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Site of Bronchoalveolar Lavage Via Flexible Bronchoscopy and Fluid Return in Children

Christian Rosas-Salazar, MD, MPH,* Stephen A. Walczak, RRT,w Geoffrey Kurland, MD,w and Jonathan E. Spahr, MDw

Background: Despite its widespread use as a diagnostic tool, the procedure for bronchoalveolar lavage (BAL) via flexible bronchoscopy is not standardized in chil- dren. Our objective was to examine the dissimilarities in fluid return between the different lobes in children undergoing flexible bronchoscopies with BAL.

Methods: We conducted a review of all pediatric flexible bronchoscopies with BAL conducted at a single insti- tution over a 2-year period. Our predictor of interest was the site of the BAL. Our outcome of interest was the percent of fluid return. We used 1-way analysis of variance with subsequent pairwise comparisons for unadjusted analyses and multivariable linear regression for adjusted analyses.

Results: We identified 529 procedures that met pre- specified criteria. The mean (SD) percent of fluid return was 52.1 (14.4) for the right middle lobe, 50.7 (16.0) for the lingula (LIN), 50.5 (18.6) for the right or left upper lobes other than LIN (R/L-UL), and 42.2 (18.7) for the right or left lower lobes (R/L-LL). The R/L-LL had significantly lower fluid return when compared with each of the other lobes (P <0.05 for all pairwise compar- isons); in contrast, there was no significant difference in fluid return between the other lobes. In our main analysis adjusting for potential confounders, performing the BAL in the right middle lobe, LIN, or R/L-UL increased the fluid return by 11.1% [95% confidence interval (CI), 6.2- 16.1], 9.5% (95% CI, 3.2-15.8), and 8.7% (95% CI, 0.9- 16.5%), respectively, when compared with the R/L-LL.

Conclusion: Our results suggest that the lower lobes provide the lowest BAL fluid return in children, whereas the other lobes seem to perform similarly.

Key Words: bronchoalveolar lavage, flexible bronchoscopy, children

(J Bronchol Intervent Pulmonol 2016;23:210–214)

Respiratory illnesses are a leading cause ofmorbidity, mortality, school absenteeism, and increased health care expenditures in children worldwide.1,2 Bronchoalveolar lavage (BAL) via flexible bronchoscopy is an essential tool that can help to establish an early diagnosis and guide appropriate management in children with respira- tory illnesses of different etiologies (including immunologic, inflammatory, and infectious proc- esses).3–6 Thus, if performed correctly, it can decrease the risk of potential complications and reduce the burden associated to these conditions.4,7

The clinical value of the BAL is thought to be linked to the volume of fluid recovered, as a lower percentage of volume retrieved may represent a proximal (nonalveolar) sample and has been asso- ciated with a decreased diagnostic yield.6,8–13 One essential aspect that can affect the volume of fluid recovered is the lobe where the BAL is performed. The available pediatric and adult guidelines for this procedure suggest that the right middle lobe (RML) and lingula (LIN) are the preferred sites as they have the highest fluid return6,7,13–15; however, there is very little evidence to support this opinion.3

We hypothesized that the site of BAL would be an important determinant of the volume return from BAL in children. To test this hypothesis, we conducted a retrospective review of all flexible bronchoscopies with BAL performed at a single institution between January 2011 and December 2012.

MATERIALS AND METHODS

Study Setting and Data Sources

Children’s Hospital of Pittsburgh of UPMC is a tertiary-care pediatric hospital located in southwestern Pennsylvania, United States. At this institution, BALs via flexible bronchoscopy are performed by a member of the Division of Pediatric Pulmonology (either an attending physician or a fellow in-training supervised by an attending physician) and assisted by a respiratory therapist. Procedures are performed under seda- tion or anesthesia in an endoscopy suite, an

Received for publication November 17, 2015; accepted April 6, 2016. From the *Department of Pediatrics, Division of Pediatric Allergy,

Immunology, and Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN; and wDepartment of Pediatrics, Division of Pediatric Pulmonology, Allergy, and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Disclosure: There is no conflict of interest or other disclosures. Reprints: Christian Rosas-Salazar, MD, MPH, Department of Pedia-

trics, Division of Pulmonary Medicine, Allergy, and Immunology, Vanderbilt University School of Medicine, 2200 Children’s Way, DOT Suite 11215, Nashville, TN 37232 (e-mail: c.rosas.salazar@ vanderbilt.edu).

