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Instructions Complete a full draft of your research paper. This should have all the sections of the final paper including: 1-Hypothesis (research questionor statement), introduction and quality of literature (references) 30% 2-Method of study and body of paper 30% 3-Discussion / conclusion, abstract 30% 4-AMA format, spelling/grammar, structure 10% ((Attached is a copy of a sample paper from a former student who won an ARCF foundation award for her paper.)) 5- please use the 10 articles that i attached 6- you should at least write one or tow paragraphs of each article
Flexible Bronchoscopy Is Safe and Effective in Adult Subjects Supported With Extracorporeal Membrane Oxygenation

Nirmal S Sharma MD, Timothy Peters MD, Tejaswini Kulkarni MD MPH, Charles W Hoopes MD, Scott C Bellot MD, Keith M Wille MD MSPH, and Enrique Diaz-Guzman MD

BACKGROUND: Previous studies have demonstrated the safety of flexible bronchoscopy (FB) in mechanically ventilated subjects. However, the safety of FB in adult subjects receiving extracor- poreal membrane oxygenation (ECMO) has not been described previously. METHODS: A retro- spective review was conducted of all adult subjects who underwent FB while receiving ECMO support at the University of Alabama at Birmingham Hospital from January 1, 2013, to December 31, 2014. Physiologic variables, pre- and post-FB ECMO, and ventilator settings were recorded. RESULTS: 79 adult subjects underwent FB receiving ECMO with a total of 223 bronchoscopies. The most common indications for bronchoscopy included diagnostic evaluation of infection in subjects with pneumonia (29%) and clearance of excessive secretions (22%). In 70% of subjects, moderate or greater amounts of secretions were noted. FB yielded positive culture data in 37 subjects (47%), which resulted in a change to the antibiotic regimen in 14 subjects (38%) with positive culture data. No significant differences in mean PaO2/FIO2, mean ECMO flow, mean sweep gas, ventilator settings, or hemodynamic parameters (heart rate, oxygen saturation, and mean blood pressure) were noted before and after FB. Complications were mild and transient: blood-tinged secretions after FB in 21% cases, which resolved spontaneously, intraprocedural hypoxemia in 2.2% of cases, and dysrhythmia in <1% of cases. There were no episodes of ECMO cannula dislodgement or inadvertent extubation. CONCLUSIONS: FB can be used safely in adult subjects supported with ECMO and is not associated with significant hemodynamics changes, bleeding, or mechanical complications during ECMO support. Key words: ECMO; bronchoscopy; ARDS; cardio- respiratory failure; veno-venous ECMO; veno-arterial ECMO. [Respir Care 2016;61(5):646–651. © 2016 Daedalus Enterprises]

Introduction

In the past decade, there has been an increase in the utilization of extracorporeal membrane oxygenation (ECMO) to support critically ill patients with cardiopul-

monary failure.1,2 ECMO-supported patients often have respiratory infections and increased airway secretions com- plicating the course of their illness.3 To aid in the diagno- sis of respiratory infections and facilitate secretion clear- ance, flexible bronchoscopy (FB) has become a necessary tool in modern critical care practice.4,5 Although FB is a relatively safe procedure in most patients, it can be asso- ciated with complications, such as worsening hypoxemia, endotracheal tube (ETT) dislodgement, and airway trauma, in critically ill subjects receiving mechanical ventilation.6-12

Additionally, FB may entail a greater risk of complications in ECMO patients due to the use of systemic anticoagu- lation and greater degree of illness in these patients.13,14

Previous studies have demonstrated the safety of FB in subjects receiving mechanical ventilation.15,16 However, its safety profile in adult patients supported with ECMO is not well established.

Drs Sharma, Peters, Kulkarni, Wille, and Diaz-Guzman are affiliated with the Division of Pulmonary and Critical Care Medicine, and Drs Hoopes and Bellot are affiliated with the Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

The authors have disclosed no conflicts of interest.

Correspondence: Enrique Diaz-Guzman MD, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birming- ham, AL 35294-0006. E-mail: diaze@uab.edu.

DOI: 10.4187/respcare.04456

646 RESPIRATORY CARE • MAY 2016 VOL 61 NO 5

In this retrospective study, we present our experience with FB in adult subjects supported with ECMO and an- alyze its safety and utility in this cohort. We hypothesize that FB is a safe and well-tolerated procedure for patients receiving ECMO support.

Methods

Subject Population and Data Collection

We performed a retrospective review of all ECMO sub- jects who underwent FB for any indication at the Univer- sity of Alabama Hospital at Birmingham from January 1, 2013, to December 31, 2014. This project was reviewed and approved by the University of Alabama Hospital at Birmingham institutional review board for human research (Protocol X140909006).

Subject Selection

A total of 141 subjects were supported with ECMO for any indication during the period of interest. Of these, 79 subjects underwent a total of 223 FBs.

Outcome Measures

Variables collected before and after bronchoscopy in- cluded demographics, FB indication, vital signs, ventilator settings, ECMO settings, chest radiograph changes, and complications. Vital signs and ventilator and ECMO set- tings recorded immediately before and 2 h after the pro- cedure were utilized for this study. Chest radiograph re- ports as interpreted by attending radiologists before ECMO and the first after FB were used for analysis.

ECMO Management

At our institution, an internal jugular double-lumen can- nula is used for venovenous (VV) support, and a jugulo- femoral route is preferred for venoarterial (VA) ECMO in a majority of patients. Less commonly, a mixed configu- ration (combination of the above) is utilized, according to the patient’s condition and oxygen requirement. Antico- agulation is managed per protocol17 and monitored using anti-factor Xa and thromoboelastography. An anti-factor Xa of 0.2–0.4 IU/ml and R time on thromoboelastography of 2.5–3 times the control value are usually maintained. No changes were made to anticoagulation before or after FB. Either a supervised critical care trainee or the attend- ing physician performed FB. In addition, a critical care nurse, respiratory therapist, and perfusionist were also pres- ent during the procedure.

Flexible Bronchoscopy

At our institution, FB is performed via the ETT, trache- ostomy, or the oral route (in extubated patients) while the patient is receiving ECMO support. The ventilator FIO2 is transiently increased to 100% for the duration of the pro- cedure and lowered back to baseline as tolerated after the procedure. Bronchoalveolar lavage (BAL) is performed if indicated. Both therapeutic (distal tip 5.9 mm, insertion tube diameter of 6.0 mm, working channel of 3.0 mm) and diagnostic bronchoscopes (distal tip 4.8 mm, insertion tube diameter of 4.9 mm, working channel of 2.0 mm) are used for FB in ECMO patients based on the clinical indications. In patients receiving mechanical ventilation, usually an ETT and tracheostomy tube size �8 mm in diameter is preferred for performing FB. Before FB, patients are pre- medicated with sedative agents, such as fentanyl, midazo- lam, or propofol, as clinically determined by the physician. Occasionally, in patients with recent lung transplants who are receiving ECMO, sedation-free awake bronchoscopy is performed. Lidocaine is atomized or nebulized via the ETT/tracheostomy before scope insertion. Most FBs are performed in the recumbent or semirecumbent position. Mean duration of FB is usually 5–15 min, depending on the indication of FB, need for BAL, and amount of secre- tions present. Although the average time period for each bronchoscope insertion is 60–90 s, this may be increased to 2–5 min if BAL is being performed. Culture specimens

QUICK LOOK

Current knowledge

In the past decade, there has been an increased utiliza- tion of ECMO to support patients with severe cardio- respiratory failure. Flexible bronchoscopy has become an important tool to diagnose respiratory infections and manage airway secretions in these critically ill patients receiving ECMO. Although the safety of flexible bron- choscopy in mechanically ventilated patients has been well described, its safety and utility have not been es- tablished in adult patients supported with ECMO.

What this paper contributes to our knowledge

Flexible bronchoscopy is safe in adult subjects sup- ported with ECMO. Flexible bronchoscopy is not associated with significant hemodynamics changes, bleeding, and/or mechanical complications during ECMO support. Flexible bronchoscopy during ECMO support facilitates pulmonary secretion clearance and improves antibiotic selection in subjects with respi- ratory infections.

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are obtained from bronchial washes, BAL (100 mL of sterile saline is used in 4 sequential aliquots of 25 mL each) or sometimes using a protected specimen brush. Although most of our patients are supported with the pressure con- trol continuous mandatory ventilation mode during ECMO support, we have not found it to be superior (in terms of reduced complication rates) compared with other modes of ventilation during FB.

Statistical Analysis

We performed descriptive analyses of measured vari- ables using proportions, means � SD, or medians with interquartile ranges as appropriate. Changes in parameters before and after FB were compared using an unpaired 2-way t test or Mann-Whitney test. A P value of �.05 was considered significant. Statistical analyses were performed with JMP 10.0 (SAS Institute, Cary, North Carolina).

Results

Baseline Characteristics

Of 141 patients supported with ECMO during the study period, 79 underwent FB and were included in the analy- sis. A total of 223 FB procedures were performed: 76 (34.1%) of subjects underwentoneFB,48(21.4%)had2FBs,34(15.1%) had 3 FBs, and 65 (29.4%) had �4 procedures. Indications for ECMO support and use of FB are detailed in Table 1. Clearance of excessive secretions and identification of pathogens involved in pneumonia were the most common indications for FB. Median age was 46 y (range 19–83 y). A majority of subjects (59%) were male. Most subjects (71%) were supported using VV ECMO, whereas 23% were supported by VA ECMO and 6% by a mixed ECMO configuration. A low tidal volume ventilation strategy was preferred for all subjects. Pressure control continuous man- datory ventilation was the ventilatory mode used in 70% of subjects (Table 2). Whereas a majority of bronchosco- pies (56%) were performed via the ETT, 42% were per- formed via a tracheostomy, and 2% were performed via the oral route. BAL was performed in 34% of the proce- dures. Mean PaO2/FIO2 ratio before ECMO initiation was 63 � 22.1. Qualitative bronchoscopy findings included no secretions in 4%, mild secretions in 25%, and moderate or greater secretions in 71%.

Bronchoscopy Outcomes

Mean pre-FB PaO2/FIO2 for all subjects was 164 � 133. The pre-FB PaO2/FIO2 was significantly lower in subjects supported with VV ECMO (149 � 109) as compared with those supported with VA ECMO (200 � 156) and mixed ECMO configurations (229 � 224), P � .009. Overall,

mean PaO2/FIO2 did not change significantly after FB (178 � 163, P � .35) (Table 3).

Mean pre-FB ECMO flow was similar for all ECMO configurations. Overall, no significant change in ECMO flow was noted before versus after FB. However, post-FB ECMO flow was significantly higher in subjects with the mixed configuration (4.3 � 0.83 L/min) group as com- pared with the VA (3.74 � 0.96 L/min) and VV (3.8 � 0.6 L/min) ECMO groups (P � .009). Likewise, baseline

Table 1. Indications for Initiation of Extracorporeal Membrane Oxygenation Support and Use of Flexible Bronchoscopy

Indications Percentage

For ECMO Bacterial pneumonia 29 Influenza pneumonia 18 Cardiogenic shock 13 Combined bacterial and viral pneumonia 8 Respiratory failure not otherwise specified 6 Trauma 6 Bridge to transplantation 6 Postoperative complication 6 Other 3 Pulmonary embolus 5

For FB Pneumonia 29 Abnormal chest radiograph 20 Excessive secretions 22 Atelectasis 7 Tracheostomy placement 6 Hemoptysis 5 Refractory hypoxemia 4 Diffuse parenchymal disease 4 Airway inspection 2 Dislodged endotracheal tube 1

ECMO � extracorporeal membrane oxygenation FB � flexible bronchoscopy

Table 2. Mode of Ventilation Used During Extracorporeal Membrane Oxygenation Support

Mode of Ventilation Percentage of Subjects

PC-CMV 70 VC-CMV 22 PSV 3 PC-IMV 3 VC-IMV 1

1% of subjects were extubated and off mechanical ventilation while on extracorporeal membrane oxygenation support. PC-CMV � pressure control continuous mandatory ventilation VC-CMV � volume control continuous mandatory ventilation PC-IMV � pressure control intermittent mandatory ventilation VC-IMV � volume control intermittent mandatory ventilation PSV � pressure support ventilation

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pre-FB sweep gas flow was higher in the mixed configu- ration group (5.4 � 1.9 L/min) as compared with the VA (2.8 � 1.6 L/min) and VV (4.1 � 1.9 L/min) (P � .001) ECMO groups. Again, no significant differences were ob- served between the pre- and post-FB sweep gas rates (see Table 3). Ventilator changes before and after FB were also evaluated. Overall, no significant differences in mean FIO2 (0.68 � 0.23 vs 0.64 � 0.22, P � .09), PEEP (9.5 � 3.1 cm H2O vs 9.4 � 4.16 cm H2O, P � .53), and peak airway pressures (33.2 � 7.65 cm H2O vs 32.3 � 7.65 cm H2O, P � .25) were noted before and after the FB. Additionally, no significant variations were observed in the pre- and post-FB vital signs, including mean blood pressure, heart rate, and oxygen saturation (see Table 3). These results did not differ when compared by the type of ECMO configuration. FB (BAL and bron- chial washings) yielded positive culture data (yeast was excluded) in 37 subjects (47%), which resulted in a change to the antibiotic regimen in 14 subjects (38%) with posi- tive culture data (Table 4).

