A comparison of mini-bronchoalveolar lavage and blind-protected specimen brush sampling in ventilated patients with suspected pneumonia

A Comparison of Mini-Bronchoalveolar Lavage and Blind-Protected Specimen Brush Sampling in Ventilated Patients With Suspected Pneumonia Paul E. Marik and Pamela Careau Purpose: Mini-bronchoalveolar lavage (m-BAL) and blind-protected brush sampling (b-PSB) are minimally invasive methods of diagnosing pneumonia in mechanically ventilated patients. The aim of this study was to compare these techniques in a prospective study at a medical and surgical intensive care unit in a university-affiliated community teaching hospital. Patients and Methods: One hundred and ninety episodes of pneumonia was suspected in 175 mechanically ventilated patients. Sequential b-PSB followed by m-BAL were performed by respiratory therapists who had undergone specialized training. A b-PSB quantitative culture greater than 1,000 cfu/mL and a m-BAL greater than 104 cfu/mL was considered diagnostic of pneumonia. Colony counts between 500 and 1,000 cfu/mL and 5,000 - 104 cfu/mL, respectively, were considered borderline positive. Results: One hundred and ninety paired specimens were obtained from 175 patients. The diagnostic agreement between the t w o techniques was 90%. Sixty-six patients (37%) were considered to have

bacterial pneumonia, In 108 episodes, patients were receiving concurrent antibiotics; pneumonia was diagnosed in 30 (27%) of these cases compared w i t h 36 of 82 (43%) episodes off antibiotics (P = .03). In 6 episodes, m-BAL was negative and b-PSB was positive (1 patient receiving antibiotics). In 13 episodes, b-PSB was negative and m-BAL was positive (7 patients were receiving antibiotics). The b-PSB took 30 -+ 8 seconds to perform and was complicated by minor bleeding in 3 cases. The m-BAL took 5 -+ 2 minutes to perform, was considered easy in 105 cases, difficult/ very difficult in 63, and failed in 2 patients. Significant coughing occurred in 98 patients w i t h other minor reversible complications occurring in a further 20 cases. Conclusions: In mechanically ventilated patients w i t h suspected pneumonia both b-PSB and m-BAL can be performed safely by respiratory therapists. The tests complement each other and likely reduce the number of false-negative results. Copyright © 1998 by W.B. Saunders Company

rENTILATOR-AS SOCIATED pneumonia (VAP) occurs in approximately 25% of parents undergoing mechanical ventilation. 1-5 The impact of VAP on patient outcome has been much debated3,6-8; however, Fagon et al 9 reported an attributable mortality of 27%. The optimal management of patients with suspected VAP requires confirmation of the diagnosis and identification of the responsible pathogen(s) to provide appropriate antimicrobial therapy. The diagnosis of VAP remains one of the most difficult clinical dilemmas in critically ill mechanically ventilated patients.l Clinical criteria alone have been shown to be unreliable in the diagnosis of this condition. 2,1°,11 A number of invasive and minimally invasive techniques have been reported to aid in the diagnosis of VAP. The number of methods currently available attest to the fact that no single method is ideal. 1,6,12-22The optimal technique(s) for diagnosis VAP remains unclear as a uniformly agreed on gold standard for the diagnosis is lacking. 4,13,23-26 However, bronchoscopic protected specimen brushing (PSB) with quantitative culture has become recognized as the standard with which to compare other techniques. The sensitivity and specificity and the cutoff values that should be used with this technique are unclear. 1,14,27,28Timsit et al 4 have demon-

strated that the classic PSB threshold of 103 cfu/mL has a sensitivity of only 67%. 4 When these investigators lowered the threshold to 500 cfu/mL, the sensitivity increased to 81% with only a moderate decrease in specificity. Dreyfuss et a129observed 29 patients with suspected VAP who had a PSB culture between 10 and 1,000 cfu/mL. 29 Repeat PSB in 12 of these patients isolated the same organism as that found in the first PSB in a concentration greater than 1,000 cfu/mL, and these patients were subsequently treated for pneumonia. The impact that diagnostic tests for VAP have on patient outcome is controversial. Using a decision analysis method, Sterling et aP ° demonstrated that invasive or semi-invasive microbiological diagnostic techniques improved the outcome of patients

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Journal of Critical Care,Vo113, No 2 (June), 1998: pp 67-72