ORIGINAL INVESTIGATION

210 | www.bronchology.com J Bronchol Intervent Pulmonol � Volume 23, Number 3, July 2016

mailto:[email protected]

operating room, or one of the intensive care units (ICUs) (pediatric ICU, neonatal ICU, or cardiac ICU). Postprocedure notes are entered into the electronic medical record by the physician doing the bronchoscopy using the Olympus EndoWorks suite version 7.3 (Olympus America Inc., Center Valley, PA) within 1 hour after completing the procedure. A separate electronic database con- taining information about all flexible bronchos- copies is maintained at the hospital’s pulmonary function laboratory. Information in this electronic database is entered on the same day of the pro- cedures by the assisting respiratory therapist.

The size of the flexible bronchoscope, the type of airway used (eg, laryngeal mask airway, endo- tracheal tube, or tracheostomy), and the site of the BAL varies according to the procedure’s indica- tion and/or the patient’s clinical status. No specific protocol exists for conducting BALs at Children’s Hospital of Pittsburgh of UPMC. In general, 1 to 3 aliquots of 1 mL/kg of nonbacteriostatic normal saline (up to a maximum of 50 mL per aliquot) at room temperature are instilled through the working channel of the bronchoscope. Fluid is recovered immediately after each aliquot is instil- led (ie, no dwell time) using either continuous wall suction or handheld syringe suction, according to the physician’s preference. Samples are then pooled and sent to the hospital’s laboratory for cytologic and microbiological analyses.

Data Collection

We reviewed the 2 electronic databases described above to gather information on all flex- ible bronchoscopies with BAL conducted at Children’s Hospital of Pittsburgh of UPMC between January 2011 and December 2012 as described previously.10 We collected information on patient’s demographics, personnel performing the procedure, indication for and location of the procedure in the hospital, and technical aspects of the flexible bronchoscopy and BAL. We excluded from the analyses procedures in patients 21 years and above and those without information on the site of the BAL, the total volume instilled for the BAL, or the total volume recovered from the BAL. For patients who underwent >1 BAL dur- ing the study period, we only included the earliest procedure in analyses to maintain independence among observations. Likewise, in children who had >1 BAL during a single procedure, we only included data from the first lavage. This study was approved by the Institutional Review Board of the University of Pittsburgh (Pittsburgh, PA).

Statistical Analyses

Our predictor of interest was the site of the BAL. Our outcome of interest was the percent of fluid return (calculated as total volume recovered�100/total volume instilled). To assess whether there was any difference in the percent of fluid return between lobes, we first used 1-way analysis of variance with subsequent pairwise comparisons for unadjusted analyses. We tested the equality of variances between groups for the analysis of variance with the Levene’s test.

Next, we used multivariable linear regression for adjusted analysis. Because of the small sample size per group and to avoid model overfitting, we selected a priori the variables to be included in our main multivariable model [child’s age, sex, and type of suction (continuous wall vs. handheld syringe)] based on published literature.10,16

Lastly, to control for multiple comparisons, we used the Tukey-Kramer test.

To further investigate the possibility of con- founding, we then built exploratory models by adding one of the following covariates to our main model: total volume instilled for the BAL (mL), location of the procedure in the hospital (any ICU vs. other), size of the flexible bronchoscope’s suc- tion channel (1.2 vs. 2.0mm), physician’s level of training (fellow vs. attending), and indication for the procedure (cough or wheezing vs. other). All statistical analyses were carried out using SAS 9.4 (SAS Institute, Cary, NC).

RESULTS

A total of 647 BALs via flexible bronchoscopy were performed at our institution during the study period. After excluding those performed in adults (n=5), those without information on the site of BAL (n=10) or percentage of volume recovered from BAL (n=10), and those conducted as fol- low-up procedures (n=93), 529 (B81.8%) of the 647 observations remained for analyses.

The baseline characteristics of children included in this study can be found in Table 1. The majority of BALs were performed in males, in a non-ICU setting, by fellows, using a flexible bronchoscope with a 1.2-mm suction channel, and through a laryngeal mask airway. A total of 20 physicians (10 fellows and 10 attending physicians) participated in the BALs. The RML was the most common site for the BAL (n=424, 80.2%). This was followed by the LIN (n=46, 8.7%). All the other lobes accounted for <12% of the procedures.

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To facilitate statistical analyses, we collapsed the different lobes into 4 groups on the basis of their anatomic location as follows: (1) right or left upper lobe other than LIN (R/L-UL, n = 21), (2) RML (n = 424), (3) LIN (n = 46), and (4) right or left lower lobe (R/L-LL, n = 38). The variances of these 4 groups seemed to be equal despite the differences in sample sizes (P = 0.08 for the Levene’s test).

