- Email: [email protected]
The Effect of Lung Lavage Volume Return on the Diagnosis of Ventilator-Associated Pneumonia
j o u r n a l o f s u r g i c a l r e s e a r c h a p r i l 2 0 2 0 ( 2 4 8 ) 5 6 e6 1
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
The Effect of Lung Lavage Volume Return on the Diagnosis of Ventilator-Associated Pneumonia Kevin N. Harrell, MD,* Jessica K. Reynolds, MD,1 Gavin R. Wilks, MD,2 J. Daniel Stanley, MD, Benjamin W. Dart IV, MD, and Robert A. Maxwell, MD Department of Surgery, University of Tennessee College of Medicine Chattanooga, Chattanooga, Tennessee
article info
abstract
Article history:
Background: Bronchoalveolar lavage (BAL) is a commonly used tool in the diagnosis of
Received 15 March 2019
ventilator-associated pneumonia (VAP). Previous protocols recommend 30% lavage return,
Received in revised form
though no studies have investigated this relationship. This study aims to assess the in-
13 August 2019
fluence of BAL volume return on VAP diagnosis.
Accepted 16 November 2019
Materials and methods: A retrospective review was performed of a prospectively maintained
Available online xxx
database for BAL performed from January 2015 to January 2016 in the trauma and surgical ICU at a level 1 trauma center. In total, 147 ventilated patients with clinical suspicion for pneu-
Keywords:
monia underwent 264 BALs. A protocol was used with five aliquots of 20 cc of saline instilled.
Bronchoalveolar lavage
Quantitative cultures were performed with 10^5 colony-forming organisms as the threshold
Ventilator-associated pneumonia
for VAP diagnosis. BAL was repeated at 6-8 d on 50 patients. Univariate and multivariate
Bronchoscopy
regression analyses were performed to investigate the predictors of VAP diagnosis.
Surgical critical care
Results: Patients with >40% lavage return had increased rates of VAP diagnosis (odds ratio [OR] 2.86, P ¼ 0.002). Increasing volume return also trended toward a lower false-negative rate. Temperature, leukocytosis, and X-ray infiltrate were not associated with increased VAP diagnosis. Concurrent antibiotic therapy at the time of BAL predicted decreased VAP diagnosis (OR 0.58, P ¼ 0.04). On multivariable analysis, only >40% return remained associated with increased rate of VAP diagnosis (OR 4.00, P ¼ 0.004). Conclusions: This study found that >40% lavage volume return was associated with increased VAP diagnosis. Clinicians should consider the reliability of a negative BAL if clinical suspicion of VAP is high and lavage return is <40%. Additional investigation is needed to further elucidate this association. ª 2019 Elsevier Inc. All rights reserved.
Introduction Flexible bronchoscopy with bronchoalveolar lavage (BAL) is one of the primary tools used in the diagnosis of ventilator-
associated pneumonia (VAP) in critically ill patients.1-3 A report published by Meduri and Chastre in 1992 has described a standard BAL protocol used in many centers across the country.4 While many studies have observed BAL’s
* Corresponding author. University of Tennessee College of Medicine Chattanooga, 979 East 3rd Street, Suite B401, Chattanooga, TN 37403. Tel.: þ423 778-7695; fax: þ423 778-2950. E-mail address: [email protected] (K.N. Harrell). 1 Present Address: Department of Surgery: University of Kentucky School of Medicine: AB Chandler Medical Center MN-150 800 Rose Street Lexington, KY 40536. 2 Present Address: Division of Surgery: Druid City Hospital 809 University Blvd. E.Tuscaloosa, AL 35401 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.11.016
harrell et al lung lavage return predicts pneumonia
effectiveness at diagnosing VAP, few have reported on the variations in the technique used to obtain the specimens.5,6 Specifically, there is sparse literature evaluating the impact of the volume of aspirate fluid recovered during the BAL collection on the diagnosis of VAP. Collins and Rylance et al. describe a preferable return of greater than 100 mL in lung mucosal cell sampling for research purposes.7 Clinically, the American Thoracic Society Clinical Practice Guidelines recommends at least a 30% return of instilled lavage fluid for minimally acceptable analysis in the diagnosis of interstitial lung disease.8 This threshold appears to be anecdotal, as no reference is provided for this recommendation. None of these studies investigates VAP diagnosis. While BAL aspirate volume is influenced by a variety of factors, a scientifically established threshold is needed for this common procedure with known patient benefits. A minimum threshold for obtained BAL aspirate will help clinicians assess the validity of the BAL data when interpreting culture results, in that low volumes of BAL aspirate may predispose the patient to a false-negative diagnosis of VAP. We hypothesized that the volume of aspirated fluid collected during BAL is associated with a diagnosis of VAP in surgical and trauma intensive care unit (ICU) patients. This study is the first to assess the influence of aspirate volume return on the incidence of VAP diagnosis.
57
portion of the lung. If lung infiltrate was seen on the chest Xray, the affected lobe was targeted. If no specific infiltrate was seen, the right lower lobe (RLL) was selected. An initial aliquot of 20 cc of normal saline was instilled and evacuated, clearing any residual upper airway secretions. Next, a trap was connected to the bronchoscope, and five additional aliquots of 20 cc saline were instilled with interval fluid collection. The trap was then removed, and the collected fluid sent for quantitative pulmonary culture and gram stain. Additional lavage and mucus evacuation was performed if needed for pulmonary hygiene after the specimen was collected. All BALs were performed by surgical residents under the supervision of surgical critical care surgeons.