Complications

Chest radiographs before and after the procedures were compared: 63.2% remained unchanged, 22.2% showed im-

provement in opacities, and 14.6% showed worsening of opacities. In addition, 4 cases of new pneumothorax and 5 cases of worsening of existing pneumothorax were noticed on the radiograph following the procedure. Of the 4 new cases of pneumothorax, one occurred after internal jugular double-lumen cannula placement that preceded the FB, 2 were after FB-guided percutaneous tracheostomy, and one was after thoracentesis before FB. In these cases, the chest radiographs were performed after FB; it is unclear whether pneumothorax was precipitated by FB or due to the pre- ceding procedures. Given that the risk of pneumothorax associated with percutaneous tracheostomy (0.5–12.5%),18

thoracentesis(4.6–7.8%),19 and internal jugular double-lu- men cannula placement (5–19%)20 is higher than the risk with FB without a trans-bronchial biopsy (�1%),21 it is possible that the pneumothorax was not a consequence of FB. The presence of preexisting pneumothorax before FB was known in 7 cases. Of these, 5 cases had worsening of existing pneumothorax, and 3 occurred in subjects who underwent BAL. All subjects with known pneumothorax before FB had preexisting small (8.5 French) or medium bore (14 French) chest tube catheters in place before FB. The intraprocedural adverse event rate was low; 96% of the FBs had no immediate procedural complication. Five subjects had hypoxia during the procedure. Of these, per- sistent hypoxia (oxygen desaturation to 60% on pulse oxi- metry) occurred in one case, requiring abortion of the procedure. Two subjects had moderate hypoxia (70 and 74%, respectively, on pulse oximetry), and another 2 had mild hypoxia (82 and 86%, respectively, on pulse oxime- try). All of these 4 episodes of hypoxia improved with transient withdrawal of the bronchoscope. Whereas 2 sub- jects had transient arrhythmias (one bradycardia and one atrial fibrillation), another 2 had reduction in ECMO blood flow due to excessive coughing during the procedure. All of the above events resolved immediately after withdrawal of the bronchoscope. Blood-tinged secretions were noted

Table 3. Bronchoscopy Outcomes on Extracorporeal Membrane Oxygenation Support

Pre-FB 2 h Post-FB P

Mean PaO2/FIO2 Overall 164 � 133 178 � 163 .35 VV subjects 149 � 109 156 � 118 .54 VA subjects 200 � 156 203 � 168 .93 Mixed configuration subjects 229 � 224 317 � 343 .36

Mean ECMO flow, L/min Overall 3.85 � 0.69 3.86 � 0.70 .97 VV subjects 3.84 � 0.60 3.83 � 0.60 .93 VA subjects 3.86 � 0.90 3.74 � 0.96 .58 Mixed configuration subjects 3.99 � 0.89 4.3 � 0.83 .24

Mean ECMO sweep gas flow, L/min Overall 4.01 � 2 4.0 � 2.05 .97 VV subjects 4.13 � 1.97 4.11 � 2.01 .92 VA subjects 2.84 � 1.62 2.87 � 1.59 .94 Mixed configuration subjects 5.4 � 1.99 5.4 � 2.2 .94

Mean ventilator FIO2 0.68 � 0.23 0.64 � 0.22 .09 Mean PEEP, cm H2O 9.5 � 3.1 9.4 � 4.16 .53 Mean peak pressure, cm H2O 33.2 � 7.65 32.3 � 7.65 .25 Mean arterial pressure, mm Hg 84 � 13 82 � 11 .14 Mean heart rate, beats/min 97 � 19 96 � 20 .81 Mean oxygen saturation, % 95 � 5 99 � 6 .29

Data are reported as means � SD. FB � flexible bronchoscopy VV � venovenous extracorporeal membrane oxygenation VA � venoarterial extracorporeal membrane oxygenation ECMO � extracorporeal membrane oxygenation

Table 4. Flexible Bronchoscopy Culture Data

Pathogen Percentage

Pseudomonas 24 Enterobacter 12 Klebsiella 12 Serratia 10 Methicillin-resistant Staphylococcus aureus 10 Acinetobacter 7 Aspergillus 7 Influenza A 5 Streptococcus pneumoniae 2 � hemolytic streptococci 2 Vancomycin-resistant enterococcus 2 Achromobacter 2 Methicillin-sensitive S. aureus 2

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in 21% of the FBs. Moderate bleeding requiring cold sa- line instillation occurred in one FB, and minor bleeding requiring no intervention occurred in 4 procedures.

ECMO Outcomes

The overall ICU survival in our cohort of ECMO sub- jects who underwent FB was 75%. Subjects supported with mixed ECMO configuration (100%) had a higher ICU survival than those with VV (73%) and VA (72%) (Table 5). Overall ICU survival for all ECMO subjects at our institution for the study period was 70%.

Discussion

Fiberoptic bronchoscopy has become an indispensable tool for both diagnostic evaluation and therapeutic inter- vention in modern day critical care practice.22 In most patients, it is a relatively low-risk procedure, and previous studies have demonstrated its safety.15,23 However, there are no studies validating the safety of FB in adult patients receiving ECMO. Data from the Extracorporeal Life Sup- port Organization1 suggest that the risk of spontaneous pulmonary hemorrhage in subjects receiving ECMO is 8.1% and may increase to 19% in subjects undergoing a proce- dure. Additionally, dislodgement of the ECMO cannula and/or loss of ECMO flow during coughing spells with FB may also occur.24

Our study confirms that FB can be safely used in adults supported with ECMO for cardiorespiratory failure. We found that FB in subjects supported with ECMO was not associated with significant worsening of hemodynamic pa- rameters or escalation of ventilator or ECMO support. None of the subjects had a major complication involving the ECMO circuit (ie, cannula dislodgement). Although 21% of the subjects had bloody secretions after FB, this was self-limited and resolved without any intervention. The majority of chest radiographs remained unchanged after the procedure, although improvement in imaging was observed among subjects who had mucous plugging or

copious secretions. As expected, worsening of imaging was observed in subjects who underwent BAL. Previous studies have shown that the prognosis of subjects with respiratory failure due to infections depends on the prompt identification of the causative organisms.25,26 In our co- hort, FB resulted in positive culture data in 47% of subjects, and a subsequent change in antibiotic therapy occurred in 38% of subjects with positive culture data. This is in line with the FB culture yield of 35–71% reported in studies conducted in critically ill subjects not receiving ECMO.8,27-30

Our literature search did not yield any studies evaluat- ing the safety of bronchoscopy in adult ECMO patients. However, our results were comparable with those of 3 studies describing the safety of FB in pediatric ECMO subjects. In 1993, Karlson et al31 reported no bleeding complications after FB in 14 pediatric subjects receiving ECMO undergoing FB. In their cohort, 14% of subjects had worsening of static lung compliance assessed on me- chanical ventilation, and 20% had radiographic worsening after FB. Although we did not notice significant worsening of static lung compliance, 14.6% of the post-FB chest radiographs worsened. Similarly, in a retrospective study of 79 pediatric subjects receiving ECMO, Kamat et al32

showed that FB was associated with low incidence of com- plications. As in our study, 30% of the ECMO subjects in their cohort also had blood-tinged secretions, although none had any mild to moderate bleeding episodes. Also, no new pneumothorax was reported in their study. The differences in bleeding between the studies may be related to the populations (adult vs pediatric) studied or the level of anticoagulation used. More recently, Prentice and Mas- tropietro33 demonstrated the safety of FB in pediatric sub- jects receiving ECMO for cardiac failure. Although their sample size was relatively small, no major bleeding was reported after FB in their cohort. Likewise, FB outcomes and/or complication rates were similar between subjects supported with VA or VV ECMO in our cohort.

Our study is not without limitations. Although our re- sults are based on objective parameters, it is unclear whether any improvement or worsening of radiographic findings after FB is a result of the procedure or rather the under- lying disease process. Additionally, given the retrospec- tive nature of the study, results may be biased by docu- mentation or collection errors.

Conclusions

We conclude that FB can be safely performed in adult patients supported with ECMO. FB is not associated with significant hemodynamics changes, bleeding, and/or me- chanical complications during ECMO support. Addition- ally, FB may improve clinical care by facilitating pulmo- nary secretion clearance and by possibly increasing

Table 5. Extracorporeal Membrane Oxygenation Outcomes

ICU Survival in Subjects Receiving ECMO Who

Underwent FB (%)

ICU Survival in Subjects on ECMO Who Did Not

Undergo FB (%)

Overall 75 65 VV subjects 73 76 VA subjects 72 60 Mixed configuration 100 67

ECMO � extracorporeal membrane oxygenation FB � flexible bronchoscopy VV � venovenous extracorporeal membrane oxygenation VA � venoarterial extracorporeal membrane oxygenation

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diagnostic yield and improving antibiotic selection in pa- tients with respiratory infections.

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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 (P1 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.

J Bronchol Intervent Pulmonol � Volume 23, Number 3, July 2016 Site of BAL Via Flexible Bronchoscopy

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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 (P0.6 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

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Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

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), 25 breaths·min−1 (or >20 breaths·min−1 if use of accessory respiratory muscles was present) in patients requiring oxygen at ⩾6 L·min−1 to attain a pulse oximetry measurement of >92%. Patients were not included if they had contraindications to bronchoscopy with BAL (including respiratory acidosis).

The Ethics Committee of the French Society of Intensive Care (SRLF, Société de Réanimation de Langue Française, Paris, France) approved the study (approval number: 12-374).

HFNC was delivered via a dedicated high-flow delivery system (Optiflow; Fisher & Paykel, Auckland, New Zealand). Oxygen flow and inspiratory oxygen fraction (FIO2) were adjusted to obtain a pulse oximetry measurement >92%. Bronchoscopy with BAL was performed under local anaesthesia and with careful monitoring. Patients were asked to rate their dyspnoea according to a visual analogue scale, and after each BAL, the operator rated the eventual discomfort related to HFNC. Baseline and subsequent arterial blood gases were collected. Failure of the oxygenation strategy was considered if NPPV or invasive ventilation were needed within 24 h of the procedure. The study centres followed similar classical intubation criteria [10].

Data were compared according to failure or success of HFNC using the Mann–Whitney U-test, the paired t-test and Fisher’s exact test, as appropriate. Changes in physiological measures over time were assessed using one-way ANOVA for repeated measures.

30 ICU patients (median (interquartile range (IQR)) age 54 (46–68) years) were included in the study. Demographics, physiological data and patient outcomes are detailed in table 1. Within 24 h, five (16.7%)

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patients experienced failure of the oxygenation strategy, between 2.5 and 14 h after BAL (four required NPPV, one of whom further required endotracheal intubation (ETI), and one was directly intubated). Reasons were onset of hypercapnia after the procedure (two patients) and worsening hypoxaemia (three patients). There was no significant difference in the patients’ baseline characteristics when comparing success and failure.

During bronchoscopy, median (IQR) HFNC flow was 50 (50–60) L·min−1 with an FIO2 of 1 (0.8–1). Median volume instilled was 150 (140–150) mL, with a median recovered volume of 41 (27–53)%. Tolerance was remarkable since no procedure was interrupted because of discomfort or respiratory failure. Variations in arterial oxygen saturation measured by pulse oximetry were minute, from a median of −1% 10 min after BAL to +2% 30 min after. Transient desaturation below 88% only occurred in two patients without compromising their respiratory status and they rapidly recovered. No other per procedure adverse events were reported. Dyspnoea was evaluated in all but four patients (because of a language barrier). Although it increased immediately after bronchoscopy (from a median (IQR) of 4.2 (2.5–6.8) to 6.1 (4.2–8.9)), dyspnoea returned to baseline level within the first hour post-procedure (4.5 (2.7–6.3); p=0.007). Operators reported no discomfort linked to the device (median (IQR) score 10 (7–10)).

BAL enabled a diagnosis to be reached in 21 patients (70%), mainly pneumonia in 14 patients, including eight cases of pneumocystis pneumonia. As a result, treatment was modified in 19 (63.3%) patients, either de-escalation (n=7, 23.3%), initiation of antimicrobial therapy (n=7), or initiation of an immunosuppressive therapy (n=7).

Eight patients required HFNC for more than 4 days of continuous use. A total of six (20%) patients underwent ETI during their stay, two of them in the first 24 h (included among the patients mentioned as experiencing failure of the oxygenation strategy), the others underwent ETI after a median (IQR) of 135 (111–222) h post-bronchoscopy, because of worsening of their respiratory disease.

ICU mortality was 16.7%, as four patients died in the ICU within a median (IQR) of 20 (15–25) days after the procedure. All deaths followed withdrawal of life support therapy. Median (IQR) ICU stay was 5 (3–9) days.

Here, we showed that HFNC enabled all BAL procedures to be completed uneventfully. BAL was remarkably well tolerated, with dyspnoea score returning to the baseline value only 1 h after the procedure.

TABLE 1 Demographics, physiological data and patient outcomes

Total Procedure success Procedure failure p-value

Subjects n 30 25 5 Age years 54 (46–68) 54 (46–61) 70 (38–76) 0.94 Male sex 18 (60) 15 (60) 3 (60) 1 SAPSII score 36 (27–43) 36 (27–43) 35 (24–66) 0.66 ODIN score 1 (1–2) 1 (1–2) 1 (1–1) 1 Prior HFNC 18 (60) 16 (64) 2 (40) 0.36 Baseline physiological data Respiratory rate breaths·min−1 28 (23–34) 28 (22–35) 25 (25–32) 0.37 Heart rate beats·min−1 95 (88–113) 95 (89–111) 96 (71–113) 0.72 Systolic blood pressure mmHg 131 (119–141) 129 (119–141) 135 (116–157) 0.37

Baseline arterial blood gases Administered flow L·min−1 15 (9–50) 15 (9–60) 9 (5–50) PaO2/FIO2 169 (145–196) 169 (148–200) 135 (113–197) 0.31 PaO2 mmHg 90 (74–123) 97 (82–140) 68 (57–90) 0.47 FIO2 0.59 (0.46–0.7) 0.6 (0.47–0.85) 0.48 (0.36–0.65) 0.82 PaCO2 mmHg 36 (33–40) 36 (31–40) 40 (37–51) 0.04

Arterial blood gases after procedure PaO2/FIO2 99 (98–126) 99 (98–113) 122 (91–186) 0.12 PaO2 mmHg 116 (86–165) 122 (91–165) 77 (67–108) 0.27 FIO2 1 (0.8–1) 1 (0.9–1) 0.8 (0.6–1) 0.13 PaCO2 mmHg 36 (33–40) 36 (32–40) 38 (36–43) 0.18

Duration of HFNC h 61 (31–95) 64 (43–94) 14 (6–123) 0.11 Post-bronchoscopy length of hospital stay days 5 (3–9) 5 (3–7) 10 (5–18) 0.66 Survival 25 (83.3) 21 (84) 4 (80) 1

Data are presented as median (interquartile range) or n (%), unless otherwise stated. SAPSII: Simplified Acute Physiology Score II; ODIN: Organ Dysfunctions and/or Infection; HFNC: high-flow nasal cannula oxygen therapy; PaO2: arterial oxygen tension; FIO2: inspiratory oxygen fraction; PaCO2: arterial carbon dioxide tension.

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Although effectively improving oxygenation [2], NPPV is associated with a number of drawbacks [11]: patient intolerance that may lead to ETI [12]; and difficult access of the bronchoscope to the nares due to the facemask. Only two studies have previously evaluated HFNC during bronchoscopy, both with significant limitations. In a randomised control study, LUCANGELO et al. [7] showed that use of HFNC enabled maintenance of arterial oxygen tension/FIO2 during the procedure, with significantly better oxygenation with a 60 L·min−1 flow rate (versus 40 L·min−1). However, their population included non-hypoxaemic patients. A second randomised study compared HFNC to NPPV in hypoxaemic patients requiring bronchoscopy. Although SIMON et al. [8] found that application of NPPV was superior to HFNC with regard to oxygenation before, during and after bronchoscopy, the need for subsequent intubation was similar in the two groups. Moreover, HFNC may have been disadvantaged in their study. First, patients randomised to HFNC were possibly sicker in terms of respiratory failure. Second, bronchoscopy was performed through the mouth, which was maintained open using a bite-block. Hence, positive pressure was substantially reduced [9, 13].

In our series, an increase in respiratory support within the first 24 h was necessary in only 16.7% of patients (with NPPV for four out of five and ETI for two out of five). This figure compares fairly well with the 25% reported by CRACCO et al. [14]. In terms of immediate outcome, the increase in respiratory support was not different between HFNC and NPPV in the study by SIMON et al. [8] and was in the same range as our study (10% and 16.7%, respectively). SIMON et al. [8] limited the time frame of HFNC failure to 8 h after BAL. We were stricter, considering it up to 24 h. With the definition used by SIMON et al. [8], our number of failures drops to two. HFNC efficacy can be explained by several mechanisms, as it relieves respiratory distress symptoms and improves oxygenation by washing the dead space, reducing inspiratory nasopharyngeal resistance, and creating a moderate positive airway pressure effect [4].

