441/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2008.06.012

Ventilator-associated pneumonia (VAP) is associated with significant morbidity and mortality as well as prolonged hospitalization with economic implications. In 1 observational series, it was noted to have an attributable mortality of 33% to 50%, prolonging hospital admission by 7 to 9 days [1]. It is common, estimated at 5 to 10 cases per 1000

473.e2 admissions in a previous study [2]. After 48 hours of ventilation, it occurs in 20% to 30% of patients [3,4]. The challenge in VAP is diagnosis because chest radiograph (CXR) infiltrates in ventilated patients can be due to many other noninfective conditions [5]. The gold standard for diagnosis requires histology (terminal bronchiole neutrophil populations surrounded by neutrophil-filled alveoli, fibrinous exudates, and cellular debris) [6], which is often not available, and clinical scoring systems alone are not specific. Therefore, other techniques have been investigated, in particular bronchoalveolar lavage (BAL) and endotracheal aspirate (ETA) sampling. Current literature conflicts as to which is the superior diagnostic technique in VAP. An increasing number of studies suggest ETA may have equivalent diagnostic utility to BAL. Only 5 randomized controlled trials have been undertaken. In the oldest multicentre randomized study of 413 patients, Fagon et al [7] demonstrated the superiority of BAL over noninvasive strategies demonstrating reduced mortality, organ failure, and antibiotic use (but not diagnostic sensitivity), albeit using nonquantitative ETA and clinical criteria for the noninvasive strategy. The subsequent 4 randomized studies have not supported this finding. In a single-centre study of 51 patients, no difference was found between BAL and quantitative ETA in mortality, duration of intensive therapy unit stay, and period of ventilation. More frequent changes in antibiotic therapy occurred in the BAL group with no change in mortality [8]. A second single-centre study of 91 patients detected no difference in ITU stay or period of ventilation, but BAL led to more frequent de-escalation of antibiotic therapy. However, nonbronchoscopic quantitative techniques were included in the BAL group and compared to qualitative ETA [9]. A third single-centre study of 76 antibiotic-naive patients revealed no difference in mortality, length of stay, and period of ventilation [10]. In the most recent multicentre randomized controlled trial of 740 patients, BAL had no advantage over ETA in mortality or antibiotic use [11]. In addition to the limited randomized controlled trials, 3 prospective observational studies (of 50-75 patients each) showed noninferiority for ETA with BAL in diagnostic yield and antibiotic changes [12-14]. In summary, debate remains over the relative merits of BAL and ETA. We hypothesized quantitative ETA would be noninferior to quantitative BAL in diagnosing VAP. This single-centre prospective study used a higher number of patients than the cited single-centre studies above.

2. Methods 2.1. Patients, setting, and study design The Southmead Hospital Ethics Committee approved this single-centre prospective study. A priori, we calculated

A.R.L. Medford et al. 138 patients would be needed to have 80% statistical power, assuming a type 1 error probability of .05, noninferiority margin of 15%, and estimated diagnostic yield of 50% based on previous studies [8,10]. A total of 150 patients were consecutively recruited during an inclusion period of 2 years (2002-2004) from a singlecentre 8-bed medical intensive care unit (ICU). Patients were not recruited more than once. Patients were ventilated for at least 48 hours, antibiotic-naive, or off antibiotics for at least 72 hours, and all had clinically suspected VAP (see definitions below); the pretest likelihood of VAP was deemed to be high. Bronchoalveolar lavage was undertaken with authorization from the responsible intensive care physician and next of kin.

2.2. Bronchoalveolar lavage One bronchoscopist performed all BAL procedures. Fiberoptic bronchoscopy (as described previously [15]) and quantitative BAL (in the lobe corresponding to the observed CXR infiltrate) were performed in ventilated patients in the ICU with suspected VAP who were antibiotic-naive or antibiotic-free for at least 72 hours. A pre-BAL (a control sample taken from the prepared bronchoscope before the actual BAL procedure on the patient) was taken to exclude bronchoscope contamination in every case. The patient was preoxygenated with 100% inspired oxygen fraction (FiO2) with adequate sedation with/ without paralysis, on continuous oximetry, electrocardiogram (ECG), and hemodynamic monitoring. Suctioning via the endotracheal tube or tracheostomy tube was performed before BAL. Care was used to minimize bronchoscope contamination with proximal airway secretions. The bronchoscope tip was wedged into the relevant lung subsegment, and 20 mL sterile saline solution was injected, aspirated, and discarded. A new trap was positioned, and additional 2 × 60-mL aliquots were injected slowly and aspirated (140 mL total volume injected). Labeled specimens were sent to the laboratory immediately for Gram stain and quantitative culture.