Statistical analysis Statistical analyses were performed using SPSS Statistics 25.0 software (IBM Armonk, NY). Patients were divided into cohorts by positive or negative BAL culture/VAP diagnosis. These groups were compared using independent t-tests and chisquare or Fisher’s exact tests for continuous and categorical variables, respectively. Univariate binary logistic regression analyses were conducted to assess variables that influenced a positive VAP diagnosis. A P-value of <0.05 was considered to be significant. Multivariable binary logistic regression models were built to include variables that had significant association on univariate analysis.
Materials and methods Patient population
Results
A retrospective review was performed of a prospectively maintained database for BAL performed from January 2015 to January 2016 in the trauma and surgical ICU at a level 1 trauma center. All patients who underwent BAL due to clinical suspicion for pneumonia such as fever, worsening leukocytosis, or new infiltrate identified on the chest X-ray during the study period were included. The electronic medical records of included patients were reviewed for clinical information following Institutional Review Board waiver of consent. Patients were excluded if there were incomplete medical records. The primary outcome was diagnosis of VAP defined as greater than 100,000 colony-forming units (CFU) grown on quantitative culture. Patients with prolonged mechanical ventilation and ICU course had BAL repeated at 6-8 d after initial culture. Patients with a negative initial culture but a positive repeat BAL were deemed to have a false-negative initial BAL. Patients diagnosed with VAP on first culture were considered successfully treated if repeat quantitative culture had less than 1000 CFU.
Study population
Bronchoscopy protocol A standard protocol was used for all bronchoscopies. Patients were placed on a ventilator mode with mandatory breaths and 100% FiO2. A sterile drape was placed over the patient. All surgeons and assistants wore gowns, masks, and sterile gloves. After adequate sedation, the bronchoscope was inserted through the secure airway and placed in the target
From January 2015 to January 2016, 147 trauma and surgical critical care patients underwent 264 bronchoscopies. Of them, 107 patients (71.8%) had traumatic injuries and were admitted to the ICU, with the remainder being surgical patients attended by the surgical critical care service. The study population had an average age of 59.2 y (19.4 y) and 96 (65.3%) were male. Bronchoscopic and clinical characteristics are presented in Table 1. The average maximum temperature 24 h prior to BAL was 100.6 1.5 F with 153 (58.0%) considered to be febrile. The average leukocyte count was 15 7.7 thousand/mm3, with 180 (68.7%) considered to have a leukocytosis. In total, 185 (71.2%) BALs were performed after new infiltrate was identified on the chest X-ray. Of the BALs performed, 71.2% were in the RLL. The BAL had greater than 40% instilled lavage volume collected for culture 64.0% of the time. Further, 39% of the BALs were performed while the patient was on concurrent antibiotics, and the average resident post-graduate year (PGY) performing the bronchoscopy was 3.3 1.07 y. In total, 107 (40.5%) BALs had greater than 100,000 colonyforming organisms and the patient was diagnosed with VAP.
Clinical characteristics stratified by BAL result Patients were stratified into groups based on positive and negative BAL results (Table 1). Patient age (54.2 18.0 versus 51.3 21.1 y, P ¼ 0.371) and sex (58.3% versus 74.6% male,
58
j o u r n a l o f s u r g i c a l r e s e a r c h a p r i l 2 0 2 0 ( 2 4 8 ) 5 6 e6 1
Table 1 e Bronchoscopic characteristics of patient population stratified by BAL results. All BAL (n ¼ 264)
Negative BAL (n ¼ 157)
Positive BAL (n ¼ 107)
24-h maximum temperature* ( F)
100.6 1.5
100.6 1.5
100.6 1.5
0.890
Leukocyte count
15.0 7.7
15.8 7.7
14.0 7.5
0.064
Variable
P value
Chest X-ray new infiltrate
185 (70.3%)
112 (71.8%)
73 (68.2%)
0.627
BAL site (RLL)
187 (71.2%)
111 (71.2%)
76 (71%)
1.000
Lavage volume return >40%
169 (64.0%)
91 (64.5%)
78 (83.9%)
0.002
Concurrent antibiotics
102 (38.8%)
69 (43.9%)
33 (31.1%)
0.050
3.3 1.02
3.32 1.05
3.27 0.98
0.677
Resident PGY level
Bold text ¼ Statistical significance defined as P-value <0.05.
P ¼ 0.061) were not significantly different between the two groups. Further, 24-h maximum temperature (100.6 1.5 versus 100.6 1.5 F, P ¼ 0.890), leukocyte count (15.8 7.7 versus 14.0 7.5 thousand/mm3, P ¼ 0.064), and new infiltrate on the chest X-ray (71.8% versus 68.2%, P ¼ 0.627) were also not significantly different between the two groups. The positive BAL group had statistically more BALs with lavage volume return >40% (83.9% versus 64.5%, P ¼ 0.002). The negative BAL group had a higher rate of concurrent antibiotic therapy at the time of culture collection (43.9% versus 31.1%, P ¼ 0.050). Resident PGY level and BAL site were not significantly different between the two groups. Figure demonstrates the rate of VAP diagnosis versus percentage of instilled lavage volume collected for specimen. BAL with less than 40% return had overall lower rates of VAP diagnosis. While increasing returns >40% had overall higher VAP diagnosis, a plateau was observed with VAP rates remaining fairly constant for increased volume collection above 40%.