Despite its prospective and multicentre design, our study has limitations. The limited number of patients is explained by the availability of noninvasive diagnostic strategies [15], but remains similar to other studies [2, 8]. Our study is not a randomised trial, as our interest was focused on the assessment of HFNC feasibility and safety in view of its potential use outside the ICU. Whereas NPPV is less commonly performed outside the ICU, HFNC is a much simpler device to implement. Further studies are required to evaluate its use outside the ICU and in which patients. NPPV would obviously be too costly and binding for every patient undergoing BAL. HFNC offers the advantage of being easily implemented in all patients.

To conclude, HFNC is a simple, effective, well-tolerated and safe technique to ensure oxygenation during nasal bronchoscopy with BAL in patients with hypoxaemic ARF.

@ERSpublications HFNC is an effective and safe method of oxygenation during nasal bronchoscopy with BAL in hypoxaemic ARF patients http://ow.ly/XAmtZ

Béatrice La Combe1,2,3, Jonathan Messika1,2,3, Vincent Labbé4, Keyvan Razazi5, Bernard Maitre6, Benjamin Sztrymf7, Didier Dreyfuss1,2,3, Muriel Fartoukh4,8 and Jean-Damien Ricard1,2,3 1AP-HP, Hôpital Louis Mourier, Service de Réanimation Médico-Chirurgicale, Colombes, France. 2INSERM, IAME, UMR 1137, Paris, France. 3Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France. 4AP-HP, Hôpital Tenon, Service de Réanimation Médico-Chirurgicale, Paris, France. 5AP-HP, Hôpital Henri Mondor, Service de Réanimation Médicale, Créteil, France. 6AP-HP, Hôpital Henri Mondor, Antenne de Pneumologie, Service de Réanimation Médicale, Créteil, France. 7AP-HP, Hôpital Antoine Béclère, Service de Réanimation Médico-Chirurgicale, Clamart, France. 8Sorbonne Universités, UPMC Univ Paris 06, Paris, France.

Correspondence: Jean-Damien Ricard, Service de Réanimation Médicale, Hôpital Louis Mourier, 92700 Colombes, France. E-mail: jean-damien.ricard@aphp.fr

Received: Aug 27 2015 | Accepted after revision: Jan 14 2016 | First published online: Feb 12 2016

Clinical trial: This study is registered at clinicaltrials.gov with identifier number NCT02523573.

Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com

Acknowledgements: Jonathan Messika, Muriel Fartoukh and Jean-Damien Ricard are members of the GREPI (French Group for Research and Education in Respiratory Infectious Diseases).

References 1 Lindholm CE, Ollman B, Snyder J, et al. Flexible fiberoptic bronchoscopy in critical care medicine. Diagnosis,

therapy and complications. Crit Care Med 1974; 2: 250–261. 2 Maitre B, Jaber S, Maggiore SM, et al. Continuous positive airway pressure during fiberoptic bronchoscopy in

hypoxemic patients. A randomized double-blind study using a new device. Am J Respir Crit Care Med 2000; 162: 1063–1067.

3 Antonelli M, Conti G, Rocco M, et al. Noninvasive positive-pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy. Chest 2002; 121: 1149–1154.

4 Ricard J-D. High flow nasal oxygen in acute respiratory failure. Minerva Anestesiol 2012; 78: 836–841.

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http://ow.ly/XAmtZ
http://ow.ly/XAmtZ
mailto:jean-damien.ricard@aphp.fr
https://clinicaltrials.gov/
erj.ersjournals.com
5 Sztrymf B, Messika J, Mayot T, et al. Impact of high-flow nasal cannula oxygen therapy on intensive care unit patients with acute respiratory failure: a prospective observational study. J Crit Care 2012; 27: 324.e9–e13.

6 Frat J-P, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015; 372: 2185–2196.

7 Lucangelo U, Vassallo FG, Marras E, et al. High-flow nasal interface improves oxygenation in patients undergoing bronchoscopy. Crit Care Res Pract 2012; 2012: 506382.

8 Simon M, Braune S, Frings D, et al. High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy – a prospective randomised trial. Crit Care 2014; 18: 712.

9 Parke R, McGuinness S, Eccleston M. Nasal high-flow therapy delivers low level positive airway pressure. Br J Anaesth 2009; 103: 886–890.

10 Messika J, Ben Ahmed K, Gaudry S, et al. Use of high-flow nasal cannula oxygen therapy in subjects with ARDS: a 1-year observational study. Respir Care 2015; 60: 162–169.

11 Chevrolet JC, Jolliet P, Abajo B, et al. Nasal positive pressure ventilation in patients with acute respiratory failure. Difficult and time-consuming procedure for nurses. Chest 1991; 100: 775–782.

12 Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000; 284: 2352–2360.

13 Groves N, Tobin A. High flow nasal oxygen generates positive airway pressure in adult volunteers. Aust Crit Care 2007; 20: 126–131.

14 Cracco C, Fartoukh M, Prodanovic H, et al. Safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure. Intensive Care Med 2013; 39: 45–52.

15 Azoulay E, Mokart D, Rabbat A, et al. Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data. Crit Care Med 2008; 36: 100–107.

Eur Respir J 2016; 47: 1283–1286 | DOI: 10.1183/13993003.01883-2015 | Copyright ©ERS 2016

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Bronchoalveolar Lavage and Lung Biopsy in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review and Meta-Analysis DeepakBabu Chellapandian, Thomas Lehrnbecher, Bob Phillips, Brian T. Fisher, Theoklis E. Zaoutis, William J. Steinbach, Joseph Beyene, and Lillian Sung

DeepakBabu Chellapandian, Joseph Beyene, and Lillian Sung, The Hospital for Sick Children, Toronto; Joseph Beyene, McMaster University, Hamil- ton, Ontario, Canada; Thomas Lehrn- becher, Johann Wolfgang Goethe University, Frankfurt, Germany; Bob Phillips, Centre for Reviews and Dissemination, University of York, York, United Kingdom; Brian T. Fisher and Theoklis E. Zaoutis, Children’s Hospital of Philadelphia, Philadelphia, PA; and William J. Steinbach, Duke University Medical Center, Durham, NC.

Published online ahead of print at www.jco.org on January 5, 2015.

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Corresponding author: Lillian Sung, MD, PhD, Division of Haematology/Oncology, The Hospital for Sick Children, 555 Univer- sity Ave, Toronto, ON, Canada M5G 1X8; e-mail: lillian.sung@sickkids.ca.

© 2015 by American Society of Clinical Oncology

0732-183X/15/3305w-501w/$20.00

DOI: 10.1200/JCO.2014.58.0480

A B S T R A C T

Purpose The objective of this study was to describe the diagnostic yield and complication rate of bronchoalveolar lavage (BAL) and lung biopsy in the evaluation of pulmonary lesions in patients with cancer and recipients of hematopoietic stem-cell transplantation (HSCT).

Methods We conducted a systematic literature review and performed electronic searches of Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were recipients of HSCT, and if they underwent BAL or lung biopsy for the evaluation of pulmonary lesions. Only English language publications were included.

Results In all, 14,148 studies were screened; 72 studies of BAL and 31 of lung biopsy were included. The proportion of procedures leading to any diagnosis was similar by procedure type (0.53 v 0.54; P � .94) but an infectious diagnosis was more common with BAL compared with lung biopsy (0.49 v 0.34; P � .001). Lung biopsy more commonly led to a noninfectious diagnosis (0.43 v 0.07; P � .001) and was more likely to change how the patient was managed (0.48 v 0.31; P � .002) compared with BAL. However, complications were more common with lung biopsy (0.15 v 0.08; P � .006), and procedure-related mortality was four-fold higher for lung biopsy (0.0078) compared with BAL (0.0018).

Conclusion BAL may be the preferred diagnostic modality for the evaluation of potentially infectious pulmonary lesions because of lower complication and mortality rates; thus, choice of procedure depends on clinical suspicion of infection. Guidelines to promote consistency in the approach to the evaluation of lung infiltrates may improve clinical care of patients.

J Clin Oncol 33:501-509. © 2015 by American Society of Clinical Oncology

INTRODUCTION

Patients who receive chemotherapy or who undergo hematopoietic stem-cell transplantation (HSCT) experience considerable toxicities of therapy: fever and neutropenia (FN) are two of the most common complications of treatment. When FN occurs, ob- taining blood cultures from all lumens of central venous catheters and a careful clinical examination for a source of infection are recommended.1 In the setting of persistent fever without an identified source, it is essential to evaluate other potential sites of infection. The lungs are a common site of infection2 and thus should be considered in second- ary evaluations.

Radiographic investigation can reveal nonspe- cific findings such as pulmonary nodules or other

lung findings. These radiographic findings present a therapeutic dilemma because they can represent a pulmonary infection from bacteria, viruses, and/or fungi. Mold infections are of particular concern given the need for prolonged therapy and the high attributable mortality rate.3 Specimen sources for diagnostic procedures that may provide insight into the etiology of pulmonary lesions include sputum evaluation, bronchoscopy with bronchoalveolar la- vage (BAL), and lung biopsy in addition to blood and urine samples.

In addition to knowing whether pulmonary abnormalities are infectious or noninfectious, knowledge of the specific pathogen is helpful for making treatment decisions. The diagnostic capabil- ities for identifying the etiology of infectious pneu- monic processes are changing over time. There has

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VOLUME 33 � NUMBER 5 � FEBRUARY 10 2015

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http://www.jco.org
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been an increase in the use of molecular biomarkers such as galacto- mannan (GM) and polymerase chain reaction (PCR) for identifying Aspergillus and in the use of various PCR platforms for identifying non-Aspergillus fungi. Noninfectious causes of pulmonary abnormal- ities, including malignancy and hemorrhage, are also important.

We recently published a guideline for the management of FN in pediatric patients.1 In this guideline, we noted the absence of data that identify the procedure with the greatest yield and lowest procedure- related risk for the evaluation of pulmonary lesions. A comparison of the benefits and risks of BAL and lung biopsy may help guide decision making when a patient presents with a potentially infectious pulmo- nary process. A systematic literature review specifically of patients with cancer and recipients of HSCT is important because the presence of neutropenia and thrombocytopenia may change the risk-benefit profile for these procedures. Consequently, the primary objective of this systematic review was to describe the diagnostic yield of BAL and lung biopsy in the evaluation of pulmonary lesions in patients with cancer and in recipients of HSCT. The secondary objectives were to describe the rate of complications and procedure-related mortality of BAL and lung biopsy. An exploratory objective was to describe the diagnostic properties of BAL GM and Aspergillus PCR in diagnosing invasive aspergillosis.

METHODS

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations for reporting.4

Data Sources and Searches We performed electronic searches of Ovid MEDLINE from 1980 to

March 14, 2014, EMBASE from 1980 to 2014 week 10, and Cochrane Central Register of Controlled Trials to January 2014. The search strategy included the Medical Subject Heading terms and text words that identified adult or pediat- ric patients with neoplasms and HSCT recipients combined with identifica- tion of BAL and lung biopsy procedures (the full search strategy can be found in Appendix Table A1 [online only]). A manual search of reference lists of identified articles was also conducted.

Study Selection Inclusion and exclusion criteria were defined a priori. Studies were in-

cluded if patients had cancer or were recipients of HSCT and if they underwent BAL or lung biopsy for the evaluation of a pulmonary lesion. We limited studies to full-text articles published in English after 1980. If a study met any of the following criteria, it was excluded: (1) was not a full-text publication; (2) contained fewer than 10 procedures; (3) was a case-control study (which does not allow calculation of prevalence of diagnoses); (4) had noncancer or non- HSCT patients; (5) had a lung procedure that was conducted for initial diag- nosis of cancer, surveillance (not for the purpose of diagnosis), or evaluation of

Potentially relevant references identified (N = 14,148)

Citations screened by title/abstract (n = 11,932)

Full-text references retrieved for detailed evaluation

(n = 266)

Studies included in meta-analysis (n = 95)

Duplicates removed (n = 2,216)

Articles excluded as did not meet eligibility criteria

(n = 11,666)

)171 = n( dedulcxE Not full-text publication (n = 45) Fewer than 10 procedures (n = 1)

)6 = n( yduts lortnoc esaC Noncancer/HSCT human population (n = 64) Procedure for initial diagnosis of cancer (n = 7) Procedure for surveillance (n = 8) Procedure for drug toxicity (n = 1) Studies focused only on PCP (n = 1) All patients with infection/disease (n = 12) Diagnostic test not validated (n = 5) Did report results of procedures (n = 16) Duplicate publications (n = 5)

Fig 1. Flow diagram illustrating flow of studies identified from the search strategy and reasons for exclusion. HSCT, hematopoietic stem-cell transplanta- tion; PCP, Pneumocystis jirovecii.

Table 1. Characteristics of Included Studies by BAL and Lung Biopsy Procedures

Characteristic and Stratum

BAL (n � 72)

Lung Biopsy (n � 31)

No. of Studies %

No. of Studies %

Study population age, years Pediatric (younger than 18) 12 17 6 19 Adult (� 18) 37 51 13 42 Both 20 28 10 32

Study population diagnosis Cancer 10 14 5 16 HSCT 32 44 17 55 Both 30 42 9 29

Year of publication 2002 or earlier 38 53 16 52 After 2002 34 47 15 48

Study design Retrospective 52 72 28 90 Prospective 20 28 3 10

EORTC/MSG criteria used� 16 22 1 3 Aspergillus testing

Galatomannan 12 17 NA PCR 10 14 1 3

Brushing used for BAL 14† 19 NA Biopsy type

Transbronchial NA 5 16 Transthoracic NA 26 84

Biopsy-image guided NA 7 23 Patient selection low-risk bias 54 75 24 77 Index test low-risk bias 16 22 2 6

Abbreviations: BAL, bronchoalveolar lavage; EORTC/MSG, European Organi- sation for Research and Treatment of Cancer/Mycoses Study Group; HSCT, hematopoietic stem-cell transplantation; NA, not applicable; PCR, polymerase chain reaction.

�Used criteria from the European Organisation for Research and Treatment of Cancer to define invasive fungal infection. †Brushing done sometimes (n � 12) or always (n � 2).

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drug toxicity; (6) focused only on Pneumocystis jirovecii pneumonia (BAL is the standard approach for diagnosing suspected Pneumocystis jirovecii pneu- monia); (7) was a case series reporting only patients with positive diagnostic tests (a case series does not provide data on how many patients underwent the procedure without a positive test); (8) performed for the purpose of validating a diagnostic test; (9) did not report results of procedure; and (10) was a duplicate publication.