2.3. Endotracheal aspirate Operators were blinded and appropriately trained. Bronchoalveolar lavage and ETA were performed in random order to reduce bias but separated by 4 hours to minimize the impact of pre-BAL suctioning on the ETA result. Patients were antibiotic-naive or antibiotic-free for at least 72 hours. The patient was preoxygenated with 100% FiO2, using bagmask ventilation if necessary with adequate sedation. A sterile suction catheter with suction trap was applied instilling 3 to 5 mL saline if an adequate specimen was not obtained. The suction tube was blindly introduced through the endotracheal tube or tracheostomy tube and wedged into the tracheobronchial tree before suction. Labeled specimens

Ventilator-associated pneumonia diagnosis were sent to the laboratory immediately for Gram stain and quantitative culture.

2.4. Definitions Ventilator-associated pneumonia was defined by the presence of new/progressive CXR infiltrates without other obvious cause in patients mechanically ventilated for more than 4 days in the ICU and at least 2 of the following: temperature ≥38°C or ≤35°C, white cell count ≥12 or ≤4 × 109/L, purulent tracheobronchial secretions, with increasing oxygen requirements, computed tomography evidence of a rapidly cavitating infiltrate, positive pleural fluid culture and/ or histological evidence of neutrophilic alveolitis, bronchiolitis, and consolidation [10]. A safe BAL/ETA was defined as causing no evidence of myocardial ischemia or arrhythmia on the ECG and less than 25% deterioration in the following indices: heart rate, systolic blood pressure, positive end-expiratory pressure (PEEP), peak inspiratory pressure (PIP), PaCO2, and oxygenation fraction (PaO2:FiO2). Diagnostic thresholds for VAP were defined as ≥104 colony-forming units per milliliter (cfu/mL) for BAL and ≥ 105 cfu/mL for ETA cultures. Cultures with normal flora (coagulase-negative Staphylococci, Corynebacterium species, Viridans streptococcus group, Neisseria species [except Neisseria meningitidis], Staphylococcus epidermidis, or Candida species) were considered nonpathogenic; these cultures were classified as negative for analysis consistent with previous studies [11].

2.5. Clinical data Acute physiology scores were obtained for each patient including Murray Lung Injury Score, Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation 2 and 3 scores. The 28- and 60-day mortality, demographic data, and PaO2:FiO2 were also obtained. Hemodynamic (heart rate, blood pressure, ECG) and ventilatory parameters (PEEP, PIP, PaCO2) were obtained during BAL/ETA and up to 1 hour post procedure. Duration of mechanical ventilation, diagnosis, and reasons for ICU admission were noted.

2.6. Independent review Two independent physicians confirmed the diagnosis of VAP (on the basis of the clinical criteria mentioned previously in conjunction pleural fluid microbiology, CT evidence, and histological evidence) and whether a positive BAL/ETA result had a positive impact on antimicrobial therapy (escalation, de-escalation, or continuing current therapy) and result-attributable 28-day mortality as well as changes in hemodynamic and ventilator parameters. The reviewers assessed the impact of each BAL and ETA result

473.e3 on whether this would have led to escalation, de-escalation, or unchanged antimicrobial therapy; for de-escalation, a positive result narrowing antibiotic therapy (eg, by reducing to specific monotherapy) or a negative result that led to reduction in antimicrobial therapy would be counted as achieving de-escalation. There were no cases of disagreement between the independent reviewers.

2.7. Statistical analysis Data were analyzed using Graph Pad Prism 4.0 software. Contingency data were analyzed using either Fisher exact test or χ2 test. A P value of less than .05 was deemed significant. Data are followed by odds ratios (ORs) with 95% confidence interval (95% CI) when the P value is significant. For noncontingency data, the Ryan-Joiner test was used to assess normality and then analyzed by Kruskal-Wallis or analysis of variance with an appropriate multiple-test post hoc correction analysis.