Repeat BAL In total, 51 patients remained on mechanical ventilation and had repeat bronchoscopy at 6 to 8 d from the original culture. Further, 29 patients with VAP were successfully treated with
less than 1000 CFU on repeat culture. Ten patients with VAPs had a positive culture on repeat BAL and required further treatment. False-negative initial cultures were found in 12 patients. These patients were also stratified by percentage of lavage volume collected. Figure shows that increasing percentage of volume collection trended toward lower false-negative rate.
Factors influencing VAP diagnosis Univariate binary logistic regression analyses performed to assess factors that influence a positive VAP diagnosis are shown in Table 2. Age, 24-h maximum temperature, leukocyte count, new chest X-ray infiltrate, BAL site, and resident PGY level were not associated with higher rates of VAP diagnosis. The presence of multiple clinical factors was also not associated with increased VAP diagnosis. Trauma patients were not more likely to have a VAP diagnosis than critical surgical patients. Lavage volume return of >40% was found to be associated with increased incidence of VAP (odds ratio [OR] 2.857, 95% confidence interval [CI], 1.489-5.481, P ¼ 0.004). Male patients (OR 0.477, 95% CI, 0.233-0.973, P ¼ 0.042) and concurrent antibiotic therapy (OR 0.577, 95% CI, 0.343-0.968, P ¼ 0.037) were associated with lower rates of VAP diagnosis.
Fig e Rate of VAP diagnosis and false negative BAL versus percent of lavage volume return. (Color version of the figure is available online.)
59
harrell et al lung lavage return predicts pneumonia
Table 2 e Univariate and multivariate binary logistic regression analyses of factors influencing VAP diagnosis. Variable
Univariate
Multivariate
OR
95% CI
P value
Age
0.992
0.976-1.009
0.368
Sex (male)
0.477
0.233-0.973
0.042
Trauma patient
1.690
0.801-3.562
0.168
24-h maximum temperature
1.012
0.860-1.190
0.890
Leukocyte count
0.968
0.935-1.002
0.067
Chest X-ray new infiltrate
0.843
0.494-1.442
0.534
OR
95% CI
P value
0.620
0.271-1.417
0.257
BAL site (RLL)
1.006
0.585-1.731
0.982
Lavage volume return >40%
2.857
1.489-5.481
0.002
4.001
1.568-10.213
0.004
Concurrent antibiotics
0.577
0.343-0.968
0.037
0.538
0.184-1.569
0.256
Resident PGY level
0.949
0.744-1.211
0.675
Bold text ¼ Statistical significance defined as P-value <0.05.
A multivariable binary logistic regression model was built to include variables significant on univariate analysis (Table 2). Sex and antibiotic therapy did not remain significant. Lavage volume return greater than 40% was significantly associated with VAP diagnosis (OR 4.001, 95% CI 1.568-10.213, P ¼ 0.004).
Lavage volume percent return Additional cut-offs of return volume percent were investigated. Return cut-off of >20%, >25%, >50%, >55%, and >60% were not significant in any analysis. Lavage volume return of >30% (OR 2.909, 95% CI 1.051-8.049, P ¼ 0.04), >35% (OR 2.062, 95% CI 1.003-4.241, P ¼ 0.049) and >45% (OR 1.811, 95% CI 1.0523.117, P ¼ ) were found to be significant on univariate analysis in addition to the >40% value shown above. Volume >30% (OR 2.149 95% CI 0.541-8.537, P ¼ 0.277) and >35% (OR 1.838, 95% CI 0.690-4.897, P ¼ 0.223) did not remain significant on multivariable analysis. Lavage return of >45% (OR 2.544, 95% CI 1.186-5.454, P ¼ 0.016) was significant on multivariable analysis, but had a lower OR than the >40% value shown in the main results above.
Discussion BAL with quantitative cultures is a standard of care for the diagnosis of VAP in trauma and surgical critical care patients.1,5,9 Cultures obtained by BAL help guide effective antimicrobial therapy while promoting good antibiotic stewardship when antibiotics are withheld in the face of negative culture results.2,10,11 The benefits of quantitative bacterial cultures in the care of the surgical patient were noted as early as 1975 by Dr Polk at the University of Louisville.12 Since then, several studies have investigated the threshold of organisms present in a BAL for the correct diagnosis of VAP, now established at greater than 100,00 colony-forming organisms.6,13,14 Studies evaluating the quality, quantity, and techniques of obtaining a BAL specimen have not been forthcoming. Standard protocols for lavage technique have been described.1,4,8 The American Thoracic Society official clinical
practice guideline published by a committee of international experts recommends a target collection of 30% of instilled volume for “optimal sampling.”8 These recommendations do not appear to be evidence-based, though the described procedure is for the diagnosis of interstitial lung disease rather than pneumonia. Another published guideline from the Spanish Thoracic Society recommends 40% collection, again without reference.15 Many other seminal papers specifically investigating BAL for VAP diagnosis provide no information about BAL volume collection.1,13,14 This study, to the authors’ knowledge, is the first to investigate the relationship between BAL volume return and the diagnosis of VAP. These data suggest that a target greater than 40% of instilled lavage volume should be collected for increased odds of establishing VAP diagnosis via bronchoscopic-directed BAL. This value of 40% was the most robust after testing multiple cut-off points, as noted above. These authors recommend spending additional bronchoscopic time to achieve this threshold in the right clinical setting. Often, additional suctioning may be all that is needed to achieve greater than 40% return. Other maneuvers such as pulse suctioning, adjusting ventilator settings as able, and advancing the bronchoscope to deeper bronchioles may assist in collection. If yields fail to improve, however, instillation of additional fluid beyond the protocol is unlikely to improve the return rate and runs the risk of diluting the colony count. A plateau effect of VAP diagnosis was observed as the collection volume increases further above 40% (Figure). This suggests that efforts to obtain even greater amounts of instilled lavage volume are not necessary. Jonker et al. found that BAL performed in both lungs at the time of culture led to higher rates of VAP diagnosis.16 They noted only an average of 16%-25% collection rate in their samples, however. Several studies have also proposed the use of lavage fluid for novel VAP diagnostic and prognostic modalities such as cytokine levels as a predictor of clinical outcomes or amylase detection to indicate aspiration.17-19 In the present study, we observed a trend toward a lower false-negative rate as lavage volume collection increased (Figure). False negative rates were few (n ¼ 12), however, limiting the conclusions drawn from these results.