Two reviewers (D.C. and L.S.) independently evaluated the titles and abstracts of publications identified by the search strategy, and any potentially relevant publication was retrieved in full. Final inclusion of studies into the systematic review was by agreement of both reviewers. Agreement on study inclusion between the two reviewers was evaluated by using the � statistic, and agreement was defined as slight (0.00 to 0.20), fair (0.21 to 0.40), moderate (0.41 to 0.60), substantial (0.61 to 0.80) or almost perfect (0.81 to 1.00).5

Data Abstraction and Methodologic Approach Two reviewers (D.C. and L.S.) abstracted all data in duplicate, and any

discrepancies were resolved by consensus. The primary outcomes were the proportion of procedures with any diagnosis, infectious diagnoses, and non- infectious diagnoses. In addition, the proportion of procedures with bacterial, viral, and fungal etiologies was described. Fungal infection was defined by each study. The secondary outcomes were complications (defined by each study) and procedure-related mortality. In the evaluation of the diagnostic properties of BAL GM and Aspergillus PCR, the gold standard was proven or probable invasive aspergillosis according to the revised criteria from the European Organisation for Research and Treatment of Cancer/Invasive Fungal Infec- tions Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG).6

Each study described BAL, lung biopsy, or both. Studies were initially separated into those that evaluated and described any infectious or noninfec- tious diagnosis versus those that focused only on a specific diagnosis. For the latter group, we were interested in the diagnostic properties of BAL, GM, and PCR for Aspergillus infection.

Potential factors that could influence the diagnostic and complication rates were age (pediatric [age 18 years or younger], adult, or both), patient population (cancer, HSCT, or both), year of study (dichotomized at 2002), bronchial brushing during BAL (yes or no), and biopsy type (transbronchial or transthoracic). We also evaluated whether patient selection bias and index test bias influenced the infection diagnosis rate or whether patient selection bias influenced the complication rate. For the diagnosis of fungal infection from BAL, we also evaluated whether the study used EORTC/MSG criteria for the diagnosis of fungal infection and whether the study included GM and Asper- gillus PCR for the BAL specimen.

Assessment of Study Quality Two reviewers assessed study quality, and any discrepancies were re-

solved by consensus. Study quality was assessed by using QUADAS-2 for review of diagnostic tests.7 Elements were patient selection (could selection of

patients have introduced bias); index test (could the conduct or interpretation of the test have introduced bias); reference standard (used only for the evalu- ation of BAL GM and PCR for Aspergillus infection; could conduct or inter- pretation of the reference standard have introduced bias); and flow and timing (were all patients included in the analysis). These elements were rated at low, high, and unclear risk of bias.

Statistical Methods This meta-analysis was performed by using Review Manager (RevMan,

version 5.2, Copenhagen, Denmark: The Nordic Cochrane Centre, The Co- chrane Collaboration, 2011). Data were synthesized by using proportions as the measure of effect. Because proportions are not normally distributed, all analyses were conducted by using the natural logarithm of the proportion as the outcome. All estimates are presented as proportions with 95% CIs. The percentage of patients with an outcome may be derived by multiplying the proportion by 100 (eg, 0.53 is synonymous with 53% of patients experiencing the outcome). Heterogeneity was described by using the I2 value, which de- scribes the percentage of variability due to heterogeneity rather than to sam- pling error.8 To explore sources of heterogeneity, we performed stratified analyses by using RevMan; heterogeneity between subgroups was evaluated by using the �2 statistic. Statistical significance was defined as P � .05. RevMan was also used to calculate sensitivity and specificity of BAL GM and Aspergillus PCR. There are statistical concerns about pooling sensitivity and specificity because these values are correlated; thus, the ranges were displayed for each test.9,10 Publication bias was not investigated, given the nature of the outcome, namely proportions.

RESULTS

The flow of study identification and selection is illustrated in Figure 1. There were 14,148 studies identified by the search strategy, of which 266 were retrieved for full evaluation; 95 of those were included in the meta-analysis. Agreement on study inclusion between the two reviewers was almost perfect, with � statistic of 87.9% (95% CI, 82.0% to 93.9%).

Overall, there were 72 studies that evaluated BAL procedures. Characteristics of these studies are provided in Appendix Table A2 (online only). The number of studies at low risk of bias for patient selection was 54 (75%), index test was 16 (22%), and flow and timing was 64 (89%). Of these studies, 53 described the prevalence of any identified organism, whereas 21 focused on a specific organism (two studies described all organisms but also evaluated the diagnostic prop- erties of BAL GM or Aspergillus PCR).11,12 Three studies focused on specific radiologic abnormalities: two included pneumonitis13,14 and one included diffuse infiltrates.15

Table 2. Proportion of Procedures With Specific Diagnosis Stratified by BAL and Lung Biopsy

Diagnosis

BAL (n � 4,893; 6,203 procedures) Lung Biopsy

(n � 976; 1,306 procedures)

P for BAL v BiopsyProportion 95% CI No. of Studies I2 Proportion 95% CI No. of Studies I2

Any 0.53 0.49 to 0.58 46 90 0.54 0.47 to 0.61 29 73 .94 Infectious 0.49 0.45 to 0.54 50 88 0.34 0.28 to 0.42 30 84 � .001 Bacterial 0.19 0.16 to 0.23 49 89 0.06 0.04 to 0.07 28 0 � .001 Viral 0.13 0.09 to 0.18 49 96 0.09 0.06 to 0.14 28 84 .24 Fungal 0.19 0.16 to 0.23 50 86 0.20 0.15 to 0.28 28 86 .71 Noninfectious 0.07 0.05 to 0.09 42 75 0.43 0.35 to 0.52 27 88 � .001 Complications 0.08 0.06 to 0.11 35 82 0.15 0.11 to 0.21 23 77 .006 Results changed management 0.31 0.26 to 0.38 25 92 0.48 0.40 to 0.57 17 82 .002

Abbreviation: BAL, bronchoalveolar lavage.

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There were 31 studies that evaluated lung biopsies; characteristics of those studies are included in Appendix Table A3 (online only). The number of studies at low risk of bias for patient selection was 24 (77%), index test was two (6%), and flow and timing was 31 (100%). Of those studies, 31 described the prevalence of any organism, whereas one focused on a specific organism. Twenty-six studies evaluated trans-

thoracic biopsy and five evaluated transbronchial biopsy. Seven studies16-22 included both BAL and lung biopsy, and one study16

reported two separate biopsy cohorts (image-guided and open-lung biopsy). Four studies focused on specific radiologic abnormalities: three83-85 included diffuse infiltrates and one86 focused on pulmonary nodules. Characteristics of BAL and lung biopsy studies are

)modnar( W IC %59 noitroporP latoT stnevE ydutS %2.2 55.0 ot 43.0 54.0 29 14 7002 ,nainemrA %2.2 94.0 ot 92.0 93.0 101 93 8002 ,yaluozA %0.2 24.0 ot 22.0 13.0 68 72 1002 ,irA−neB %4.2 37.0 ot 35.0 36.0 101 46 0102 ,noregreB %5.2 18.0 ot 36.0 37.0 59 96 5002 ,regnissiB %7.1 04.0 ot 71.0 72.0 36 71 7002 ,amsreoB %7.1 86.0 ot 92.0 84.0 72 31 7002 ,regruB %6.1 76.0 ot 62.0 64.0 42 11 8002 ,inadroC %3.2 57.0 ot 15.0 46.0 66 24 6891 ,reinnodroC %9.1 75.0 ot 92.0 24.0 25 22 5891 ,reinnodroC %1.2 47.0 ot 24.0 95.0 14 42 7891 ,reinnodroC %1.2 16.0 ot 63.0 84.0 46 13 7991 ,naganuD %2.2 75.0 ot 63.0 74.0 09 24 5002 ,yrrebnekiE %8.1 25.0 ot 32.0 73.0 94 81 8991 ,giwE %3.2 57.0 ot 15.0 36.0 86 34 0102 ,wolsroF %2.2 89.0 ot 55.0 58.0 31 11 8002 ,ayuruF %0.1 25.0 ot 11.0 92.0 12 6 3102 ,sassaG %4.2 76.0 ot 15.0 95.0 541 68 3102 ,trebliG %3.2 36.0 ot 04.0 25.0 97 14 8991 ,rezalG %8.1 95.0 ot 62.0 24.0 83 61 9991 ,nosurG %4.2 94.0 ot 63.0 34.0 322 59 7002 ,atpuG %0.1 26.0 ot 21.0 33.0 51 5 8991 ,yssenneH %0.2 48.0 ot 34.0 56.0 32 51 6991 ,nilrueH %0.2 39.0 ot 84.0 57.0 61 21 9891 ,nilrueH %3.2 77.0 ot 05.0 46.0 35 43 9991 ,lessueH %2.2 15.0 ot 03.0 14.0 19 73 6002 ,retsiemfoH %2.2 44.0 ot 82.0 63.0 531 84 5002 ,lahtnehoH %0.2 63.0 ot 02.0 72.0 421 43 0002 ,agnirauH %5.2 45.0 ot 24.0 84.0 642 811 8002 ,lemmuH %4.2 87.0 ot 65.0 86.0 87 35 7002 ,wosaK %9.1 07.0 ot 33.0 25.0 13 61 6991 ,oninaL %8.1 76.0 ot 92.0 84.0 92 41 2991 ,nibbuCcM %4.2 98.0 ot 26.0 87.0 04 13 7891 ,nrubliM %6.1 74.0 ot 81.0 13.0 54 41 4002 ,civoricebaluM %4.1 75.0 ot 81.0 63.0 52 9 1002 ,yarruM %1.1 18.0 ot 91.0 05.0 01 5 2002 ,nnamueN %4.2 26.0 ot 44.0 45.0 721 86 7991 ,onagaP %6.1 24.0 ot 71.0 82.0 35 51 2002 ,kraP %4.2 65.0 ot 14.0 94.0 961 28 5002 ,letaP %1.2 24.0 ot 52.0 33.0 121 04 8002 ,tabbaR %7.1 67.0 ot 23.0 55.0 22 21 0002 ,alimaR %1.2 07.0 ot 93.0 55.0 44 42 3102 ,oaR %5.2 00.1 ot 77.0 59.0 22 12 8891 ,otiaS %9.1 58.0 ot 14.0 56.0 02 31 0002 ,nenolaS %6.2 95.0 ot 15.0 55.0 895 923 0102 ,nonnahS %0.1 24.0 ot 90.0 22.0 72 6 1002 ,inabuoS %4.1 83.0 ot 31.0 42.0 05 21 9891 ,sekotS %2.2 97.0 ot 94.0 56.0 34 82 2002 ,nedlE nav %4.2 57.0 ot 65.0 66.0 301 86 5991 ,ffiE nov %7.1 04.0 ot 81.0 82.0 86 91 7991 ,etihW

%001 45.0 ot 54.0 94.0 669,3 ledom stceffe modnaR Heterogeneity: I2 = 87.7%, Τ2 = 0.0769, P < .001

0.80.60.40.2

Fig 2. Forest plot of proportion of infec- tious diagnosis among studies. Squares indicate proportion of procedures with an in- fectious diagnosis. Horizontal lines through the squares represent 95% CIs. W, weight.

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summarized in Table 1; 86% of BAL studies and 84% of lung biopsy studies included patients undergoing HSCT.

Table 2 provides the main outcomes of the study. The proportion of procedures leading to any diagnosis was similar for BAL and lung biopsy (0.53 v 0.54; P � .94). However, an infectious diagnosis was more common with BAL compared with lung biopsy (0.49 v 0.34; P � .001; Fig 2). In contrast, noninfectious diagnosis was more common with lung biopsy compared with BAL (0.43 v 0.07; P � .001). Change in management occurred more often with lung biopsy compared with BAL (0.48 v 0.31; P � .002). However, complica- tions were more common with lung biopsy compared with BAL (0.15 v 0.08; P � .006). Among the 30 BAL studies that reported procedure-related mortality, there were five BAL-related deaths among 2,792 procedures (0.0018). Among the 20 biopsy studies that reported procedure-related mortality, there were five biopsy- related deaths among 637 procedures (0.0078).

Table 3 provides the results of the stratified analyses that evaluate the proportion of procedures leading to an infectious diagnosis for BAL and lung biopsy. Study characteristics did not explain heterogeneity in the proportion of BAL procedures yield- ing an infectious diagnosis. However, transthoracic lung biopsy was more likely to yield an infectious diagnosis compared with transbronchial biopsy (0.39 v 0.12; P � .001).

There were 50 BAL studies that reported the rate of invasive fungal infection in addition to any infection. There was no difference in the rate of fungal diagnosis among the six studies27-32 that used

EORTC/MSG criteria to define invasive fungal infection (0.19; 95% CI, 0.11 to 0.31) compared with the 44 studies that did not use these criteria (0.19; 95% CI, 0.16 to 0.23; P � .95). Invasive fungal infection detection among the four studies27,32-34 that used BAL GM (0.31; 95% CI, 0.23 to 0.43) was significantly higher compared with the 46 studies that did not use the test (0.18; 95% CI, 0.15 to 0.22; P � .005). Only two studies35,36 used BAL Aspergillus PCR in the setting of evaluation of any infection; invasive fungal infection was diagnosed in 0.24 (95% CI, 0.14 to 0.40).

Table 4 provides the results of the stratified analyses that evalu- ated complications. When stratified by procedure type, the use of brushings during BAL was associated with more complications com- pared with BAL procedures without brushings (P � .03). Among lung biopsy procedures, children were more likely to experience complica- tions compared with adults or mixed-age populations (P � .003). Transthoracic procedures were also more commonly associated with complications compared with transbronchial procedures (0.18 v 0.05; P � .005). When stratified by study characteristics, lung biopsy, when compared with BAL, was more commonly associated with complica- tions in children (0.37 v 0.08; P � .001).

For BAL studies that evaluated a specific organism, the most common organism was Aspergillus in 13 studies11,12,32,37-46; GM only was evaluated in seven studies,32,37-42 Aspergillus PCR only was evaluated in four studies,43-46 and both were evaluated in two studies.11,12 Diagnostic properties were evaluated in seven GM and four PCR studies. Among these 11 studies, the number at low risk

Table 3. Proportion of Procedures With Infection Diagnosis Stratified by Study Characteristics

Characteristic

BAL Lung Biopsy

P for BAL v Biopsy No. of

Procedures Infection Diagnosis 95% CI P

No. of Procedures

Infection Diagnosis 95% CI P

Age group Children 542 0.45 0.37 to 0.56 .10 155 0.32 0.21 to 0.49 .02 .15 Adult 2,238 0.48 0.42 to 0.55 651 0.24 0.15 to 0.36 .002 Both 1,062 0.56 0.50 to 0.63 402 0.45 0.37 to 0.56 .08

Underlying diagnosis Cancer 393 0.49 0.38 to 0.64 .97 263 0.46 0.23 to 0.90 .47 .84 HSCT 2,309 0.50 0.45 to 0.55 645 0.30 0.23 to 0.40 � .001 Both 1,264 0.48 0.40 to 0.58 364 0.36 0.26 to 0.50 .13

Year published 2002 or earlier 1,376 0.49 0.42 to 0.57 .97 580 0.41 0.34 to 0.50 .06 .16 After 2002 2,590 0.49 0.44 to 0.54 692 0.28 0.19 to 0.40 .002

Study design Retrospective 3,455 0.50 0.45 to 0.55 .50 1,237 0.33 0.27 to 0.41 .02 � .001 Prospective 511 0.46 0.36 to 0.58 35 0.52 0.38 to 0.72 .51

Brushing used for BAL Yes 799 0.52 0.42 to 0.63 .56 NA NA NA NA No 3,167 0.48 0.44 to 0.53 NA

Biopsy type Transbronchial NA NA NA 211 0.12 0.06 to 0.24 .001 NA Transthoracic 1,061 0.39 0.32 to 0.47 NA

Patient selection bias Low risk 3,135 0.50 0.46 to 0.55 .46 1,130 0.33 0.27 to 0.42 .36 � .001 Not low risk 831 0.46 0.35 to 0.59 142 0.39 0.30 to 0.52 .45

Index test bias Low risk 275 0.43 0.29 to 0.65 .51 76 0.31 0.12 to 0.76 .79 .50 Not low risk 3,691 0.50 0.45 to 0.54 1,196 0.35 0.28 to 0.42 .001

Abbreviations: BAL, bronchoalveolar lavage; HSCT, hematopoietic stem-cell transplantation; NA, not applicable.