3. Results 3.1. Demographics Patient demographics are shown in Table 1. There was a significant male preponderance (OR, 0.6; 95% CI, 0.38-0.94, P = .04) with hypoxemia (similar to that in acute respiratory distress syndrome [ARDS], PaO2:FiO2 b200 mm Hg [16]) and physiological disturbance. The mean duration of ventilation before VAP diagnosis was approximately 72 hours, and 56% were antibiotic-naive. As expected, 60-day mortality rates were higher than at 28 days (46.7% vs 35.9%).

Table 1 Patient demographics, oxygenation and physiology scores, duration of ventilation, previous antibiotic therapy and mortality Parameter (N = 150)

Mean

SE

Age Sex (female/male) PaO2:FiO2 (mm Hg) LIS SAPS2 APACHE2 APACHE3 Duration of ventilation before VAP suspected (d) Previous antibiotic therapy (all N72 h) 28-d mortality 60-d mortality

62.3 56:94 a 173.5 2.39 44.3 19.2 72.1 2.61

1.22 N/A 8.53 0.08 1.22 0.65 2.28 0.17

44

N/A

35.9 46.7

N/A N/A

LIS indicates Murray Lung Injury Score; SAPS2, Simplified Acute Physiology Score II; APACHE2/3, Acute Physiology and Chronic Health Evaluation 2 and 3. a OR, 0.6; 95% CI, 0.38-0.94, P = .04.

473.e4 Table 2

A.R.L. Medford et al. Reasons for ICU admission

Parameter

%

Reason for ICU admission Pneumonia Septicemia with multisystem organ failure Intra-abdominal sepsis Massive hemorrhage and hypertransfusion Aspiration/Inhalational lung injury Acute pancreatitis Acute renal failure Heart failure Neurological sepsis

26.7 18.0 16.7 10.7 9.3 6.0 5.3 4.7 2.7

Table 4 Sensitivity, specificity, positive and negative predictive values of BAL and ETA for VAP diagnosis Parameter

BAL (%)

ETA (%)

OR (95% CI)

P

Sensitivity Specificity Positive predictive value Negative predictive value

64.1 83.0 89.2

42.6 83.7 84.3

2.41 (1.37-4.23) 0.95 (0.33-2.78) 1.54 (0.54-4.39)

.003 ⁎ 1.00 .43

51.3

41.4

1.49 (0.82-2.72)

.22

⁎ denotes significant result P b .05

moderate intertest agreement of 68% (102 of 150) of cases with a κ coefficient of 0.35 (0.20-0.49).

3.2. Reason for ICU admission and diagnosis The reasons for ICU admission and underlying diagnoses are displayed in Table 2. Respiratory failure due to pneumonia was the commonest reason for admission, and sepsis was the commonest contributor to the underlying diagnosis.

3.3. Diagnostic yield and clinical outcomes Diagnostic utility of both techniques is shown in Table 3. Bronchoalveolar lavage had a significantly higher diagnostic yield than ETA (49.3% vs 34.0%; OR, 1.89; 95% CI, 1.193.01, P = .01) and led significantly more modifications in antimicrobial therapy than ETA (48.0% vs 32.7%; OR, 1.90; 95% CI, 1.19-3.04, P = .01). There were no differences in Gram stain or polymicrobial culture results between BAL and ETA. Analyzing positive (significant) BAL and ETA culture results only, there were no differences in ventilator alterations and 28-day mortality.

3.5. Antibiotic therapy and differential cell count Table 6 describes the impact of BAL and ETA on antibiotic therapy. Overall, BAL had a more significant impact on antibiotic therapy (escalation, de-escalation, or continuing) than ETA (48% vs 33%; OR, 1.90; 95% CI, 1.19-3.04, P = .01). On the basis of BAL results, this led to a net reduction in antibiotic consumption of 25 prescriptions for the 150 patients. Considering ETA results, the net change was a reduction of 18 prescriptions. De-escalation was commonest after both diagnostic techniques: usually removal of an antipseudomonal penicillin/carbapenem/ cephalosporin or anti–methicillin-resistant Staphylococcus aureus (MRSA) glycopeptide. Escalation was second commonest with both techniques usually the addition of further anti-MRSA cover.