60
j o u r n a l o f s u r g i c a l r e s e a r c h a p r i l 2 0 2 0 ( 2 4 8 ) 5 6 e6 1
Based on the presented data, lavage return of less than 40% could be considered an inadequate sample. These authors suggest that adequacy of BAL should be questioned in the setting of negative culture with high clinical suspicion. Patients with concerning clinical signs and increasing respiratory requirements should be considered for continued antibiotic coverage in spite of a “negative” culture. Conversely, however, an adequate sample with negative culture in the setting of a worsening clinical picture should not dictate cessation of antibiotic therapy. The literature is sparse regarding factors that influence the reliability of lavage collection. One randomized prospective study observed differences in the type of suction used for BAL collection.20 The authors noted that more aspirate volume was retrieved with hand-held syringe suction compared to continuous wall suction. Volume yield was also found to be significantly higher when the right middle lobe and lingula were sampled, agreeing with other literature.20,21 They did not correlate lavage return with rates of pneumonia diagnosis. A few studies have also investigated the storage of BAL aspirate and its effect on culture, with one study suggesting that using a blood culture bottle for collection can help with antibiotic selection.22,23 Clinical factors such as ventilator settings, presence of cough reflex, history of chronic obstructive pulmonary disease, pulmonary edema, and operator experience have been also been implicated in effecting volume of lavage fluid return. Though taken from a prospectively maintained database, this study is limited by its retrospective nature. Additionally, the bronchoscopies were performed by a cohort of residents of variable experience, though resident PGY year was not associated with improved VAP diagnosis. The rate of repeat bronchoscopy and false negative first BAL result was also low, limiting the generalizability of these results. Clinical judgment was also used to prompt BAL in this study rather than objective criteria, which may be a source of bias. Still, this report represents the first of its kind to investigate the important relationship between the clinical incidence of VAP and BAL collection volume.
Conclusions This study found that return of >40% instilled lavage volume was associated with an increase in the incidence of VAP diagnosis. Clinicians should consider the reliability of a negative BAL culture if the clinical suspicion of VAP is high and lavage volume return is less than 40%. Currently available protocols could be amended to include this evidence-based recommendation as a target for BAL volume collection. Additional investigation is needed to further elucidate this association and if the addition of extra lavage fluid would further enhance the diagnosis of VAP.
Acknowledgment Author contributions: RM and JR designed this study. KH, GW, and JR contributed to the data acquisition. KH and RM
performed the data analysis. KH, BD, GW, RM contributed to data interpretation. KH, JR, BD, GW, RM assisted with manuscript preparation.
Disclosure This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors.
references
1. Croce MA, Fabian TC, Waddle-Smith L, et al. Utility of Gram’s stain and efficacy of quantitative cultures for posttraumatic pneumonia: a prospective study. Ann Surg. 1998;227:743e751 [discussion 751-755]. 2. Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest. 1997;111:676e685. 3. Meduri GU. Ventilator-associated pneumonia in patients with respiratory failure. A diagnostic approach. Chest. 1990;97:1208e1219. 4. Meduri GU, Chastre J. The standardization of bronchoscopic techniques for ventilator-associated pneumonia. Chest. 1992;102(5 Suppl 1):557Se564S. 5. Wood AY, Davit 2nd AJ, Ciraulo DL, et al. A prospective assessment of diagnostic efficacy of blind protective bronchial brushings compared to bronchoscope-assisted lavage, bronchoscope-directed brushings, and blind endotracheal aspirates in ventilator-associated pneumonia. J Trauma. 2003;55:825e834. 6. Sharpe JP, Magnotti LJ, Weinberg JA, et al. Adherence to an established diagnostic threshold for ventilator-associated pneumonia contributes to low false-negative rates in trauma patients. J Trauma Acute Care Surg. 2015;78:468e473 [discussion 473-474]. 7. Collins AM, Rylance J, Wootton DG, et al. Bronchoalveolar lavage (BAL) for research; obtaining adequate sample yield. J Vis Exp. 2014:e4345. 8. Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185:1004e1014. 9. Croce MA, Fabian TC, Shaw B, et al. Analysis of charges associated with diagnosis of nosocomial pneumonia: can routine bronchoscopy be justified? J Trauma. 1994;37:721e727. 10. Sharpe JP, Magnotti LJ, Weinberg JA, et al. Impact of pathogen-directed antimicrobial therapy for ventilatorassociated pneumonia in trauma patients on charges and recurrence. J Am Coll Surg. 2015;220:489e495. 11. Kim ES, Kim EC, Lee SM, et al. Bacterial yield from quantitative cultures of bronchoalveolar lavage fluid in patients with pneumonia on antimicrobial therapy. Korean J Intern Med. 2012;27:156e162. 12. Polk Jr HC. Quantitative tracheal cultures in surgical patients requiring mechanical ventilatory assistance. Surgery. 1975;78:485e491. 13. Miller PR, Meredith JW, Chang MC. Optimal threshold for diagnosis of ventilator-associated pneumonia using bronchoalveolar lavage. J Trauma. 2003;55:263e267 [discussion 267-268]. 14. Croce MA, Fabian TC, Mueller EW, et al. The appropriate diagnostic threshold for ventilator-associated pneumonia using quantitative cultures. J Trauma. 2004;56:931e934 [discussion 934-396].