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of reference standard bias was five (45%). Against the EORTC/ MSG gold standard, the sensitivity of BAL GM ranged from 0.58 (95% CI, 0.39 to 0.75) to 1.00 (95% CI, 0.85 to 1.00), and the specificity ranged from 0.78 (95% CI, 0.71 to 0.84) to 1.00 (95% CI, 0.85 to 1.00). The sensitivity of Aspergillus PCR ranged from 0.69 (95% CI, 0.50 to 0.84) to 0.94 (95% CI, 0.80 to 0.99) and the specificity ranged from 0.75 (95% CI, 0.43 to 0.95) to 0.94 (95% CI, 0.88 to 0.98).

DISCUSSION

In this study, which focuses on lung procedures for the diagnosis of infectious and noninfectious causes of pulmonary infiltrates among patients with cancer and HSCT recipients, we found that BAL resulted in a diagnosis in 0.53 procedures and lung biopsy resulted in a diag- nosis in 0.54 procedures. An infectious diagnosis was made more frequently for BAL (0.49 v 0.34) whereas a noninfectious diagnosis was made more frequently for lung biopsy (0.43 v 0.07). However, the rate of complications was almost twice as high for lung biopsies compared with BAL (0.15 v 0.08), and children were at higher risk of complica- tions. Procedure-related mortality was four-fold higher for lung bi- opsy compared with BAL (0.0078 v 0.0018).

These results suggest that BAL may be the preferred initial diagnostic modality for evaluating potentially infectious pulmo- nary lesions among patients with cancer and recipients of HSCT. BAL procedures were at lower risk of complications and procedure-related deaths with similar yield compared with trans- thoracic biopsies. Furthermore, with the advent of improvements

in diagnostic capabilities such as GM and PCR, the diagnostic yield of BAL should improve. If invasive fungal infection is suspected, we suggest that BAL GM should be included in the evaluation because BAL GM significantly improves the detection of fungi and has adequate diagnostic properties in this population.

The procedure-related mortality rate of lung biopsy is not negli- gible. This is not surprising, given the nature of these patients, many of whom are thrombocytopenic. This review suggests that lung biopsies are more likely to be useful when noninfectious diagnoses are sus- pected. Indeed, a BAL is by design a diagnostic test focused on captur- ing infectious complications, whereas lung biopsy is a more comprehensive approach and can obtain much needed information regarding histopathologic changes, including the presence of malig- nancy. Lung biopsies did lead to a change in management in almost half the patients. However, the risk of complications and procedure- related deaths should be considered when deciding whether the pro- cedure is worthwhile as an initial diagnostic procedure. Transthoracic biopsies were more likely to yield a diagnosis compared with trans- bronchial biopsies and may be particularly useful when a noninfec- tious diagnosis is suspected.

Our interpretation that BAL may be the preferred initial diagnostic modality in the setting of a potentially infectious pathology is consistent with a review among immunocompromised children in general, which also recommended BAL as the initial diagnostic tool.90 Our recommen- dation to include BAL GM in the evaluation of potential pulmonary fungus is also consistent with guideline statements from other groups.1,91

What is striking from our review is the percentage of times that any diagnosis, approximately 50% using either BAL or lung biopsy,

Table 4. Proportion of Procedures With Complications Stratified by Study Characteristics

Characteristic

BAL Lung Biopsy

P BAL v Biopsy No. of

Procedures Complications 95% CI P No. of

Procedures Complications 95% CI P

Age group Children 408 0.08 0.04 to 0.17 .10 115 0.37 0.22 to 0.62 .003 .001 Adult 2102 0.11 0.07 to 0.16 621 0.12 0.07 to 0.21 .72 Both 784 0.05 0.02 to 0.09 246 0.13 0.08 to 0.21 .008

Underlying diagnosis Cancer 346 0.03 0.00 to 0.22 .64 297 0.11 0.04 to 0.34 .88 .27 HSCT 1926 0.08 0.05 to 0.13 356 0.15 0.09 to 0.25 .11 Both 1022 0.08 0.05 to 0.14 352 0.16 0.09 to 0.27 .10

Year 2002 or earlier 1159 0.04 0.02 to 0.08 .008 334 0.15 0.10 to 0.25 .91 � .001 After 2002 2135 0.11 0.08 to 0.16 671 0.15 0.09 to 0.24 .33

Study design Retrospective 2714 0.07 0.05 to 0.10 .22 948 0.16 0.11 to 0.22 .37 .002 Prospective 580 0.11 0.06 to 0.19 57 0.11 0.05 to 0.23 .99

Brushing used for BAL Yes 929 0.04 0.02 to 0.09 .03 NA NA NA NA No 2365 0.10 0.07 to 0.14 NA

Biopsy type Transbronchial NA NA NA 147 0.05 0.02 to 0.11 .005 NA Transthoracic 858 0.18 0.13 to 0.24 NA

Patient selection bias Low risk 2468 0.08 0.05 to 0.11 .98 908 0.16 0.11 to 0.23 .66 .006 Not low risk 826 0.08 0.04 to 0.17 97 0.14 0.08 to 0.24 .24

Abbreviations: BAL, bronchoalveolar lavage; HSCT, hematopoietic stem-cell transplantation; NA, not applicable.

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can be made when radiographic lung nodules or other findings are directly pursued via either approach. Irrespective of the initial diagnostic approach, we suggest that investigation be conducted expeditiously because treatment may influence diagnostic yield.92

If a BAL is the initial evaluation and is negative or yields a pathogen of questionable significance, it is then important to consider whether transthoracic biopsy results may alter patient manage- ment. It is also important to stress that our results were heteroge- neous and thus, yield and complication rates of BAL and biopsies may vary at different institutions on the basis of operator expertise and indications for the procedure.

The strength of this systematic review is the pooling of clinically meaningful end points and restriction to patients with cancer and HSCT. However, there are several limitations. First, we relied on the definition of diagnostic etiologies provided in individual studies. For example, BAL is not a sterile procedure, and some studies identified viruses and bacteria which may not have been causally related to the pulmonary process. Similarly, biopsy studies sometimes focused only on specific diagnoses such as invasive fungal infection and malig- nancy. However, some biopsy studies included entities such as diffuse alveolar damage and fibrosis. Without access to the primary data, we were not able to further classify the different types of lung biopsy diagnoses, although change in management based on the lung biopsy is probably more meaningful to clinicians. Second, studies were con- ducted over a long period of time, although our stratified analyses did not suggest that the year of publication had an impact on the propor- tion of procedures with an infectious diagnosis or complication. Third, our results are confounded by indication for the procedure. In addition, there were too few studies that stratified results by specific radiologic patterns to permit analysis, and thus, we are uncertain whether the specific radiologic patterns should influence the choice of procedure. Fourth, there is the potential for reporting bias, both at the study and the outcome level because no registry of

such studies exists, and study protocols are not available for inspec- tion. Furthermore, it was not possible to undertake mathematical estimates of publication bias because, to the best of our knowledge, robust methods for evaluating publication bias are not available when the outcome is a proportion.

Future studies should focus on the development of clinical practice guidelines and algorithms for the evaluation of patients with lung infiltrates in the oncology and HSCT setting. In addition, the use of biomarkers should be further explored. In conclusion, BAL may be the preferred initial diagnostic modality for the eval- uation of potentially infectious pulmonary lesions among patients with cancer and HSCT recipients. Guidelines for promoting con- sistency in the approach to the evaluation of lung infiltrates may improve clinical care of patients.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: DeepakBabu Chellapandian, Thomas Lehrnbecher, Lillian Sung Financial support: Lillian Sung Collection and assembly of data: DeepakBabu Chellapandian, Lillian Sung Data analysis and interpretation: Thomas Lehrnbecher, Bob Phillips, Brian T. Fisher, Theoklis E. Zaoutis, William J. Steinbach, Joseph Beyene, Lillian Sung Manuscript writing: All authors Final approval of manuscript: All authors

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13. Cathomas G, Morris P, Pekle K, et al: Rapid diagnosis of cytomegalovirus pneumonia in marrow transplant recipients by bronchoalveolar lavage us- ing the polymerase chain reaction, virus culture, and the direct immunostaining of alveolar cells. Blood 81:1909-1914, 1993

14. Cordonnier C, Bernaudin JF, Bierling P, et al: Pulmonary complications occurring after allogeneic bone marrow transplantation: A study of 130 con- secutive transplanted patients. Cancer 58:1047- 1054, 1986

15. Gupta S, Jain A, Warneke CL, et al: Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 40: 71-78, 2007

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21. Soubani AO, Qureshi MA, Baynes RD, et al: Flexible bronchoscopy in the diagnosis of pulmonary infiltrates following autologous peripheral stem cell transplantation for advanced breast cancer. Bone Marrow Transplant 28:981-985, 2001

22. White P, Bonacum JT, Miller CB: Utility of fiberoptic bronchoscopy in bone marrow transplant patients. Bone Marrow Transplant 20:681-687, 1997

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63. Lanino E, Sacco O, Kotitsa Z, et al: Fiberoptic bronchoscopy and bronchoalveolar lavage for the evaluation of pulmonary infiltrates after BMT in children. Bone Marrow Transplant 18:117-120, 1996

64. Heurlin N, Bergström SE, Winiarski J, et al: Fungal pneumonia: The predominant lung infection causing death in children undergoing bone marrow transplantation. Acta Paediatr 85:168-172, 1996

65. Dunagan DP, Baker AM, Hurd DD, et al: Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 111: 135-141, 1997

66. Pagano L, Pagliari G, Basso A, et al: The role of bronchoalveolar lavage in the microbiological di- agnosis of pneumonia in patients with haematologi- cal malignancies. Ann Med 29:535-540, 1997

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75. Ben-Ari J, Yaniv I, Nahum E, et al: Yield of bronchoalveolar lavage in ventilated and non- ventilated children after bone marrow transplanta- tion. Bone Marrow Transplant 27:191-194, 2001

76. van Elden LJ, van Kraaij MG, Nijhuis M, et al: Polymerase chain reaction is more sensitive than viral culture and antigen testing for the detection of respiratory viruses in adults with hematological can- cer and pneumonia. Clin Infect Dis 34:177-183, 2002

77. Park JR, Fogarty S, Brogan TV: Clinical utility of bronchoalveolar lavage in pediatric cancer pa- tients. Med Pediatr Oncol 39:175-180, 2002

78. Neumann M, von Bredow C, Ratjen F, et al: Bronchoalveolar lavage protein patterns in children with malignancies, immunosuppression, fever and pulmonary infiltrates. Proteomics 2:683-689, 2002

79. Ison MG, Hayden FG, Kaiser L, et al: Rhino- virus infections in hematopoietic stem cell trans- plant recipients with pneumonia. Clin Infect Dis 36:1139-1143, 2003

80. Martino R, Porras RP, Rabella N, et al: Pro- spective study of the incidence, clinical features, and outcome of symptomatic upper and lower re- spiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell trans- plants for hematologic malignancies. Biol Blood Marrow Transplant 11:781-796, 2005

81. Eikenberry M, Bartakova H, Defor T, et al: Natural history of pulmonary complications in chil- dren after bone marrow transplantation. Biol Blood Marrow Transplant 11:56-64, 2005

82. Burger CD: Utility of positive bronchoalveolar lavage in predicting respiratory failure after hemato- poietic stem cell transplantation: A retrospective analysis. Transplant Proc 39:1623-1625, 2007

83. Crawford SW, Hackman RC, Clark JG: Open lung biopsy diagnosis of diffuse pulmonary infil- trates after marrow transplantation. Chest 94:949- 953, 1988

84. Springmeyer SC, Silvestri RC, Sale GE, et al: The role of transbronchial biopsy for the diagnosis of diffuse pneumonias in immunocompromised mar- row transplant recipients. Am Rev Respir Dis 126: 763-765, 1982

85. Wang JY, Chang YL, Lee LN, et al: Diffuse pulmonary infiltrates after bone marrow transplanta- tion: The role of open lung biopsy. Ann Thorac Surg 78:267-272, 2004

86. Gulbahce HE, Pambuccian SE, Jessurun J, et al: Pulmonary nodular lesions in bone marrow transplant recipients: Impact of histologic diagnosis on patient management and prognosis. Am J Clin Pathol 121:205-210, 2004

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■ ■ ■

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Bronchoalveolar Lavage and Lung Biopsy in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review and Meta-Analysis

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I � Immediate Family Member, Inst � My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

DeepakBabu Chellapandian No relationship to disclose

Thomas Lehrnbecher Honoraria: Gilead Sciences, Astellas Pharma, Pfizer, MSD, Merck, Bristol-Myers Squibb Consulting or Advisory Role: Gilead Sciences, MSD, Merck Speakers’ Bureau: Gilead Sciences, Merck, MSD, Astellas Pharma, Pfizer Research Funding: Gilead Sciences Travel, Accommodations, Expenses: Gilead Sciences, Astellas Pharma, Merck, MSD, Pfizer, Baxter International

Bob Phillips No relationship to disclose

Brian T. Fisher Research Funding: Pfizer (Inst), Enzon Pharmaceuticals (Inst), Wyeth (Inst)

Theoklis E. Zaoutis Consulting or Advisory Role: Merck, Pfizer, Cubist Pharmaceuticals Research Funding: Merck (Inst), Cubist Pharmaceuticals (Inst)

William J. Steinbach Consulting or Advisory Role: Merck, Astellas Pharma Research Funding: Merck, Astellas Pharma

Joseph Beyene No relationship to disclose

Lillian Sung No relationship to disclose

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Acknowledgment We thank Elizabeth Uleryk for her support in conducting the literature search and Amanda Celis and Cathy O’Sullivan for their

administrative assistance.

Appendix

Table A1. Search Strategies

Database Inclusive Dates Search Set History

MEDLINE 1946 to March 13, 2014 1 43 exp �neoplasms/or exp �Stem Cell Transplantation/or �Bone Marrow Transplantation/or �Cryptogenic Organizing Pneumonia/or exp �Lung Diseases, Fungal/or exp �Aspergillus/ or exp �Aspergillosis/or �Opportunistic Infections/

2 bronchoalveolar lavage/or bronchoalveolar lavage fluid/or (bronchoalveolar adj2 lavage).mp.