The mean (SD) percent of fluid return was 52.1 (14.4) for the RML, 50.7 (16.0) for the LIN, 50.5 (18.6) for the R/L-UL, and 42.2 (18.7) for the R/L-LL (Fig. 1). The difference in these means was statistically significant (P = 0.002). The R/L-LL had a significantly lower fluid return when compared with each of the other lobes (P < 0.05 for all pairwise comparisons involving the R/L-LL); in contrast, there was no significant difference in fluid return between the other lobes (P > 0.6 for all other pairwise comparisons).

In view of the above findings, we then pro- ceeded to perform multivariable linear regression models using the R/L-LL as the reference

category. The significant lower fluid return of the R/L-LL persisted even after adjustment for potential confounders. For instance, there was an estimated 11.1% (95% confidence interval, 6.2-16.1; P<0.001) increase in the fluid return in the RML and an estimated 9.5% (95% confidence interval, 3.2-15.8; P=0.003) in the LIN when compared with the R/L-LL in our main multi- variable analysis adjusting for the child’s age, sex, and the type of suction (Table 2). We obtained similar results in our exploratory analyses adjusting for other potential confounders (data not shown).

The differences in fluid return of the R/L-LL with the RML and LIN remained significant after adjustment for multiple comparisons (P < 0.001 and 0.02 in our main model, respectively), although the difference with the R/L-UL did not (P = 0.1), likely because of the small sample size.

DISCUSSION

Despite being one of the most common invasive procedures performed by pediatric pul- monologists worldwide, the technique for BAL via flexible bronchoscopy is not standardized in children.7,17–19 Although the decision of where to perform a BAL must be on the basis of the child’s clinical and/or radiologic findings, the site of the BAL can substantially affect the efficacy of this procedure. Unfortunately, only scant evi- dence on the optimal site of the BAL exists.6 In our study, we found that the RML and LIN seem to have a similar BAL fluid return. In

TABLE 1. Baseline Characteristics of Pediatric Flexible Bronchoscopies With Bronchoalveolar Lavage (BAL) Included in the Study (n = 529)

Child’s age (y) 5.6 (5.2) Female sex 223 (42.2%) Procedure performed in an intensive care unit

55 (10.6%)

Procedure performed by a fellow in-training supervised by an attending

299 (57.5%)

Indication for the procedure Cough or wheezing 295 (55.8%) Cystic fibrosis 24 (4.5%) Respiratory failure 58 (10.9%) Lung transplant 14 (2.7%) Immunosuppression 15 (2.8%) Other 123 (23.3%)

Flexible bronchoscope with a 2.0-mm suction channel

106 (20.1%)

Flexible bronchoscopy through a laryngeal mask airway

402 (79.9%)

Continuous wall suction 384 (72.6%) Total volume instilled for BAL (mL) 37.7 (21.8) Site of the BAL Right upper lobe 10 (1.9%) Right middle lobe 424 (80.2%) Right lower lobe 19 (3.6%) Left upper lobe 11 (2.1%) Lingula 46 (8.7%) Left lower lobe 19 (3.6%)

Data are presented as the mean (SD) for continuous variables and number (%) for binary variables.

Percentages were calculated for procedures with complete data.

FIGURE 1. Box plots of the percentage of fluid return according to site of the bronchoalveolar lavage (BAL) via flexible bronchoscopy in children (n = 529). The box-plots display the median (middle line), the mean (diamond), the interquartile range (box hinges), and the minimum and maximum value of the data (upper and lower whiskers).

Rosas-Salazar et al J Bronchol Intervent Pulmonol � Volume 23, Number 3, July 2016

contrast, the lower lobes have a lower fluid return when compared with the other ones.