3.6. Individual pathogens

3.4. Sensitivity, specificity, predictive value, agreement Table 4 illustrates the superior sensitivity of BAL over ETA in VAP diagnosis (64.1% vs 42.6%; OR, 2.41; 95% CI, 1.37-4.23, P = .003), but there was no difference in specificity or positive or negative predictive values. Table 5 indicates

Table 7 displays the detected pathogen distribution. Coliforms, Pseudomonas, and S aureus were the commonest detected by both techniques. In addition, BAL isolated more enterococcal cultures (9.5% vs 1.4%; OR, 7.02; 95% CI, 1.56-31.7, P = .006). Pre-BAL did not yield any significant results (data not shown).

3.7. Safety Table 3 Diagnostic yield of BAL and ETA, Gram stains, polymicrobial cultures, resultant clinical outcomes Parameter

BAL (%)

ETA (%)

OR (95% CI)

Diagnostic yield Gram stain Polymicrobial cultures Ventilator changes a 28-d mortality a

49.3 41.3 10.7

34.0 32.0 7.1

1.89 (1.19-3.01) 1.49 (0.93-2.40) 1.67 (0.73-3.82)

30.3 50.0

29.0 48.4

1.06 (0.36-3.11) 1.07 (0.40-2.83)

a

P .01 a .12 .31 1.00 1.00

NB: ventilator change and mortality for BAL/ETA culture–positive cases only where result influenced antibiotic therapy (see Table 6).

No complications occurred relating to BAL or ETA. Specifically, no cardiac arrhythmias or ECG ischemic changes occurred in the first hour post procedure. No deterioration of greater than 25% was seen in any of the Table 5

Agreement between BAL and ETA in diagnosis

Investigation

BAL negative

BAL positive

ETA negative ETA positive

66 13

35 36

κ coefficient, 0.35; 95% CI, 0.20-0.49; SE, 0.074.

Ventilator-associated pneumonia diagnosis Table 6

Effect of BAL and ETA on antibiotic therapy

Parameter Escalate De-escalate Continue Positive No (N = 150) (%) (%) (%) impact impact (%) (%) BAL ETA a

18 (12) 12 (8)

43 (29) 30 (20)

11 (7) 7 (5)

72 (48) a 78 (52) 49 (33)a 101 (67)

OR, 1.90; 95% CI, 1.19-3.04, P = .01.

hemodynamic or ventilatory indices in the first hour postprocedure. Specifically, over the 60 minutes intra- and postprocedure, systolic blood pressure increased by 12.1% (115-129 mm Hg), heart rate increased by 20% (90-108/ min), PaCO2 increased by 12.1% (5.88-6.59 kPa), PaO2:FiO2 decreased by 18.4% (173.5-141.6 mm Hg), PEEP increased by 12.5% (7-8 cm), and PIP increased by 18.2% (33-39 cm).

4. Discussion Our principal finding was that quantitative BAL had greater diagnostic utility and sensitivity than ETA in ICU patients with suspected VAP contrary to our original hypothesis. This translated into a significantly higher positive impact on antimicrobial therapy (most commonly de-escalation of therapy) and also a higher yield of enterococci. However, specificity and positive and negative predictive values of ETA were noninferior, and there was moderate intertest agreement. In addition, there were no overall differences in Gram stain results, polymicrobial cultures and positive BAL or ETA cultures were matched in terms of subsequent changes to ventilator settings and 28-day mortality. Bronchoalveolar lavage differential cell count profiles were as expected. Finally, we did confirm BAL was safe in ventilated hypoxemic patients consistent with previous studies using BAL in ARDS [17]. The apparent superiority of BAL in diagnosis of VAP is not in keeping with the previously cited randomized controlled trials and prospective observational studies [11-14]. It is important to note superiority of BAL is biologically plausible due to its superior distal airway sampling under visual guidance. Why should evidence conflict here? Firstly, many of the cited studies above have methodological limitations or low numbers. Wu et al [14] studied only 48 patients, and none were antibiotic-naive or antibiotic-free. Brun-Buisson et al [12] studied only 68 patients, and a significant proportion were not antibiotic-free at 72 hours before the study. The recent multicenter randomized controlled trial excluded 40% of patients because of antibiotic-resistant pathogen risk factors, and 30% of the BAL group were not antibiotic-free within 72 hours [11]. Rajasekhar et al [17] found quantitative ETA noninferior to blind bronchial sampling but did not include a bronchoscopic group. Cook et al [18] reviewed 9 ETA studies, but conclusions were limited by wide variations in sensitivity