3 biopsy/or biopsy, needle/or biopsy, fine-needle/or endoscopic ultrasound-guided fine needle aspiration/or biopsy, large-core needle/or image-guided biopsy/

4 exp Lung/ 5 3 and 4 6 2 or 5 7 1 and 6 8 limit 10 to yr � “1980-Current”

EMBASE 1947 to 2014 Week 10 1 exp �neoplasm/or exp �stem cell transplantation/or exp �bone marrow transplantation/or �bronchiolitis obliterans organizing pneumonia/or exp �aspergillosis/or exp �Aspergillus/ or exp �lung mycosis/or �opportunistic infection/

2 65 lung lavage/or ((pulmonary or lung or bronchoalveolar) adj2 (lavage� or wash�)).ti,ab. or bal.ti,ab

3 lung biopsy/or open lung biopsy/or transthoracic biopsy/or (transthoracic adj2 biops�).ti,ab. 4 2 or 3 5 1 and 4 6 limit 5 to yr � “1980-Current”

EBM Reviews, Cochrane Central Register of Controlled Trials

January 2014 1 exp �neoplasms/or exp �Stem Cell Transplantation/or �Bone Marrow Transplantation/or �Cryptogenic Organizing Pneumonia/or exp �Lung Diseases, Fungal/or exp �Aspergillus/ or exp �Aspergillosis/or �Opportunistic Infections/or exp �Neoplasm/or exp �stem cell transplantation/or exp �bone marrow transplantation/or �bronchiolitis obliterans organizing pneumonia/or exp �lung mycosis/or �opportunistic infection/

2 lung lavage/or ((pulmonary or lung or bronchoalveolar) adj2 (lavage� or wash�)).ti,ab. or bal.ti,ab. or bronchoalveolar lavage/or bronchoalveolar lavage fluid/

3 lung biopsy/or open lung biopsy/or transthoracic biopsy/or (transthoracic adj2 biops�).ti,ab. or ((exp lung/and biopsy/) or biopsy, needle/or biopsy, fine-needle/or endoscopic ultrasound-guided fine needle aspiration/or biopsy, large-core needle/or image-guided biopsy/)

4 2 or 3 5 1 and 4 6 limit 5 to yr � “1980-Current”

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Table A2. Characteristics of Included Studies of BAL in the Meta-Analysis

Reference Year

Published Year Study

Ended Diagnosis

Type Study Design Population Brushing� Indication Protocol†

Risk of Bias

Patient Selection

Index Test

Flow and Timing

Cordonnier et al51 1985 1983 HSCT Retrospective Both No No High High Low Cordonnier et al14 1986 1984 HSCT Retrospective Both No No High High Low Cordonnier et al52 1987 1985 HSCT Retrospective Both No Yes Low High Low Milburn et al53 1987 NA HSCT Retrospective Both No No Low High Low Saito et al54 1988 1987 Both Retrospective Adult Sometimes No High High Low Crawford et al55 1988 1987 HSCT Prospective Both No No Low Low Low Heurlin et al56 1989 1987 HSCT Retrospective Adult Sometimes No Low High Low Gleaves et al57 1989 NA HSCT Retrospective NA No No Low High Low Stokes et al58 1989 1988 Both Retrospective Pediatric Sometimes No Low High Low Levy et al59 1992 1988 Both Retrospective Adult Sometimes No High High Low McCubbin et al60 1992 1990 HSCT Retrospective Pediatric No No Low High High Weiss et al61 1993 1991 HSCT Prospective Both No No Low High Low Cathomas et al13 1993 1991 HSCT Prospective NA No No High Low Low Verweij et al11 1995 NA Both Prospective Adult No No Low Low Low von Eiff et al62 1995 1992 Cancer Prospective Both Yes No Low High Low Englund et al47 1996 1994 Both Prospective Adult No No Low Low Low Lanino et al63 1996 1996 HSCT Retrospective Pediatric No No Low High Low Heurlin et al64 1996 NA HSCT Retrospective Pediatric Sometimes No Low High Low White et al22 1997 1995 HSCT Retrospective Adult No No Low High Low Dunagan et al65 1997 1994 HSCT Retrospective Adult Sometimes No Low High Low Pagano et al66 1997 1996 Cancer Retrospective Both Sometimes No Low High Low Hennessy et al67 1998 1997 HSCT Retrospective Adult No No High High Low Glazer et al68 1998 1995 HSCT Retrospective Both No No Low High Low Jones et al44 1998 NA Cancer Retrospective Both No No Low High Low Ewig et al69 1998 1993 Both Retrospective Both Sometimes No High High Low Gruson et al70 1999 1997 HSCT Prospective Adult No Yes High High Low Heussel et al71 1999 NA Both Prospective Adult No Yes High High Low Salonen et al34 2000 1999 Both Retrospective Adult No No Low High Low Ramila et al72 2000 NA Both Prospective Both No Yes Low High Low Huaringa et al73 2000 NA HSCT Retrospective NA No No Low High Low Soubani et al21 2001 NA HSCT Retrospective Adult No No High High Low Murray et al74 2001 1999 Both Retrospective Adult No No Low High Low Ben-Ari et al75 2001 1999 HSCT Retrospective Pediatric No No Low High Low van Elden et al76 2002 2000 Both Retrospective Adult No No High High Low Buchheidt et al43 2002 2000 Both Prospective Adult No Yes Low Low Low Raad et al46 2002 1997 Cancer Prospective Both No No Low Low Low Park et al77 2002 1998 Cancer Retrospective Pediatric No No Low High Low Neumann et al78 2002 NA Cancer Prospective Pediatric No Yes Low Low Low Becker et al37 2003 2001 Both Prospective Adult No Yes Low Low Low Ison et al79 2003 NA HSCT Retrospective Both No No High High High Mulabecirovic et al19 2004 2002 Both Retrospective Adult Yes No Low High Low Patel et al20 2005 2001 HSCT Retrospective Adult No No Low High Low Hohenthal et al27 2005 2002 Both Retrospective Adult No No Low High Low Bissinger et al35 2005 NA Both Retrospective Adult No No Low High Low Martino et al80 2005 2003 HSCT Prospective Adult No Yes Low Low Low Eikenberry et al81 2005 1999 HSCT Retrospective Pediatric No Yes Low High Low Hofmeister et al30 2006 2004 HSCT Retrospective Both No No Low High High Gupta et al15 2007 2004 HSCT Retrospective Adult No No High High Low Burger et al82 2007 1998 HSCT Retrospective Adult No No Low High Low Boersma et al23 2007 NA Cancer Prospective Adult Sometimes Yes Low Low High Kasow et al24 2007 2002 HSCT Retrospective Both No No Low High Low Armenian et al16 2007 2003 Both Retrospective Pediatric No No Low High Low Rabbat et al25 2008 2002 Both Prospective Adult No No High High Low Penack et al41 2008 NA Both Prospective Adult No No Low High Low Khot et al45 2008 2003 Both Retrospective Adult No No Low High Low Azoulay et al31 2008 NA Both Prospective Adult No No High Low Low Cordani et al33 2008 2008 Cancer Retrospective Adult Sometimes No Low High Low Hummel et al36 2008 2003 Both Retrospective Both No Yes Low High High

(continued on following page)

Chellapandian et al

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Table A2. Characteristics of Included Studies of BAL in the Meta-Analysis (continued)

Reference Year

Published Year Study

Ended Diagnosis

Type Study Design Population Brushing� Indication Protocol†

Risk of Bias

Patient Selection

Index Test

Flow and Timing

Furuya et al26 2008 2005 Cancer Retrospective Pediatric No Yes Low High Low Frealle et al38 2009 2004 Both Retrospective Adult No No Low Low Low Kuehnhardt et al48 2009 2004 Both Retrospective Both No No Low High Low Shannon et al28 2010 1999 HSCT Retrospective Adult No No Low High Low Azoulay et al49 2010 2007 Both Prospective Adult No Yes High Low Low Luong et al39 2010 2008 Both Retrospective Adult No No High Low High Bergeron et al32 2010 2006 Both Retrospective Adult No Yes Low Low Low Forslow et al29 2010 2004 HSCT Retrospective Both Sometimes No Low High Low Nguyen et al40 2011 2006 Both Retrospective Adult No No Low High Low Racil et al42 2011 2009 Cancer Retrospective Adult No No Low High High Reinwald et al12 2012 2011 Both Prospective Both No No Low Low High Gilbert et al18 2013 2009 HSCT Retrospective Adult Sometimes No Low High Low Gassas et al17 2013 2010 HSCT Retrospective Pediatric No No High High Low Rao et al50 2013 2009 Both Retrospective Pediatric No No Low High Low

NOTE. Under Diagnosis Type, “both” means the study included both HSCT and patients with cancer. Under Population, “both” means the study included both adult and pediatric patients. Abbreviations: BAL, bronchoalveolar lavage; HSCT, hematopoietic stem-cell transplantation; NA, not applicable. �Brushing used during the BAL process. †Indication for BAL standardized.

Lung Procedures in Cancer and Stem-Cell Transplantation

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Table A3. Characteristics of Included Studies of Lung Biopsy in the Meta-Analysis

Reference Year

Published Year Study

Ended Diagnosis

Type Study Design Population Type of Biopsy

Indication Protocol�

Risk of Bias

Patient Selection

Index Test

Flow and Timing

Shulman et al93 1982 1980 HSCT Retrospective NA Transthoracic No Low High Low Springmeyer et al84 1982 1978 HSCT Prospective NA Transthoracic No High Low Low McCabe et al94 1985 1982 Cancer Retrospective Both Transthoracic No High High Low Hall et al95 1987 1986 Both Retrospective Both Transthoracic No Low High Low Crawford et al83 1988 1987 HSCT Retrospective Both Transthoracic No Low High Low Shorter et al96 1988 1986 HSCT Retrospective Pediatric Transthoracic No Low High Low Snyder et al97 1990 1988 HSCT Retrospective Both Transthoracic No Low High Low White et al22 1997 1995 HSCT Retrospective Adult Transbronchial No Low High Low Won et al98 1998 1997 Both Prospective Both Transthoracic No High High Low White et al99 2000 1998 Both Retrospective Adult Transthoracic No Low High Low Soubani et al21 2001 NA HSCT Retrospective Adult Transbronchial No High High Low Dunn et al100 2001 1998 HSCT Retrospective Pediatric Transthoracic No Low High Low Hayes-Jordan et al101 2002 1998 HSCT Retrospective Pediatric Transthoracic No Low High Low Kim et al102 2002 2001 Both Retrospective Both Transthoracic No Low High Low Shaikh et al103 2002 1999 HSCT Retrospective Both Transthoracic No Low High Low Jantunen et al104 2002 1998 HSCT Retrospective Both Transthoracic No Low High Low Nosari et al105 2003 2002 Cancer Retrospective Adult Transthoracic No Low High Low Gulbahce et al86 2004 1998 HSCT Retrospective Both Transthoracic No High High Low Wang et al85 2004 2001 HSCT Retrospective Both Transthoracic No High High Low Mulabecirovic et al19 2004 2002 Both Retrospective Adult Transbronchial No Low High Low Patel et al20 2005 2001 HSCT Retrospective Adult Transbronchial No Low High Low Zihlif et al106 2005 2003 Both Retrospective Adult Transthoracic No Low High Low Carrafiello et al107 2006 2003 Cancer Retrospective Adult Transthoracic No Low High Low Yang et al108 2007 2005 HSCT Retrospective Adult Transthoracic No High High Low Armenian et al16 2007 2003 Both Retrospective Pediatric Transthoracic† No Low High Low Armenian et al16 2007 2003 Both Retrospective Pediatric Transthoracic† No Low High Low Kallenberg et al87 2009 2007 Both Retrospective Adult Transthoracic No Low Low Low Gupta et al88 2010 2005 Cancer Retrospective Adult Transthoracic No Low High Low Gilbert et al18 2013 2009 HSCT Retrospective Adult Transbronchial No Low High Low Gassas et al17 2013 2010 HSCT Retrospective Pediatric Transthoracic No Low High Low Sharma et al89 2013 2011 Cancer Prospective Adult Transthoracic Yes Low High Low

NOTE. Under Diagnosis Type, “both” means the study included both HSCT and patients with cancer. Under Population, “both” means the study included both adult and pediatric patients. Abbreviations: HSCT, hematopoietic stem-cell transplantation; NA, not available. �Indication for bronchoalveolar lavage standardized. †Study described open and image-guided lung biopsies as two separate cohorts.

Chellapandian et al

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Bronchoalveolar Lavage and Lung Biopsy in Patients With Cancer and Hematopoietic Stem-Cell Trans …
INTRODUCTION
METHODS
Data Sources and Searches
Study Selection
Data Abstraction and Methodologic Approach
Assessment of Study Quality
Statistical Methods
RESULTS
DISCUSSION
REFERENCES
Acknowledgment
Appendix
731

□ ORIGINAL ARTICLE □

Safety and Efficacy of Bronchoalveolar Lavage Using a Laryngeal Mask Airway in Cases of Acute Hypoxaemic

Respiratory Failure with Diffuse Lung Infiltrates

Takafumi Matsumoto, Yoko Sato, Satoshi Fukuda, Shinshu Katayama, Yuya Miyazaki, Makoto Ozaki and Toru Kotani

Abstract

Objective Fibre-optic bronchoscopy with bronchoalveolar lavage (FOB-BAL) is an important tool for diag- nosing and selecting treatment for acutely hypoxaemic patients with diffuse lung infiltrates. However, FOB- BAL carries a risk of significant hypoxaemia and subsequent tracheal intubation during and after the proce- dure. The application of FOB-BAL using a laryngeal mask airway (LMA) in combination with continuous positive airway pressure (CPAP) may minimize the incidence of hypoxaemia; however, the safety and effi- cacy of this procedure have not been investigated. Methods A retrospective chart review was performed from April to September 2013. Data regarding the re- covered volume of BAL fluid, incidence of tracheal intubation within eight hours after the completion of FOB-BAL, respiratory and haemodynamic parameters and treatment modifications were collected for the evaluation. Results Ten trials of FOB-BAL using an LMA and CPAP were performed in nine patients with severe acute hypoxaemia associated with diffuse lung infiltrates. The BAL fluid recovery rate was 56%, and the pro- cedure was completed without subsequent complications. In addition, the percutaneous arterial oxygen satura- tion decreased to 95.7%±3.8%, although it was never lower than 90.0% during the procedure, and no patients required intubation. Furthermore, the arterial blood pressure significantly but transiently decreased due to se- dation, and the procedure yielded diagnostic information in all nine patients. Conclusion FOB-BAL using LMA and CPAP appears to be safe and effective in patients who develop se- vere acute hypoxaemia.