From the Department of Medicine, University of Massachusetts, the Medical Intensive Care Unit, and CliniTech Services, St. Vincent Hospital, Worcester, MA. Address reprint requests to Paul E. Marik, MD, Department of Critical Care, St. Vincent Hospital, 25 Winthrop St, Worcester, MA 01604. The study was supported by the St. Vincent Hospital Critical Care Research Fund. The authors have no financial involvement with any of the products mentioned in this article. Copyright © 1998 by W.B. Saunders Company 0883-9441/98/1302-000458.00/0

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with suspected VAP. However, Luna et a131 and Rello et aP 2 have demonstrated that the most important factor affecting outcome in patients with VAP is the early initiation of appropriate antibiotic therapy. In the study by Luna et al, 3t the mortality of patients who were changed from inadequate antibiotic therapy to appropriate therapy based on the results of the bronchoalveolar lavage (BAL) was comparable to the mortality of those patients who continued to receive inadequate therapy. However, diagnostic tests will result in a change in antibiotics in about 25% of patients with pneumonia and allow the discontinuation of antibiotics in those patients who are proven not to have pneumonia. 31,32 This will result in significant cost savings and impact on the selection of resistant organisms. 10 Several factors limit the routine use of bronchoscopic-directed PSB and BAL in the clinical setting; bronchoscopy is expensive (about $1,000), time consuming, and not readily available in many intensive care units (ICUs). Furthermore, bronchoscopy is not without risks in patients requiring high levels of positive end-expiratory pressure (PEEP) and high fractional inspired oxygen concentrations (Fi02). Recently, a number of studies have examined the utility of nonbronchoscopic PSB as well as nonbronchoscopic BAL in the diagnosis of VAP. 17'19'33-37 These studies have found the results obtained from these "blind" techniques to be comparable to those obtained with the bronchoscope. However, apart from the small study by Wearden et al, 37 these two techniques have not been directly compared, and therefore the test(s) of choice in any particular patient remains unclear. The aim of this study was to compare the quantitative culture results of blind-PSB (b-PSB) and mini-BAL (m-BAL) and to determine the safety and feasibility of respiratory therapists performing these procedures in ventilated patients suspected to have pneumonia.

cytosis (>10 × 109/L); and purulent tracheal secretions.4A3,38In addition, patients who required endotracheal intubation and mechanical ventilation after in-hospital aspiration and developed features suggestive of pneumonia were also included in this study. All eligible patients were enrolled consecutively. A group of respiratory therapists (RTs) were instructed in the techniques of b-PSB and m-BAL. The RTs were supervised by the principle investigator or the chief RT until they were deemed competent to perform the procedures independently. Patients were administered 80% to 100% oxygen throughout the procedure and monitored by continuous pulse oximetry. Midazolam was used for sedation as required, b-PSB was performed first as previously reported.19 Using a standard microbiology specimen brush (Microvasive cat. No 1650; Boston Scientific Corporation, Watertown, MA), the catheter was inserted through the endotracheal tube to approximately 35 cm or until resistance was met. A specimen was obtained by expressing and retracting the inner catheter and brush in the standard fashion. The brush was then placed in 1 mL of thioglycolate broth (Remel, Lenexa, KS) and processed by our microbiology laboratory within 30 minutes. Quantitative culture was performed using standardized techniques.39 m-BAL sampling was performed after B-PSB sampling. This sequence was followed, as m-BAL is presumed to result in greater lower respiratory tract contamination than does b-PSB sampling. 17,37The m-BAL specimen was obtained using a BAL catheter (cat. No. 140; Ballard Medical Products, Draper, UT). The BAL catheter was inserted through the adapter into the endotracheal tube. With the catheter just protruding into the endotracheal tube, wide-bore suction tubing was connected to end of catheter. The catheter stop cock was then opened to suction, the pressure adjusted to 40 to 60 mm Hg and then closed. The catheter was then advanced into the malnstem bronchus of the lung suspected of pneumonia by orientating the directional tip. The tip of the catheter was flushed with 2 mL of sterile physiological saline. The inner catheter was then advanced until resistance confirmed a wedge position. A Luki sputum trap (Davis and Geck, Wayne, NJ) was placed in line with the catheter and wide-bore suction. With the inner catheter in a wedged position, 20 mL of sterile, physiological saline was instilled into the lung and allowed to dwell for approximately 20 seconds. The stop cock was then turned into the open position, allowing aspiration of lavage fluid. If no return was obtained, a further 20-mL aliquot was injected and re-suctioned. This procedure was repeated until at least 2 to 3 mL of return was obtained. The aspirated lavage sample was then processed by our laboratory for quantitative culture. No attempt was made to radiographically determine which lobe of the lung the m-BAL/bPSB sampling was performed.