harrell et al lung lavage return predicts pneumonia
15. Castella J, Ancochea J, Llorente L, et al. [Bronchoalveolar lavage]. Arch Bronconeumol. 1997;33:515e526. 16. Jonker MA, Sauerhammer TM, Faucher LD, Schurr MJ, Kudsk KA. Bilateral versus unilateral bronchoalveolar lavage for the diagnosis of ventilator-associated pneumonia. Surg Infect (Larchmt). 2012;13:391e395. 17. Clavel M, Barraud O, Moucadel V, et al. Molecular quantification of bacteria from respiratory samples in patients with suspected ventilator-associated pneumonia. Clin Microbiol Infect. 2016;22:812.e1e812.e7. 18. Kumar S, Bhardwaj N, Khurana S, et al. Bronchoalveolar lavage fluid cytokine bead array profile for prognostication of ventilated trauma patients. Indian J Crit Care Med. 2016;20:513e517. 19. Samanta S, Poddar B, Azim A, Singh RK, Gurjar M, Baronia AK. Significance of mini bronchoalveolar lavage fluid amylase
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23.
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level in ventilator-associated pneumonia: a prospective observational study. Crit Care Med. 2018;46:71e78. Seijo LM, Flandes J, Somiedo MV, et al. A prospective randomized study comparing manual and wall suction in the performance of bronchoalveolar lavage. Respiration. 2016;91:480e485. Radhakrishna N, Farmer M, Steinfort DP, King P. A comparison of techniques for optimal performance of bronchoalveolar lavage. J Bronchology Interv Pulmonol. 2015;22:300e305. Heo EY, Shin S, Chung HS, Jeong YJ, Oh SH, Kim DK. The effect of using blood culture bottle of bronchoalveolar larvage fluid in pneumonia. BMC Infect Dis. 2016;16:247. Kneidinger N, Warszawska J, Schenk P, et al. Storage of bronchoalveolar lavage fluid and accuracy of microbiologic diagnostics in the ICU: a prospective observational study. Crit Care. 2013;17:R135.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
The Effect of Lung Lavage Volume Return on the Diagnosis of Ventilator-Associated Pneumonia Kevin N. Harrell, MD,* Jessica K. Reynolds, MD,1 Gavin R. Wilks, MD,2 J. Daniel Stanley, MD, Benjamin W. Dart IV, MD, and Robert A. Maxwell, MD Department of Surgery, University of Tennessee College of Medicine Chattanooga, Chattanooga, Tennessee
article info
abstract
Article history:
Background: Bronchoalveolar lavage (BAL) is a commonly used tool in the diagnosis of
Received 15 March 2019
ventilator-associated pneumonia (VAP). Previous protocols recommend 30% lavage return,
Received in revised form
though no studies have investigated this relationship. This study aims to assess the in-
13 August 2019
fluence of BAL volume return on VAP diagnosis.
Accepted 16 November 2019
Materials and methods: A retrospective review was performed of a prospectively maintained
Available online xxx
database for BAL performed from January 2015 to January 2016 in the trauma and surgical ICU at a level 1 trauma center. In total, 147 ventilated patients with clinical suspicion for pneu-
Keywords:
monia underwent 264 BALs. A protocol was used with five aliquots of 20 cc of saline instilled.
Bronchoalveolar lavage
Quantitative cultures were performed with 10^5 colony-forming organisms as the threshold
Ventilator-associated pneumonia
for VAP diagnosis. BAL was repeated at 6-8 d on 50 patients. Univariate and multivariate
Bronchoscopy
regression analyses were performed to investigate the predictors of VAP diagnosis.
Surgical critical care
Results: Patients with >40% lavage return had increased rates of VAP diagnosis (odds ratio [OR] 2.86, P ¼ 0.002). Increasing volume return also trended toward a lower false-negative rate. Temperature, leukocytosis, and X-ray infiltrate were not associated with increased VAP diagnosis. Concurrent antibiotic therapy at the time of BAL predicted decreased VAP diagnosis (OR 0.58, P ¼ 0.04). On multivariable analysis, only >40% return remained associated with increased rate of VAP diagnosis (OR 4.00, P ¼ 0.004). Conclusions: This study found that >40% lavage volume return was associated with increased VAP diagnosis. Clinicians should consider the reliability of a negative BAL if clinical suspicion of VAP is high and lavage return is <40%. Additional investigation is needed to further elucidate this association. ª 2019 Elsevier Inc. All rights reserved.