Key words: bronchoalveolar lavage, continuous positive airway pressure, fibre-optic bronchoscopy, laryngeal mask airway, sedation

(Intern Med 54: 731-735, 2015) (DOI: 10.2169/internalmedicine.54.2686)

Introduction

In acutely hypoxaemic patients with diffuse pulmonary infiltrates, it is important to establish the specific cause of pulmonary disease so that appropriate therapy may be pro- vided immediately. Fibre-optic bronchoscopy with bron- choalveolar lavage (FOB-BAL) is an important tool for di- agnosing diffuse pulmonary infiltrates (1). Although FOB- BAL is generally considered to be safe (2), it is well known

that the arterial blood oxygen saturation usually decreases during and/or after the procedure (3-6). Therefore, FOB- BAL is contraindicated in non-intubated, severely hypoxae- mic patients (7). Positive end-expiratory pressure ameliorates hypoxaemia by preventing alveolar collapse, although some type of airway management is necessary for its use. While tracheal intubation is the most reliable airway management technique, certain complications may occur during intuba- tion and/or after extubation (8). Therefore, the development of a strategy other than intubation to prevent hypoxaemic

Department of Anesthesiology and Intensive Care Medicine, Tokyo Women’s Medical University, Japan Received for publication February 12, 2014; Accepted for publication August 17, 2014 Correspondence to Dr. Toru Kotani, tkotani@anes.twmu.ac.jp

Intern Med 54: 731-735, 2015 DOI: 10.2169/internalmedicine.54.2686

732

events during FOB-BAL is required. The laryngeal mask airway (LMA) is a supraglottic air-

way device that provides an end-to-end airtight seal around the larynx and maintains effective gas exchange (9, 10). An advantage of LMA is that it can be blindly inserted without laryngoscopy; thus, cardiovascular responses to the introduc- tion of an LMA are less severe than those induced by tra- cheal intubation (11, 12). The LMA technique for both spontaneous and controlled ventilation is reportedly both safe and effective (13), and a recent study demonstrated that FOB-BAL can be safely and effectively performed with an LMA in immunosuppressed patients with pneumonia and se- vere hypoxaemia (14).

In our intensive care unit, FOB-BAL is routinely per- formed using an LMA in combination with continuous posi- tive airway pressure (CPAP) under light sedation in acutely hypoxaemic patients with diffuse lung infiltrates in order to prevent hypoxaemic events during and after the examination. We subsequently conducted a retrospective case-series study of FOB-BAL to demonstrate its safety and efficacy.

Materials and Methods

A retrospective chart review was performed from April to September 2013. Data were collected for patients with dif- fuse pulmonary infiltrates who exhibited acute hypoxaemic respiratory failure requiring oxygen therapy or non-invasive positive airway pressure ventilation (NPPV) and who under- went FOB-BAL for diagnostic or therapeutic reasons. Data for demographic variables, the ratio of arterial blood oxygen saturation to the fraction of inspired oxygen under CPAP of 5 cm H2O, Simplified Acute Physiological Score II and un- derlying diseases were also obtained. NPPV was applied us- ing a ventilator (Respironics V60; Respironics California, Carlsbad, USA) via a full-face mask. Local research ethics committee approval was received for the retrospective re- view of the patients.

FOB-BAL was performed according to the standard pro- cedures in place at our intensive care unit. Briefly, none of the patients had a contraindication to the insertion of an LMA (15) before undergoing the procedure. One physician was in charge of sedation and haemodynamic management. A flexible fibre-optic bronchoscope (BF-P60; Olympus, To- kyo, Japan), LMA (LMA Supreme; Teleflex Medical, San Diego, USA or i-gel; Intersurgical, Wokingham, Berkshire, UK), topical anaesthetic (4% lidocaine hydrochloride), seda- tives (propofol and fentanyl), vasopressor (phenylephrine hy- drochloride) and warm sterile 0.9% saline solution for BAL were prepared prior to the examination. A properly sized LMA (size 3 or 4) was chosen for each patient and lubri- cated with 2% lidocaine gel. The medical team was pre- pared for tracheal intubation and invasive ventilation while performing the procedure.

An electrocardiogram, non-invasive and/or invasive blood pressure measurements, percutaneous arterial oxygen satura- tion and respiratory rate were continuously monitored during

the procedure. Initially, CPAP was applied via a full-face mask. The positive end-expiratory pressure was set at 5 cm H2O or the pre-bronchoscopy level. The fraction of inspired oxygen was increased to 1.0. Topical anaesthesia was ap- plied to the oral cavity and larynx by thoroughly spraying 4% lidocaine hydrochloride. Sedation was initiated by the incremental administration of a combination of 25 μg of fentanyl and 20 to 30 mg of propofol followed by the infu- sion of 1 to 3 mg/kg/h of propofol to maintain spontaneous breathing. After confirming the patient’s unconsciousness, the LMA was inserted and connected to the ventilator via a swivel connector (Sontek Suction-Safe Swivel Y; Sontek Medical, Hingham, USA). Mechanical ventilation was ap- plied in the spontaneous/timed mode in order to maintain the minute volume in case of suppression of spontaneous breathing secondary to sedation. The bronchoscope was in- troduced through the swivel connector. After examining the tracheobronchial tree and providing topical anaesthesia, the tip of the bronchoscope was wedged into the subsegmental area with the most severe X-ray abnormalities. The bronchus was instilled with sterile saline (five 20-mL aliquots) and gently aspirated. The obtained fluid was pooled, processed and immediately sent to the laboratory for cytologic and mi- crobiological examinations. The LMA was removed when the patient had completely emerged from anaesthesia and was able to obey commands. After removing the LMA, NPPV was continued with a full-face mask. The fraction of inspired oxygen was gradually decreased to the pre- bronchoscopy level. Patients who did not require NPPV be- fore the examination were switched back to conventional oxygen therapy.

The rate of intubation within eight hours after the com- pletion of FOB-BAL and the changes in the respiratory rate, mean arterial pressure and heart rate just before sedation, during FOB-BAL and one hour after FOB-BAL were re- corded and compared. The lowest arterial blood oxygen saturation noted during the procedure was recorded, and the volume of BAL aspirated was documented as a percentage of the instilled aliquot. Treatment modifications based on the BAL analysis were also evaluated.

The results are expressed as the mean ± standard devia- tion (95% confidence interval). An analysis of variance was used to compare respiratory and haemodynamic parameters obtained just before sedation and during and after the FOB- BAL procedure. A p value of <0.05 was considered to be statistically significant.

Results

Data for 14 cases of FOB were collected during the study period. Ten FOB-BAL procedures using an LMA and CPAP were performed in nine consecutive patients. The character- istics of the patients are shown in Table 1. Eight patients (89%) received immunosuppressive therapy for renal trans- plantation (n=5), rheumatoid arthritis (n=2) and rapidly pro- gressive glomerulonephritis (n=1). The mean ratio of arterial

Intern Med 54: 731-735, 2015 DOI: 10.2169/internalmedicine.54.2686

733

Table 1. Patient Characteristics

Demographic data No. of patients 9 Age (years) 67.5 ± 12.7 (57.7-77.3) Gender ratio (F/M) 2/7 BMI (kg/m2) 21.5 ± 2.5 (19.6-23.5)

Physiological data SAPSII 39.9 ± 10.3 (31.9-47.9) PaO2/FiO2 206.7 ± 55.5 (170.0-246.4)

Underlying diseases and comorbidities Immunocompromised

Renal transplantation 5 (55.6%) Rheumatoid arthritis 2 (22.2%) Rapidly progressive glomerulonephritis 1 (11.1%)

Haematological malignancy 1 (11.1%) Use of vasopressor 1 (11.1%) Use of NPPV prior to FOB-BAL 6 (66.7%) PEEP (cm H2O) 6.7 ± 1.3 (5.4-8.0)

The data are presented as the mean ± standard deviation (95% confidence interval) or n (%). F: female, M: male, BMI: body mass index, SAPS II: Simplified Acute Physiological Score II, PaO2/FiO2: ratio of arterial blood oxygen saturation to fraction of inspired oxygen, NPPV: non-invasive positive airway pressure ventilation, FOB-BAL: fibre-optic bronchoscopy with bronchoalveolar lavage, PEEP: positive end-expiratory pressure

blood oxygen saturation to the fraction of inspired oxygen before FOB-BAL was 206.7±55.5 (170.0-246.4) mmHg. NPPV was performed in six patients (67%) prior to FOB- BAL, with a positive end-expiratory pressure of 6.7±1.3 (5.4-8.0) cm H2O.

The duration of FOB-BAL was 20.3±3.7 (17.6-30.0) min- utes. The total doses of propofol and fentanyl were 129.9± 59.6 (93.6-166.1) mg and 102.5±18.4 (89.3-115.7) μg, re- spectively. The mean positive end-expiratory pressure during the procedure was 6.5±1.4 (5.4-7.5) cm H2O. The spontane- ous/timed mode was temporarily applied with an inspiratory positive airway pressure of 14.0±0.7 (11.7-16.2) cm H2O in four patients (44.4%). No patients required tracheal intuba- tion within eight hours after FOB-BAL. Only one patient was intubated three days after FOB due to progression of the underlying disease.

The procedure was completed without subsequent compli- cations in all cases. The cardiorespiratory parameters ob- tained just before sedation, during FOB-BAL and one hour after FOB-BAL are shown in Figure. The changes in the respiratory rate and heart rate induced by the procedure did not reach statistical significance. In contrast, the mean arte- rial blood pressure during the procedure significantly de- creased. However, the haemodynamic changes were modest and transient, with the use of phenylephrine hydrochloride. The mean arterial oxygen saturation was 95.7%±3.8% (93.0%-98.4%), and no patients exhibited an arterial blood oxygen saturation of <90.0% during the procedure. Two pa- tients were switched back to oxygen therapy after the proce- dure. No other adverse events were noted, such as laryn- gospasms, coughing, haemorrhage, arrhythmia or pneumot- horax.

The results of FOB-BAL are shown in Table 2. The mean percentage volume of recovered BAL fluid was 56.1%±

11.1% (48.1-64.0%). The procedure yielded diagnostic in- formation for nine patients (90%). Pneumocystis pneumonia was diagnosed in eight patients, and acute exacerbation of collagen vascular disease-associated interstitial pneumonia was diagnosed in one case. Treatment was modified in nine procedures based on the results of the BAL analysis (90%).

Discussion

In this study, we found that FOB-BAL using an LMA and CPAP prevented hypoxaemic events and major compli- cations, including tracheal intubation, and contributed to treatment modification, suggesting that this technique is safe and effective in patients with severe acute hypoxaemia and diffuse lung infiltrates. The procedure was well tolerated in all patients. This is the first study to assess the feasibility of FOB-BAL using an LMA in combination with CPAP under light sedation.

The occurrence of hypoxaemia during FOB has been re- ported in several studies (3, 4, 6). Such hypoxaemia may be caused by partial airway obstruction induced by the bron- choscope, airway suction, anaesthetics or presence of lavage fluid in the alveoli (4, 16). Mechanical ventilation with air- way management must be performed in patients undergoing FOB-BAL to ameliorate hypoxaemia and maintain adequate gas exchange during the procedure, and tracheal intubation is the most reliable method for achieving these goals. How- ever, various complications may occur, such as cardiovascu- lar responses to tracheal intubation, with subsequent vocal dysfunction and/or laryngeal disorders after extuba- tion (8, 17, 18). In the current study, the arterial blood oxy- gen saturation was maintained above 91% in all patients.

NPPV delivers positive pressure without the use of an ar- tificial airway and is a safe and effective method for amelio- rating hypoxaemia in patients with acute respiratory fail- ure (19, 20). The feasibility and safety of NPPV using a full-face mask for FOB-BAL has been reported in previous studies (5, 21-28). However, in the majority of these studies, bronchoscopy was performed with only topical anaesthesia (5, 22-24, 26, 27), and essential problems included low tol- erance to mask fitting and FOB-BAL in conscious patients. Patient agitation may lead to desaturation and possibly com- promise the success of the FOB-BAL procedure (25). One previous study described the difficulties in performing bron- choscopy without sedation, with analgosedation used in all patients (14). LMAs provide upper airway patency even in cases of deep sedation or general anaesthesia, which subse- quently ensures excellent visualization of the vocal cords, glottis and trachea without decreasing the airway diameter as do tracheal tubes, thus avoiding increases in airway resis- tance (9, 10, 29-31). In our procedure, the use of appropri- ate sedation and positive pressure ventilation with an LMA helped to yield diagnostic information by allowing for the recovery of a sufficient volume of bronchoalveolar lavage fluid (BALF).

It is important to minimize the cardiorespiratory response

Intern Med 54: 731-735, 2015 DOI: 10.2169/internalmedicine.54.2686

734

Figure. Variation in cardiorespiratory parameters. The respiratory rate (panel A ), heart rate (pan- el B ) and mean arterial pressure (panel B ) were recorded as follows: just before sedation (before), during fibre-optic bronchoscopy with bronchoalveolar lavage (during) and one hour after fibre-optic bronchoscopy with bronchoalveolar lavage (one hour after). The data are expressed as the mean ± standard deviation. *p<0.05 for comparison with the baseline data (obtained just before sedation). The lowest value of each parameter observed during the procedure was recorded. RR: respiratory rate, HR: heart rate, MAP: mean arterial pressure

Table 2. Characteristics and Results of Fibre- optic Bronchoscopy with Bronchoalveolar Lavage

Duration of FOB-BAL (min) 20.3 ± 3.7 (17.6-30.0) No. of FOB-BAL 10 (100%) BAL Volume instilled (mL) 100 Volume recovered (mL) 56.1 ± 11.1 (48.1-64.0) Diagnostic yield of FOB-BAL 9 (90%)

The data are presented as the mean ± standard deviation (95% confidence interval) or n (%). FOB-BAL: fibre-optic bronchoscopy with bronchoalveolar lavage

during the procedure in severely hypoxaemic patients, and inducing coughing is critical in subjects on long-term steroid therapy. In our strategy, the application of topical anaesthe- sia to the oral cavity followed by the maintenance of anaes- thesia using propofol and fentanyl resulted in better toler- ance of FOB. The administration of propofol enables the level of sedation to be adjusted, with rapid elimination of the drug. The majority of previous studies have used this medication to both insert the LMA (15, 32) and perform FOB (9, 14, 21, 25, 33). Fentanyl is a strong analgesic and antitussive that can be employed to reduce the amount of propofol required. In general, the amount of anaesthetics or analgesics needed to establish an LMA is less than that re- quired for tracheal intubation. Recent studies have also dem- onstrated the occurrence of alveolar hypoventilation, as esti- mated by an increase in the partial pressure of carbon diox- ide, during FOB under sedation (21, 34). In our procedure, mechanical ventilation is immediately applied to maintain the appropriate minute volume if the sedatives suppress the patient’s spontaneous breathing. Furthermore, the mean per- centage of BALF volume recovered was higher in this re- port than in previous studies involving the use of NPPV- assisted FOB-BAL (21, 25, 28). Positive pressure ventilation may allow for a sufficient volume of BALF to be recovered,

thus providing diagnostic information. Our procedure is associated with some limitations. It

should be emphasized that well-trained physicians are needed to perform both bronchoscopy and anaesthesia, and the procedure should be carried out in the intensive care unit in order to allow for close monitoring. Therefore, our results may not be generalizable to other settings. In addition, this was a retrospective observational study, and the sample size was small. Although we included patients consecutively dur- ing the study period, the background characteristics of the patients were biased. Furthermore, the use of blood gas analyses under CPAP of 5 cm H2O may reflect a higher ra- tio of arterial blood oxygen tension to the fraction of in- spired oxygen before FOB-BAL compared to that seen in previous studies. A prospective study is therefore warranted to confirm the advantages of LMA over tracheal intubation under the same conditions.

In conclusion, the use of LMA in combination with CPAP under light sedation can be used to provide a safe and effective FOB-BAL procedure in patients with severe acute hypoxaemic respiratory failure.

The authors state that they have no Conflict of Interest (COI).