MATERIALS AND METHODS This study was conducted between April 1996 and June 1997 in the Medical and Surgical ICUs at St. Vincent Hospital, Worcester, MA. This study was approved by our Institutional Review Board. As both m-BAL and b-PSB were considered within the standard of care in our ICUs, the IRB waived the need for informed consent. Patients were eligible for inclusion in this study if they had been mechanically ventilated for more than 48 hours and were believed to have VAP based on clinical grounds. The clinical suspicion of VAP was based on recent and persistent pulmonary infiltrates on the chest radiograph and at least two of the following clinical criteria: fever greater than 38.5°C; leuko-

Data Collection and Analysis The patients' clinical, demographic, and radiographic data were recorded in a computerized database (Access 97; Microsoft, Redmond, WA) The duration of each procedure was recorded from the time of insertion of the catheter into the endotracheal tube to the withdrawal of the catheter. The ease with which the m-BAL procedure was performed was subjectively ranked by the respiratory therapists as follows: (1) relatively easy, (2) difficult, (3) very difficult, and (4) failure. In addition, the following complications were recorded: (1) minor bleeding, defined as blood-tinged or streaked secretions post

m-BAL AND b-PSB IN VENTILATOR ASSOCIATED PNEUMONIA

procedure, (2) major bleeding, defined as aspiration of more than 30 mL of fresh blood from the endotracheal tube, (3) severe coughing during the procedure, (4) arterial desaturation, defined as a fall in the saturation by greater than 3% from the preprocedure saturation (on the same Fio2), and (5) hypertension or tachycardia, defined as an increase in the heart rate or systolic blood pressure by greater than 20% during or after the procedure. The amount of saline instilled and the return was also recorded. The results of the b-PSB and m-BAL quantitative culture were recorded (and interpreted) as follows4: (1) b-PSB; no growth, less than 500 cfu/mL (contaminant), 500 to 1,000 cfu/mL (borderline positive), and greater than 1,000 cfu/mL (positive), and (2) m-BAL; no growth, less than 5,000 cfu/mL (contaminant), 5,000 to 10,000 cfu/mL (borderline positive), and greater than 10,000 cfu/mL (positive). For the purposes of this study, patients with borderline positive or positive quantitative culture on either b-PSB or m-BAL were considered to have pneumonia. Specimens that grew normal oral flora, candida, or coagulase-negative staphylococci were recorded as no growth. In patients with positive and borderline positive cultures, the antibiotic regimen was tailored according to the sensitivities of the pathogen(s) isolated. In patients with negative cultures, the decision to continue or stop the antibiotics was made by the patients' attending physicians. At the end of the data collection, summary statistics were compiled to allow a description of the study population. Chi-squared analysis with Fisher's exact test (when appropriate) was used to compare categorical data. Unless otherwise stated, all data are expressed as mean ± SD, with statistical significance declared for probability values of 0.05 or less.

RESULTS

During the study period, 190 paired specimens were obtained from 175 patients. There were 113 male and 62 female patients, with a mean age of 66 _ 16 years, and an APACHE II score on admission of 16 __+ 5. The patients' diagnoses are listed in Table 1. Twenty-one patients required intubation and mechanical ventilation for suspected aspiration pneumonia. The m-BAL/b-PSB was performed within 24 hours of the suspected episode of aspiration in all of these patients. The m-BAL/bTable 1. Admitting ICU Diagnoses Diagnosis

Number of Patients

COPD/pneumonia Post bowel surgery Congestive cardiac failure Sepsis syndrome/septic shock

37 28 24 15

Cerebrovascular accident Delirium tremens

12 7

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Table 2. Results of the b-PSB and m-BAL Quantitative Culture b-PSB (n - 190) No growth

m-BA/(n = 190) 103

No growth

94

<500 cfu/mL 500-1,000 cfu/mL

23 5

<5,000 cfu/mL 5,000-10,000 cfu/mL

25 8

>1,000 cfu/mL

59

> 10,000 cfu/mL

63

Abbreviations: b-PSB, blind protected specimen brush sampling; m-BAL, mini bronchoalveolar lavage.