473.e5 and specificity, recent antibiotic use, quantitative culture use and thresholds, and definitions. Secondly, other studies concur with some of our findings. A greater impact on antibiotic therapy has been reported in randomized, prospective observational studies, and metaanalyses [7,9,19,20]. A particular feature noted has been the superior de-escalation after BAL. Traditionally, this has been thought to relate to the reduction in polymicrobial cultures and greater specificity of BAL. However, in our study, we noted a greater (albeit not statistically different) number of polymicrobial cultures in the BAL group. We suspect this reflects the noted greater sensitivity of BAL (accounting for the higher number of escalations with BAL than ETA) rather than a lack of specificity, which may account for the greater number of de-escalations. Most of our other findings are consistent with previous studies. We confirmed the safety of BAL in ventilated hypoxemic patients. Many previous studies have demonstrated BAL is tolerated well in ARDS [21], and this should allow isolated reports to be put into context [22]. S aureus, Pseudomonas, and Coliforms were most frequently detected and are prominent in problematic VAP infections [20,23]. Our overall mortality figures are consistent with previously published VAP mortality rates of 20% to 50% [5,7,24]. The higher detection of enterococcus with BAL was unexpected and requires further study. The pre-BAL results excluded bronchoscopic contamination as a reason here. Enterococcus is not a typical cause of VAP but has the propensity to cause life-threatening infections in the ICU as it is found in the endotracheal biofilm and ETA culture of ICU patients [25]. We acknowledge some limitations in this study. Firstly, this is a single-centre prospective study in a medical ICU; it is not a multicenter randomized controlled trial in design. Secondly, we have used a clinical gold standard using CT, pleural and histological evidence where possible but we accept that histology in every case would be the ideal gold standard. Thirdly, the number of antibiotic-free and ventilator-free days was not included as secondary end points. Fourthly, the 2 independent physicians, assessing contribution to antibiotic therapy of each technique, were aware of the results of both ETA and BAL and so were not completely blinded. Fifthly, although the presuctioning Table 7 Microbiological yield of BAL and ETA: individual microorganisms Pathogen

BAL (%) ETA (%) OR (95% CI)

Coliform 19.0 MRSA 10.7 Pseudomonas 9.5 Enterococcus 9.5 MRSA 7.1 Pneumococcus 2.7 Hemophilus 2.0

16.3 7.1 10.3 1.4 4.9 0.7 0.7

⁎ denotes significant result P b .05

P

1.17 (0.622.21) .75 1.67 (0.73-3.82) .30 0.92 (0.42-2.03) 1.00 7.02 (1.56-31.7) .006 ⁎ 1.46 (0.54-3.94) .62 4.08 (0.45-36.9) .37 3.04 (0.31-29.6) .62

473.e6 before BAL may theoretically have influenced the ETA result, we used a separation time of 4 hours and random ordering to reduce bias. Indeed, our data show no evidence of a negative ETA culture in association with being performed after BAL, which one might expect had this been a factor. Finally, not all patients were antibiotic-naive, but previous studies have confirmed the validity of antibiotic-free status at 72 hours [26]. This study adds weight to the use of BAL over ETA in VAP diagnosis to facilitate de-escalation of antibiotics. We included a high number of patients who were rigorously phenotyped and antibiotic-naive or antibiotic-free. The study is applicable because the patients studied were in a general medical ICU. In conclusion, contrary to our original hypothesis, quantitative BAL was more sensitive than quantitative ETA and safe in diagnosing VAP in a cohort of ventilated medical ICU patients in a prospective single-centre study. There was moderate intertest agreement with no difference in specificity and positive or negative predictive values. Bronchoalveolar lavage impacted more on antimicrobial therapy (principally by facilitating de-escalation), but a positive BAL result did not translate to changes in ventilation or mortality. Finally, BAL unexpectedly diagnosed more enterococcal VAP infections; this association requires further study. Further randomized controlled studies are needed to compare BAL and ETA as well as emerging less-invasive, quantitative lower airway techniques such as non-bronchoscopic lavage [27].

Acknowledgments We would like to thank Emma Weston, Ann Hann, and Southmead Hospital Intensive Therapy Unit staff for their assistance in patient recruitment, and Sharon Standen for her secretarial assistance.