In a study of 5 children aged 2 years and below, Midulla et al20 also found that the fluid return from the RML is similar to that of the LIN. However, this study was limited by the very small sample size, the lack of comparison with other lobes, and the use of unadjusted analysis. Furthermore, 4 of these 5 children had no evi- dence of lower airway or parenchymal lung dis- ease, and it is believed that the fluid recovery may differ between healthy children and those with acute or chronic respiratory illnesses.18 To the best of our knowledge, no other studies in this field have been published in children. There is also very limited data in adults, with most16,21,22 but not all23 studies reporting a higher fluid return in the RML or LIN when compared with other lobes. Nonetheless, the RML and LIN are fre- quently cited as the lobes with the best fluid return in both pediatric and adult guidelines.6,7,24

We can only speculate on the reasons for our findings as the dynamics of fluid return are complex.25 It is possible that the low recovery in the lower lobes is related to their larger surface area, the difficulty in wedging with the flexible bronchoscope, or their dependent situation in the supine position.15,22

Our study has considerable strengths, such as the large number of procedures reviewed and the statistical methods accounting for potential confounders. Most importantly, our study adds to the small but necessary literature comparing the different techniques of BAL in children. Indeed, as noted in the recently published American Thoracic Society guidelines for flexible bronchoscopy in children,6 most current recom- mendations for this procedure are based on clinical experience, as only very few pediatric hypothesis-driven studies have been conducted.

We also acknowledge several limitations to our findings. First, we were unable to determine

whether the difference in percent of fluid return between the lower lobes and the other ones (which ranged from 8.7% to 11.1% in our study) was associated with a higher diagnostic yield, as we lacked patient-related outcomes. It has been previously suggested that a higher fluid return is an adequate marker of optimal alveolar sam- pling and procedure adequacy,13,15,26 although this has not been sufficiently studied. In an adult study comparing 2 different BAL suction tech- niques, a higher fluid return of only 8% was associated with 17% higher number of final diagnoses.8 In all groups studied, a higher per- centage of BAL fluid return was associated with an increased likelihood of establishing a diag- nosis based on the BAL, which suggests that our results may be clinically significant.8 In addition, larger BAL samples could potentially provide investigators with more cells for culture and analyses and, thus, be important to advance high-quality pediatric pulmonary research.9,26

Second, we were unable to analyze the right and left upper or lower lobes separately because of the small sample sizes in each group. Third, as it is the case with any other observational study, selection bias could have affected our results. The majority of the procedures in our sample (80.2%) were performed in the RML. This is likely due to the fact that most pulmonologists are taught that this is the best lobe for BAL (despite the little evidence to support this belief, as noted above).7 However, it is also possible (albeit unlikely) that these BALs were performed in the RML because this was the site most severely affected or the lung disease was only localized to this lobe (which could have biased our results). Fourth, there could be residual confounding by measured or unmeasured vari- ables. Because of the small sample sizes in each group, we were not able to include more than a few variables per multivariable model. However, we obtained almost identical results to our main model (that included a priori selected covariates) in our exploratory models that adjusted for a variety of potential confounders, which further supports our conclusions. Therefore, it is unlikely that any of the variables included in our explor- atory models (such as child’s age, sex, type of suction, total volume instilled for the BAL, ICU status, size of the flexible bronchoscope’s suction channel, or physician’s level of training) could have biased our results. Unfortunately, we were unable to fully adjust for the diagnostic indication for the procedure, as the databases we used did

TABLE 2. Main Multivariable Analysis of the Site of the Bronchoalveolar Lavage (BAL) and Percent of Fluid Return

Site of the BAL Percent of Fluid Return

Right or left lower lobe Reference Right middle lobe 11.1 (6.2-16.1), <0.001 Lingula 9.5 (3.2-15.8), 0.003 Right or left upper lobe* 8.7 (0.9-16.5), 0.03

Data presented as b coefficient (95% confidence interval), P-value. Multivariable model adjusted for child’s age, sex, and type of suction. *Left upper lobe other than lingula.

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not accurately record the patient’s specific lung disease. For instance, nonspecific symptoms (such as wheezing and cough) accounted for B55% of the indications, thus residual confounding by the specific lung disease is a possibility. Likewise, the interprovider and intraprovider variability, the dwell time to aspirate the fluid, the generation number where the tip of the flexible bronchoscope was wedged, or the presence of positive-pressure ventilation are all factors that were not included in our analyses and may have affected our results.

In summary, our data support the concept that BAL of the lower lobes will have a decreased percent fluid return than a lavage performed elsewhere. Although widely stated in both pediatric and adult literatures, there have been little data to date, to back up the belief that the RML or LIN are the sites with the highest fluid return. The decision of where to perform a BAL should be on the basis of the patient’s clinical and/or radiologic findings. However, when there is no clear reason for an alternate choice, our objective data suggest that the BAL should be performed in the RML or LIN. More studies comparing the different techniques for flexible bronchoscopy with BAL in children are needed to standardize this common procedure, enhance its diagnostic yield, and improve the care of children with respiratory diseases.

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