PSB was performed 5 -+ 4 days after intubation in the patients with suspected VAR The quantitative culture data are listed in Tables 2 and 3. Sixty-six patients (37%) were considered to have bacterial pneumonia (positive or borderline positive m-BAL or b-PSB culture). Seventy-seven pathogens were isolated from these patients, with Staphylococcus aureus and Pseudomonas aeruginosa being the commonest isolates. Eleven patients had polymicrobial infection. Streptococcus pneumonia and Haemophilus influenzae were isolated from 9 patients; these patients had been ventilated for 3 _+ 2 days before sampling. R aeruginosa was isolated from 17 patients, 7 -+ 3 days after intubation. In 108 episodes, patients were receiving antibiotics at the time of the sampling. Pneumonia was diagnosed in 30 (27%) of these cases compared with 36 of 82 (43%) episodes of suspected pneumonia in patients not receiving antibiotics (P = .03). In 6 episodes, the b-PSB was negative and the m-BAL positive, 1 of these patients was receiving antibiotics. The pneumonia was localized to the right lower lobe (RLL) in 3 of these cases and was bilateral in 3 cases. In 13 episodes, the b-PSB was negative and m-BAL positive, 7 of these patients were receiving antibiotics (NS). The pneumonia was localized to the RLL in 9 of these cases, the left lower lobe in 1, and was bilateral in 2 cases. The diagnostic agreement between the two techTable 3. Bacterial Isolates and Quantitative Culture According to b-PSB and m-BAL PSB > 500 & BAL > 5,000

PSB < 500 & BAL > 5,000

PSB > 500 & BAL < 5,000

S. aureus

11

5

2

P. a e r u g i n o s a

11

3

3

Enterobacter spp.

5

2

--

S. p n e u m o n i a e

5

--

--

Head injury Drug overdose Aortic aneurysm repair

6 6 5

H. i n f l u e n z a e

4

--

--

E. c o i l

3

--

--

Klebsiella spp.

3

--

--

Seizures

5

A. baumannfi

2

--

--

14

3

Other

30

Other

1

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MARIK AND CAREAU

niques was 90% (19 cases of quantitative disagreement). There were 5 cases of qualitative disagreement (either no growth with one technique and insignificant growth with the other, or borderline growth with one technique and a positive result with the other). The m-BAL failed to obtain a return in two patients (classified as no growth). The m-BAL was considered easy in 105 episodes, somewhat difficult in 62, and very difficult in 21 cases. The average volume of saline injected was 30 --- 18 mL with a return of 6 --- 3 mL. The average time to complete the m-BAL was 5 + 2 minutes compared with 30 + 8 seconds for the b-PSB. The b-PSB was complicated by minor bleeding in 3 cases. Significant coughing occurred during 98 m-BAL samplings, minor bleeding in 5 cases, arterial desaturation in 7 cases, and hypertension or tachycardia in 8 cases. All these complications were transient and resolved shortly after the procedure with no sequelae. DISCUSSION

In this study, we demonstrated a good agreement between b-PSB and m-BAL sampling. Furthermore, our study shows that respiratory therapists can safely and reliably perform these procedures in patients with respiratory failure requiring mechanical ventilation. The b-PSB was particularly easy to perform with essentially no complications. Although the m-BAL was more difficult to perform and associated with more complications, these were relatively minor and only transient in nature. These findings are in keeping with the study by Kollef et al. 17. A number of studies suggest that the results obtained from nonbronchoscopic sampling techniques are similar to those obtained by the same techniques performed through a bronchoscope. In a study of 15 patients, Weardon et a137 compared bronchoscopic PSB with b-PSB and m-BAL. These authors reported a 93% concordance between b-PSB and bronchoscopic PSB and 100% concordance between m-BAL and bronchoscopic PSB. Kollef et aP 7 compared m-BAL and bronchoscopic PSB in 42 patients. These authors demonstrated an overall concordance of 83%. Bello et al33 compared blind protected specimen brushing using a doublesheathed, balloon-tipped, plugged catheter with bronchoscopic PSB and BAL in 88 suspected episodes of VAP. They demonstrated a concordance