Introduction Flexible bronchoscopy with bronchoalveolar lavage (BAL) is one of the primary tools used in the diagnosis of ventilator-
associated pneumonia (VAP) in critically ill patients.1-3 A report published by Meduri and Chastre in 1992 has described a standard BAL protocol used in many centers across the country.4 While many studies have observed BAL’s
* Corresponding author. University of Tennessee College of Medicine Chattanooga, 979 East 3rd Street, Suite B401, Chattanooga, TN 37403. Tel.: þ423 778-7695; fax: þ423 778-2950. E-mail address: [email protected] (K.N. Harrell). 1 Present Address: Department of Surgery: University of Kentucky School of Medicine: AB Chandler Medical Center MN-150 800 Rose Street Lexington, KY 40536. 2 Present Address: Division of Surgery: Druid City Hospital 809 University Blvd. E.Tuscaloosa, AL 35401 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.11.016
harrell et al lung lavage return predicts pneumonia
effectiveness at diagnosing VAP, few have reported on the variations in the technique used to obtain the specimens.5,6 Specifically, there is sparse literature evaluating the impact of the volume of aspirate fluid recovered during the BAL collection on the diagnosis of VAP. Collins and Rylance et al. describe a preferable return of greater than 100 mL in lung mucosal cell sampling for research purposes.7 Clinically, the American Thoracic Society Clinical Practice Guidelines recommends at least a 30% return of instilled lavage fluid for minimally acceptable analysis in the diagnosis of interstitial lung disease.8 This threshold appears to be anecdotal, as no reference is provided for this recommendation. None of these studies investigates VAP diagnosis. While BAL aspirate volume is influenced by a variety of factors, a scientifically established threshold is needed for this common procedure with known patient benefits. A minimum threshold for obtained BAL aspirate will help clinicians assess the validity of the BAL data when interpreting culture results, in that low volumes of BAL aspirate may predispose the patient to a false-negative diagnosis of VAP. We hypothesized that the volume of aspirated fluid collected during BAL is associated with a diagnosis of VAP in surgical and trauma intensive care unit (ICU) patients. This study is the first to assess the influence of aspirate volume return on the incidence of VAP diagnosis.
57
portion of the lung. If lung infiltrate was seen on the chest Xray, the affected lobe was targeted. If no specific infiltrate was seen, the right lower lobe (RLL) was selected. An initial aliquot of 20 cc of normal saline was instilled and evacuated, clearing any residual upper airway secretions. Next, a trap was connected to the bronchoscope, and five additional aliquots of 20 cc saline were instilled with interval fluid collection. The trap was then removed, and the collected fluid sent for quantitative pulmonary culture and gram stain. Additional lavage and mucus evacuation was performed if needed for pulmonary hygiene after the specimen was collected. All BALs were performed by surgical residents under the supervision of surgical critical care surgeons.
Statistical analysis Statistical analyses were performed using SPSS Statistics 25.0 software (IBM Armonk, NY). Patients were divided into cohorts by positive or negative BAL culture/VAP diagnosis. These groups were compared using independent t-tests and chisquare or Fisher’s exact tests for continuous and categorical variables, respectively. Univariate binary logistic regression analyses were conducted to assess variables that influenced a positive VAP diagnosis. A P-value of <0.05 was considered to be significant. Multivariable binary logistic regression models were built to include variables that had significant association on univariate analysis.
Materials and methods Patient population
Results
A retrospective review was performed of a prospectively maintained database for BAL performed from January 2015 to January 2016 in the trauma and surgical ICU at a level 1 trauma center. All patients who underwent BAL due to clinical suspicion for pneumonia such as fever, worsening leukocytosis, or new infiltrate identified on the chest X-ray during the study period were included. The electronic medical records of included patients were reviewed for clinical information following Institutional Review Board waiver of consent. Patients were excluded if there were incomplete medical records. The primary outcome was diagnosis of VAP defined as greater than 100,000 colony-forming units (CFU) grown on quantitative culture. Patients with prolonged mechanical ventilation and ICU course had BAL repeated at 6-8 d after initial culture. Patients with a negative initial culture but a positive repeat BAL were deemed to have a false-negative initial BAL. Patients diagnosed with VAP on first culture were considered successfully treated if repeat quantitative culture had less than 1000 CFU.
Study population
Bronchoscopy protocol A standard protocol was used for all bronchoscopies. Patients were placed on a ventilator mode with mandatory breaths and 100% FiO2. A sterile drape was placed over the patient. All surgeons and assistants wore gowns, masks, and sterile gloves. After adequate sedation, the bronchoscope was inserted through the secure airway and placed in the target
From January 2015 to January 2016, 147 trauma and surgical critical care patients underwent 264 bronchoscopies. Of them, 107 patients (71.8%) had traumatic injuries and were admitted to the ICU, with the remainder being surgical patients attended by the surgical critical care service. The study population had an average age of 59.2 y (19.4 y) and 96 (65.3%) were male. Bronchoscopic and clinical characteristics are presented in Table 1. The average maximum temperature 24 h prior to BAL was 100.6 1.5 F with 153 (58.0%) considered to be febrile. The average leukocyte count was 15 7.7 thousand/mm3, with 180 (68.7%) considered to have a leukocytosis. In total, 185 (71.2%) BALs were performed after new infiltrate was identified on the chest X-ray. Of the BALs performed, 71.2% were in the RLL. The BAL had greater than 40% instilled lavage volume collected for culture 64.0% of the time. Further, 39% of the BALs were performed while the patient was on concurrent antibiotics, and the average resident post-graduate year (PGY) performing the bronchoscopy was 3.3 1.07 y. In total, 107 (40.5%) BALs had greater than 100,000 colonyforming organisms and the patient was diagnosed with VAP.