References [1] Fagon JY, Chastre J, Vuagnat A, et al. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA 1996;275 (11):866-9. [2] Craven DE, Steger KA, Barber TW. Preventing nosocomial pneumonia: state of the art and perspectives for the 1990s. Am J Med 1991;91 (3B):44S-53S. [3] Torres A, Aznar R, Gatell JM, et al. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990;142(3):523-8. [4] Rello J, Quintana E, Ausina V, et al. Incidence, etiology, and outcome of nosocomial pneumonia in mechanically ventilated patients. Chest 1991;100(2):439-44. [5] American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171(4):388-416. [6] Baselski VS, el-Torky M, Coalson JJ, et al. The standardization of criteria for processing and interpreting laboratory specimens in patients with suspected ventilator-associated pneumonia. Chest 1992;102(5 Suppl 1):571S-9S.

A.R.L. Medford et al. [7] Fagon JY, Chastre J, Wolff M, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med 2000;132(8): 621-30. [8] 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 1998;157(2):371-6. [9] Sole Violan J, Fernandez JA, Benitez AB, et al. Impact of quantitative invasive diagnostic techniques in the management and outcome of mechanically ventilated patients with suspected pneumonia. Crit Care Med 2000;28(8):2737-41. [10] Ruiz M, Torres A, Ewig S, et al. Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome. Am J Respir Crit Care Med 2000;162(1):119-25. [11] Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med 2006;355(25):2619-30. [12] Brun-Buisson C, Fartoukh M, Lechapt E, et al. Contribution of blinded, protected quantitative specimens to the diagnostic and therapeutic management of ventilator-associated pneumonia. Chest 2005;128(2):533-44. [13] Michel F, Franceschini B, Berger P, et al. Early antibiotic treatment for BAL-confirmed ventilator-associated pneumonia: a role for routine endotracheal aspirate cultures. Chest 2005;127(2):589-97. [14] Wu CL, Yang D, Wang NY, et al. Quantitative culture of endotracheal aspirates in the diagnosis of ventilator-associated pneumonia in patients with treatment failure. Chest 2002;122(2):662-8. [15] Thickett DR, Armstrong L, Millar AB. A role for vascular endothelial growth factor in acute and resolving lung injury. Am J Respir Crit Care Med 2002;166(10):1332-7. [16] Bernard GR, Artigas A, Brigham KL, et al. Report of the AmericanEuropean consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med 1994;20(3):225-32. [17] Rajasekhar T, Anuradha K, Suhasini T, et al. The role of quantitative cultures of non-bronchoscopic samples in ventilator associated pneumonia. Indian J Med Microbiol 2006;24(2):107-13. [18] Cook D, Mandell L. Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia. Chest 2000;117(4 Suppl 2): 195S-7S. [19] Giantsou E, Liratzopoulos N, Efraimidou E, et al. De-escalation therapy rates are significantly higher by bronchoalveolar lavage than by tracheal aspirate. Intensive Care Med 2007;33(9):1533-40. [20] Shorr AF, Sherner JH, Jackson WL, et al. Invasive approaches to the diagnosis of ventilator-associated pneumonia: a meta-analysis. Crit Care Med 2005;33(1):46-53. [21] Steinberg KP, Mitchell DR, Maunder RJ, et al. Safety of bronchoalveolar lavage in patients with adult respiratory distress syndrome. Am Rev Respir Dis 1993;148(3):556-61. [22] Bauer TT, Torres A, Ewig S, et al. Effects of bronchoalveolar lavage volume on arterial oxygenation in mechanically ventilated patients with pneumonia. Intensive Care Med 2001;27(2):384-93. [23] Davis KA. Ventilator-associated pneumonia: a review. J Intensive Care Med 2006;21(4):211-26. [24] Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002;165(7):867-903. [25] Chatterjee I, Iredell JR, Woods M, et al. The implications of enterococci for the intensive care unit. Crit Care Resus 2007;9(1):69-75. [26] 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 1998;26 (2):236-44. [27] Perkins GD, Chatterjie S, McAuley DF, et al. Role of nonbronchoscopic lavage for investigating alveolar inflammation and permeability in acute respiratory distress syndrome. Crit Care Med 2006;34 (1):57-64.