of 85% between the bronchoscopic and blind PSB technique and 84% between the bronchoscopic BAL and b-PSB technique. Rouby et al36 performed m-BAL in 69 patients before their death. The results of the m-BAL were compared with the histological and bacteriological results obtained from postmortem pneumonectomies. Using both histological and bacteriological criteria, the m-BAL had a sensitivity of 88% and a specificity of 80%. Furthermore, these workers demonstrated that VAP is always multifocal and predominantly involves the dependent bronchopulmonary segments. We have previously reported our results from a study in which we compared b-PSB with bronchoscopic PSB in 55 patients with suspected VAE 19 The concordance in this study was 85%. Quantitative culture of endotracheal aspirates has been proposed to be a simple and noninvasive method of diagnosing VAP. However, the operating characteristics of this technique are, unclear with some studies showing a poor sensitivity, specificity, and predictive values, ~5,28 whereas others have shown good characteristics. 29 When a cutoff of 105 to l 0 6 cfu/mL is used, this method has a low sensitivity (--70%). When a lower threshold is used, the rate of false-positive results sharply increases, and overtreatment becomes a problem, t Furthermore, if quantitative culture of endotracheal aspirates can correctly identify patients with pneumonia, microbiological results cannot be used to infer which microorganisms present in the culture are responsible for the pneumonia. 1 A number of studies have suggested that the prior use of antibiotics may effect the recovery of pathogens with the PSB technique. 4° Timsit et a141 investigated the effects of previous antibiotics on the recovery of pathogens by bronchoscopic PSB and BAL in patients with suspected VAP. In 6 of 51 (11%) patients on antibiotics, the BAL yielded greater than 104 organisms, whereas the PSB yielded less than 1,000 cfu/mL. In our study, in 7 of 108 (6%) patients on antibiotics, the m-BAL yielded greater than 5,000 cfu/mL, whereas the b-PSB had less than 500 cfu/mL. As the b-PSB technique is likely to result in less contamination of the lower respiratory tract than does m-BAL, it is unclear if the b-PSB-negative and m-BAL-positive cases represent false-positive m-BAL or false-negative b-PSB results. In a small percentage of patients, particularly patients with

m-BAL AND b-PSB IN VENTILATOR ASSOCIATED PNEUMONIA

chronic obstructive l u n g disease, it is practically impossible to obtain a good return of the instilled B A L fluid. 14 In these patients, the diagnostic value of B A L techniques are m i n i m a l , and only the PSB technique can be used. However, as the lavage procedure samples a greater area o f the lung than the PSB technique, this m e t h o d m a y lead to the detection of some false-negative results observed with PSB. C o m b i n i n g the two techniques m a y then i m p r o v e the overall diagnostic accuracy. 1,14 This approach is likely to reduce the n u m b e r of falsenegatives, at the expense of overtreating a small percentage of patients. 1,14 However, given the high mortality and morbidity rates of VAP, we believe that e v e n a low rate of false-negatives is probably unacceptable in clinical practice. To increase the sensitivity of the diagnostic tests, m a n y investigators have chosen to c o m b i n e the results of multiple tests. Indeed, in the study by B r e g e o n et al, 6 up to five different techniques were used to diagnose VAP. That c o m b i n a t i o n of tests that provides the highest sensitivity and specificity at the lowest cost is u n k n o w n . We believe that b-PSB and m - B A L c o m p l e m e n t each other, provide clinically useful

71

information, and m a y provide an alternative to more invasive diagnostic testing. Furthermore, these techniques can be performed readily and safely b y respiratory therapists who have undergone adequate training. This m a y be particularly important in ICUs where bronchoscopy is not readily available. The major limitation of our study is that we could not determine the exact operating characteristics for b-PSB and m - B A L . However, no true gold standard exists, and e v e n open lung biopsies have limitations o w i n g to sampling error, the effects of previous antibiotic therapy, and the lack of consensus as to the histological diagnosis of p n e u m o n i a , not withstanding that it w o u l d be considered clinically unacceptable to use this technique to confirm the presence of VAP. 24,25 However, additional studies are required to determine the operating characteristics of these minimally invasive diagnostic techniques to make more informed clinical decisions. ACKNOWLEDGMENT

The authors acknowledge with gratitude the excellent work done by the Respiratory Therapy Department at St. Vincent Hospital and the CliniTech microbiology technicians.

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