Clinical characteristics stratified by BAL result Patients were stratified into groups based on positive and negative BAL results (Table 1). Patient age (54.2 18.0 versus 51.3 21.1 y, P ¼ 0.371) and sex (58.3% versus 74.6% male,
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j o u r n a l o f s u r g i c a l r e s e a r c h a p r i l 2 0 2 0 ( 2 4 8 ) 5 6 e6 1
Table 1 e Bronchoscopic characteristics of patient population stratified by BAL results. All BAL (n ¼ 264)
Negative BAL (n ¼ 157)
Positive BAL (n ¼ 107)
24-h maximum temperature* ( F)
100.6 1.5
100.6 1.5
100.6 1.5
0.890
Leukocyte count
15.0 7.7
15.8 7.7
14.0 7.5
0.064
Variable
P value
Chest X-ray new infiltrate
185 (70.3%)
112 (71.8%)
73 (68.2%)
0.627
BAL site (RLL)
187 (71.2%)
111 (71.2%)
76 (71%)
1.000
Lavage volume return >40%
169 (64.0%)
91 (64.5%)
78 (83.9%)
0.002
Concurrent antibiotics
102 (38.8%)
69 (43.9%)
33 (31.1%)
0.050
3.3 1.02
3.32 1.05
3.27 0.98
0.677
Resident PGY level
Bold text ¼ Statistical significance defined as P-value <0.05.
P ¼ 0.061) were not significantly different between the two groups. Further, 24-h maximum temperature (100.6 1.5 versus 100.6 1.5 F, P ¼ 0.890), leukocyte count (15.8 7.7 versus 14.0 7.5 thousand/mm3, P ¼ 0.064), and new infiltrate on the chest X-ray (71.8% versus 68.2%, P ¼ 0.627) were also not significantly different between the two groups. The positive BAL group had statistically more BALs with lavage volume return >40% (83.9% versus 64.5%, P ¼ 0.002). The negative BAL group had a higher rate of concurrent antibiotic therapy at the time of culture collection (43.9% versus 31.1%, P ¼ 0.050). Resident PGY level and BAL site were not significantly different between the two groups. Figure demonstrates the rate of VAP diagnosis versus percentage of instilled lavage volume collected for specimen. BAL with less than 40% return had overall lower rates of VAP diagnosis. While increasing returns >40% had overall higher VAP diagnosis, a plateau was observed with VAP rates remaining fairly constant for increased volume collection above 40%.
Repeat BAL In total, 51 patients remained on mechanical ventilation and had repeat bronchoscopy at 6 to 8 d from the original culture. Further, 29 patients with VAP were successfully treated with
less than 1000 CFU on repeat culture. Ten patients with VAPs had a positive culture on repeat BAL and required further treatment. False-negative initial cultures were found in 12 patients. These patients were also stratified by percentage of lavage volume collected. Figure shows that increasing percentage of volume collection trended toward lower false-negative rate.
Factors influencing VAP diagnosis Univariate binary logistic regression analyses performed to assess factors that influence a positive VAP diagnosis are shown in Table 2. Age, 24-h maximum temperature, leukocyte count, new chest X-ray infiltrate, BAL site, and resident PGY level were not associated with higher rates of VAP diagnosis. The presence of multiple clinical factors was also not associated with increased VAP diagnosis. Trauma patients were not more likely to have a VAP diagnosis than critical surgical patients. Lavage volume return of >40% was found to be associated with increased incidence of VAP (odds ratio [OR] 2.857, 95% confidence interval [CI], 1.489-5.481, P ¼ 0.004). Male patients (OR 0.477, 95% CI, 0.233-0.973, P ¼ 0.042) and concurrent antibiotic therapy (OR 0.577, 95% CI, 0.343-0.968, P ¼ 0.037) were associated with lower rates of VAP diagnosis.
Fig e Rate of VAP diagnosis and false negative BAL versus percent of lavage volume return. (Color version of the figure is available online.)
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harrell et al lung lavage return predicts pneumonia
Table 2 e Univariate and multivariate binary logistic regression analyses of factors influencing VAP diagnosis. Variable
Univariate
Multivariate
OR
95% CI
P value
Age
0.992
0.976-1.009
0.368
Sex (male)
0.477
0.233-0.973
0.042
Trauma patient
1.690
0.801-3.562
0.168
24-h maximum temperature
1.012
0.860-1.190
0.890
Leukocyte count
0.968
0.935-1.002
0.067
Chest X-ray new infiltrate
0.843
0.494-1.442
0.534
OR
95% CI
P value
0.620
0.271-1.417
0.257
BAL site (RLL)
1.006
0.585-1.731
0.982
Lavage volume return >40%
2.857
1.489-5.481
0.002
4.001
1.568-10.213
0.004
Concurrent antibiotics
0.577
0.343-0.968
0.037
0.538
0.184-1.569
0.256
Resident PGY level
0.949
0.744-1.211
0.675
Bold text ¼ Statistical significance defined as P-value <0.05.
A multivariable binary logistic regression model was built to include variables significant on univariate analysis (Table 2). Sex and antibiotic therapy did not remain significant. Lavage volume return greater than 40% was significantly associated with VAP diagnosis (OR 4.001, 95% CI 1.568-10.213, P ¼ 0.004).
Lavage volume percent return Additional cut-offs of return volume percent were investigated. Return cut-off of >20%, >25%, >50%, >55%, and >60% were not significant in any analysis. Lavage volume return of >30% (OR 2.909, 95% CI 1.051-8.049, P ¼ 0.04), >35% (OR 2.062, 95% CI 1.003-4.241, P ¼ 0.049) and >45% (OR 1.811, 95% CI 1.0523.117, P ¼ ) were found to be significant on univariate analysis in addition to the >40% value shown above. Volume >30% (OR 2.149 95% CI 0.541-8.537, P ¼ 0.277) and >35% (OR 1.838, 95% CI 0.690-4.897, P ¼ 0.223) did not remain significant on multivariable analysis. Lavage return of >45% (OR 2.544, 95% CI 1.186-5.454, P ¼ 0.016) was significant on multivariable analysis, but had a lower OR than the >40% value shown in the main results above.
Discussion BAL with quantitative cultures is a standard of care for the diagnosis of VAP in trauma and surgical critical care patients.1,5,9 Cultures obtained by BAL help guide effective antimicrobial therapy while promoting good antibiotic stewardship when antibiotics are withheld in the face of negative culture results.2,10,11 The benefits of quantitative bacterial cultures in the care of the surgical patient were noted as early as 1975 by Dr Polk at the University of Louisville.12 Since then, several studies have investigated the threshold of organisms present in a BAL for the correct diagnosis of VAP, now established at greater than 100,00 colony-forming organisms.6,13,14 Studies evaluating the quality, quantity, and techniques of obtaining a BAL specimen have not been forthcoming. Standard protocols for lavage technique have been described.1,4,8 The American Thoracic Society official clinical
practice guideline published by a committee of international experts recommends a target collection of 30% of instilled volume for “optimal sampling.”8 These recommendations do not appear to be evidence-based, though the described procedure is for the diagnosis of interstitial lung disease rather than pneumonia. Another published guideline from the Spanish Thoracic Society recommends 40% collection, again without reference.15 Many other seminal papers specifically investigating BAL for VAP diagnosis provide no information about BAL volume collection.1,13,14 This study, to the authors’ knowledge, is the first to investigate the relationship between BAL volume return and the diagnosis of VAP. These data suggest that a target greater than 40% of instilled lavage volume should be collected for increased odds of establishing VAP diagnosis via bronchoscopic-directed BAL. This value of 40% was the most robust after testing multiple cut-off points, as noted above. These authors recommend spending additional bronchoscopic time to achieve this threshold in the right clinical setting. Often, additional suctioning may be all that is needed to achieve greater than 40% return. Other maneuvers such as pulse suctioning, adjusting ventilator settings as able, and advancing the bronchoscope to deeper bronchioles may assist in collection. If yields fail to improve, however, instillation of additional fluid beyond the protocol is unlikely to improve the return rate and runs the risk of diluting the colony count. A plateau effect of VAP diagnosis was observed as the collection volume increases further above 40% (Figure). This suggests that efforts to obtain even greater amounts of instilled lavage volume are not necessary. Jonker et al. found that BAL performed in both lungs at the time of culture led to higher rates of VAP diagnosis.16 They noted only an average of 16%-25% collection rate in their samples, however. Several studies have also proposed the use of lavage fluid for novel VAP diagnostic and prognostic modalities such as cytokine levels as a predictor of clinical outcomes or amylase detection to indicate aspiration.17-19 In the present study, we observed a trend toward a lower false-negative rate as lavage volume collection increased (Figure). False negative rates were few (n ¼ 12), however, limiting the conclusions drawn from these results.
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Based on the presented data, lavage return of less than 40% could be considered an inadequate sample. These authors suggest that adequacy of BAL should be questioned in the setting of negative culture with high clinical suspicion. Patients with concerning clinical signs and increasing respiratory requirements should be considered for continued antibiotic coverage in spite of a “negative” culture. Conversely, however, an adequate sample with negative culture in the setting of a worsening clinical picture should not dictate cessation of antibiotic therapy. The literature is sparse regarding factors that influence the reliability of lavage collection. One randomized prospective study observed differences in the type of suction used for BAL collection.20 The authors noted that more aspirate volume was retrieved with hand-held syringe suction compared to continuous wall suction. Volume yield was also found to be significantly higher when the right middle lobe and lingula were sampled, agreeing with other literature.20,21 They did not correlate lavage return with rates of pneumonia diagnosis. A few studies have also investigated the storage of BAL aspirate and its effect on culture, with one study suggesting that using a blood culture bottle for collection can help with antibiotic selection.22,23 Clinical factors such as ventilator settings, presence of cough reflex, history of chronic obstructive pulmonary disease, pulmonary edema, and operator experience have been also been implicated in effecting volume of lavage fluid return. Though taken from a prospectively maintained database, this study is limited by its retrospective nature. Additionally, the bronchoscopies were performed by a cohort of residents of variable experience, though resident PGY year was not associated with improved VAP diagnosis. The rate of repeat bronchoscopy and false negative first BAL result was also low, limiting the generalizability of these results. Clinical judgment was also used to prompt BAL in this study rather than objective criteria, which may be a source of bias. Still, this report represents the first of its kind to investigate the important relationship between the clinical incidence of VAP and BAL collection volume.
Conclusions This study found that return of >40% instilled lavage volume was associated with an increase in the incidence of VAP diagnosis. Clinicians should consider the reliability of a negative BAL culture if the clinical suspicion of VAP is high and lavage volume return is less than 40%. Currently available protocols could be amended to include this evidence-based recommendation as a target for BAL volume collection. Additional investigation is needed to further elucidate this association and if the addition of extra lavage fluid would further enhance the diagnosis of VAP.
Acknowledgment Author contributions: RM and JR designed this study. KH, GW, and JR contributed to the data acquisition. KH and RM
performed the data analysis. KH, BD, GW, RM contributed to data interpretation. KH, JR, BD, GW, RM assisted with manuscript preparation.
Disclosure This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors.
references
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