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Ⓒ 2015 The Japanese Society of Internal Medicine http://www.naika.or.jp/imonline/index.html
RESEARCH ARTICLE

Flexible Bronchoscopy with Multiple Modalities for Foreign Body Removal in Adults Yueh-Fu Fang1,2‡, Meng-Heng Hsieh1,2‡, Fu-Tsai Chung1,2, Yao-Kuang Huang2,3, Guan- Yuan Chen1,2, Shu-Min Lin1,2, Horng-Chyuan Lin1,2, Chin-HwaWang1,2, Han-Pin Kuo1,2*

1 Department of Thoracic Medicine, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 2 College of Medicine, Chang Gung University, Taoyuan, Taiwan, 3 Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chia-Yi, Taiwan

‡Contributed equally to this work with: Yueh-Fu Fang, Meng-Heng Hsieh. * q8828@ms11.hinet.net

Abstract

Objectives Aspiration of the lower airways due to foreign body is rare in adults. This study aimed to de- termine the outcome of patients who received flexible bronchoscopy with different modali- ties for foreign body removal in the lower airways.

Patients and Methods Between January 2003 and January 2014, 94 patients diagnosed with foreign body in the lower airways underwent flexible bronchoscopy with different modalities, which included for- ceps, loop, basket, knife, electromagnet, and cryotherapy. The clinical presentation, foreign body location and characteristics, and applications of flexible bronchoscopy were analyzed.

Results Forty (43%) patients had acute aspiration, which developed within one week of foreign body entry and 54 (57%) had chronic aspiration. The most common foreign bodies were teeth or bone. More patients with chronic aspiration than those with acute aspiration were referred from the out-patient clinic (48% vs. 28%), but more patients with acute aspiration were re- ferred from the emergency room (35% vs. 6%) and intensive care unit (18% vs. 2%). Flexi- ble bronchoscopy with different modalities was used to remove the foreign bodies (85/94, 90%). Electromagnet or cryotherapy was used in nine patients to eliminate the surrounding granulation tissue before foreign body removal. In the nine patients with failed flexible bron- choscopy, eight underwent rigid bronchoscopy instead and one had right lower lung lobec- tomy for lung abscess.

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OPEN ACCESS

Citation: Fang Y-F, Hsieh M-H, Chung F-T, Huang Y- K, Chen G-Y, Lin S-M, et al. (2015) Flexible Bronchoscopy with Multiple Modalities for Foreign Body Removal in Adults. PLoS ONE 10(3): e0118993. doi:10.1371/journal.pone.0118993

Academic Editor: Jeffrey A. Gold, Oregon Health and Science University, UNITED STATES

Received: June 24, 2014

Accepted: January 8, 2015

Published: March 13, 2015

Copyright: © 2015 Fang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability Statement: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing Interests: The authors have declared that no competing interests exist.

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Conclusions Flexible bronchoscopy with multiple modalities is effective for diagnosing and removing for- eign bodies in the lower respiratory airways in adults, with a high success rate (90%) and no difference between acute and chronic aspirations.

Introduction Foreign body aspiration into the lower airway is less likely in adults than in children.(1–8) Some adult patients have acute aspiration within one week but often have no acute symptoms that occur in children or infants. Others have no acute aspiration history within one month but may have only chronic cough without dyspnea, wheeze, or chest pain. Thus, the diagnoses of aspirated foreign bodies may be delayed.(1, 2) In such patients, foreign bodies are incidental findings during bronchoscopy for lung collapse or delayed pneumonia resolution. Foreign bod- ies may be embedded in granulation tissue and difficult to remove.(2, 9)

Flexible or rigid bronchoscopy is the method used to diagnose and remove foreign bodies. Flexible bronchoscopy is more convenient as patients are only lightly sedated. Granulation tis- sue may grow and cover the foreign body in patients with chronic aspiration. As such, the for- eign body may be hard to remove if only suction, forceps, loops, or baskets are used. In therapeutic bronchoscopy or cryobiopsy, electromagnet or cryotherapy is applied.(10–14) These methods can be performed in flexible bronchoscopy for patients with foreign body and granulation tissue. The electromagnet or cryotherapy can cut or destroy the granulation tissue before the forceps, loops or baskets are used to remove the foreign body.

This study reviewed the records of patients who received bronchoscopy between January 2003 and January 2014 for foreign body in the lower airways to determine their outcomes and the success rate of the procedure for removing foreign bodies.

Patients and Methods All patients who received flexible bronchoscopy at the Interventional Bronchoscopy Center of Chang Gung Memorial Hospital, Linkou Medical Center between January 2003 and January 2014 were initially included. The patients were referred from the outpatient clinic, emergency room, general ward, and intensive care unit. Flexible bronchoscopy was the first method used, within 24 hours or immediately at the emergency room, to diagnose the presence of a foreign body in the lower airways in adult patients in the hospital. Based on the hospital protocol, the foreign body was removed in the same bronchoscopic examination used for diagnosing the for- eign body in the lower airway.

Patients diagnosed with foreign body in their lower respiratory tract were selected. They all received flexible bronchoscopy as diagnostic and therapeutic management. The modalities used included forceps, loop, basket, knife, electromagnet, and cryotherapy. Electromagnet, electro-forceps, Nd-YAG, or cryotherapy was used to destroy or remove granulation tissue. In some patients, endobronchial ultrasound was used to detect foreign bodies embedded in the granulation tissue.

The patients’ general characteristics, indications of bronchoscopy, foreign body location, types of foreign bodies, and modality used for removing the foreign bodies were assessed. Acute aspiration was defined as aspiration that developed within one week of foreign body entry while chronic aspiration was defined as chocking history more than one month or no

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definite chocking history. Asymptomatic patients with abnormal X-ray results, including those with incidental findings of suspected foreign bodies in the airways, lung collapse, or delayed resolution of pneumonia were considered as chronic aspiration. Differences between the acute and chronic aspiration groups, including the locations and types of foreign bodies, use of elec- tromagnet or cryotherapy, and success rate were analyzed.

Ethics statement Our study was a retrospective study of chart review. All the patients had signed the permits of interventional bronchoscopy, included removing foreign body, and electrocoagulation or cryo- therapy for granulation tissue. The permits of all procedures were reviewed by the institutional Review Board of the Chang Gung Medical Foundation. The additional informed consents were not required for this retrospective study of chart review. The identified information of the

Table 1. Patient Characteristics.

Sex

Male 67 71%

Female 27 29%

Age range (median),years 18–98 (66)

Patient source

Outpatient clinic 37 39%

Emergency room 17 18%

Ward 32 34%

Intensive Care Unit 8 9%

Indications of bronchoscopy

Chocking and/or visible foreign body in image 51 54%

Lung collapse or delayed resolution 43 46%

Location

Trachea 4 4%

Right lung 55 59%

Right main bronchus 4 (4%)

Right intermediate bronchus 21(22%)

Right middle bronchus 6 (6%)

Right lower bronchus 24(26%)

Left lung 35 37%

Left main bronchus 20(21%)

Left upper bronchus 5 (5%)

Left lower bronchus 10(11%)

Foreign body

Tooth (original or artificial) 20 23%

Bone (chicken, fish, pork) 29 31%

Teeth stick 2 2%

Bean/corn/vegetable 17 18%

Shrimp 2 2%

Fiber/cotton 6 6%

Plump 4 4%

Peanut 4 4%

Mental wire 2 2%

Others 8 9%

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patients, included their names and chart numbers, was deleted for de-identification before data analysis. The method assurance of patient confidentiality, and design of project were all ap- proved by the institutional Review Board of the Chang Gung Medical Foundation (IRB No. 100–3211B)

Results Clinical Characteristics After reviewing 38314 patients who received flexible bronchoscopy, 94 were diagnosed with foreign bodies in their lower respiratory tract, including 67 (71%) males and 27 (29%) females. (Table 1) Thirty-seven (39%) were referred from the out-patient clinic, 17 (18%) from the emergency room, 32 (34%) from the general ward, and eight (9%) from the intensive care unit. Fifty-one (54%) patients had a definite history of acute aspiration or chest x-rays that showed suspected a foreign body in the lower airways, while 43 (46%) had no definite history of aspira- tion or visible foreign body on their chest X-ray or computed tomography (CT) imaging.

Removal of Foreign Body In the 94 patients, four (4%) had a foreign body in the trachea, 55 (59%) had it in the right lung, and 35 (37%) had it in the left lung (Table 1). Twenty-nine (31%) had bone as the foreign body and 20 (23%) had a tooth. The other foreign bodies included vegetables, flosser, cotton, shrimp, core of plum, peanut, and metal wire. The modalities used for removing the foreign bodies were direct suction by bronchoscopy, forceps, loops, knife, basket, electromagnet, and cryotherapy (Fig. 1).

Foreign body removal was successful in 85 (90%) patients but failed in nine (10%). Eight of the nine patients received rigid bronchoscopy for removal of the foreign body, while one had right lung lobectomy for lung abscess. Nine (10%) of the 94 patients used electromagnet or cryotherapy to remove the granulation tissue that covered the foreign body.

Acute and Chronic Aspiration Forty (47%) patients were referred for acute aspiration, which occurred within one week, while 54 (53%) had chronic aspiration. (Table 2) More patients with acute aspiration than those with chronic aspiration were referred from the emergency room (14 [35%] vs. 3 [6%]) and intensive care unit (7 [18%] vs. 1 [2%]). On the other hand, more patients with chronic aspiration were referred from the out-patient clinic (26 [48%] vs. 11 [28%]) and general ward (24 [44%] vs. 8 [20%]).

In acute aspiration, most patients had chocking of tooth (18/40, 45%). In patients with chronic aspiration, the most common foreign bodies were bone (24/54, 44%) or vegetables (13/ 54, 24%). Eight (15%) of fifty-four patients with chronic aspiration needed electromagnet or cryotherapy, whereas only one patient with acute aspiration needed electromagnet for foreign body removal. The success rate of foreign body removal was not different between the two groups (36 [90%] vs. 49 [91%]).

Electromagnet and Cryotherapy Forty-three patients had granulation tissue, including nine who needed electromagnet or cryo- therapy to remove the granulation tissue that partially or totally covered the foreign bodies (Fig. 2A and 2B). Electromagnet or cryotherapy was done for the granulation tissue or masses in the lower airway (Fig. 2C). The foreign body was removed after removal of the granulation tissue (Fig. 2D), which revealed a patent bronchial lumen (Fig. 2E and 2F).

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Fig 1. Themultiple modalities of the flexible bronchoscopy included forceps, basket, loop, coagulation forceps, coagulation knife, and probe for cryotherapy.

doi:10.1371/journal.pone.0118993.g001

Table 2. Comparison of Patients with Acute and Chronic Aspiration.

Acute aspiration Chronic aspiration p value#

Number of patients 40 54

Sex

Male 28 29 0.11

Female 12 25

Age range (median), years 20–98 (67) 18–83(63)

Patient source <0.001

Outpatient clinic 11 26

Emergency room 14 3

Ward 8 24

Intensive Care Unit 7 1

Location 0.90

Trachea 2 2

Right lung 24 31

Left lung 14 21

Foreign body <0.001

Tooth (original or artificial) 18 2

Bone (chicken, fish, pork) 5 24

Teeth stick 1 1

Bean/corn/vegetable 4 13

Shrimp 2 0

Fiber/cotton 3 3

Plump 2 2

Peanut 1 3

Mental wire 1 1

Others 3 5

Granulations 6 37

Electromagnet or cryotherapy 1 8 0.049

Removal of foreign body

Success 36 49 0.90

Failed 4 5

#Fisher’s exact tests.

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Failed Foreign Body Removal by Flexible Bronchoscopy Nine patients had failed foreign body removal by flexible bronchoscopy. Four patients with acute aspiration received rigid bronchoscopy to remove the foreign body. One patient had gar- lic in the right intermediate bronchus and one had of plum in the right main bronchus with lung collapse. These two patients had complete airway obstruction. The other two patients had a prosthetic tooth in the right intermediate bronchus or the left main bronchus, with mucosal invasion and bleeding.

In the other five patients with chronic aspiration, two had a bone in the right lower lung bronchus, one had bone in the right intermediate bronchus, one had fish bone in the left main bronchus, and one had a catheter in the right intermediate bronchus. The one patient with a bone in the right lower lung bronchus had lung abscess that eventually needed lobectomy. The other four cases had foreign bodies that were deeply embedded in granulation tissue. There was easy bleeding whenever the bronchoscope passed the mucosa, making removal of the for- eign bodies more difficult. These four patients received rigid bronchoscopy instead.

Discussion This study demonstrates a high prevalence of chronic aspiration secondary to a foreign body in adult patients. Lung collapse and obstructive pneumonia are common complications and the most common foreign bodies are bone in chronic aspiration and teeth in acute aspiration. There is also a predominance of male patients and involvement of the right bronchus. These re- sults are similar to those of previous reports.(1, 2, 8)

About half of the patients have no history of acute aspiration or a visible foreign body in chest imaging. The manifestations are different in adults and in children, (1–3, 5, 7, 8)although some reports of adult patients also show similar results.(1, 2) This is due to the larger diameter of the adult bronchus, which cannot be totally obstructed by a foreign body. Some adult

Fig 2. (A) Atelectasis of the right lower lung. (B) Foreign body in the right intermediate bronchus. (C) Granulation tissue covered the foreign body. (D) Bony foreign body after removing the granulation tissue by cryotherapy and forceps. (E) A patent right intermediate bronchus is noted after foreign body removal. (F) The foreign body.

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patients are asymptomatic, causing delayed diagnoses, such that these patients are diagnosed only after lung collapse or the development of obstructive pneumonia.

The prevalence of acute aspiration is higher in this study than in the report of Chen from another medical center in Taiwan.(2) In the current study setting, the Interventional Bronchos- copy Center can perform bronchoscopy for acute aspiration within 24 hours and immediately at the emergency room for patients with respiratory distress or respiratory failure. Thus, many patients with acute aspiration are referred to the emergency room and any special situation may increase the patient numbers with acute aspiration.

Of the eight patients in the intensive care unit, five had original tooth or artificial dentures in their lower airway. Two had aspiration of false teeth before intubation and two had aspira- tion of original teeth after intubation. Two had cotton aspiration and one had aspiration of shrimp. These patients received bronchoscopy under ventilator support and their foreign bod- ies were all removed by flexible bronchoscopy with different modalities. In the five patients with teeth in their lower airway, the foreign body was removed by bronchoscopy and the endo- tracheal tube withdrawn at the same time. The endotracheal tube was changed by broncho- scopic guidance after retrieval of the foreign body.

In the acute aspiration group, 18 (45%) patients have aspiration of teeth. This is because most patients can easily find their lost original or prosthetic teeth via chest X-ray or CT imag- ing. In contrast, the most common foreign bodies among chronic aspiration patients are bone and vegetable. This may be due to the different food preparations and habits of eating Chinese food.(1, 2, 6, 15, 16) In preparing Chinese food, people cook whole fish and like to eat small pieces of fish meat around fish bone. People also like to mixed meat and vegetables in soup or in the dinner plate. Bone or vegetables can easily enter the lower airways while eating soup. In Chinese food, people often take rice or noodles mixed with meat or vegetables. As the patient chews the rice or noodles, bone or vegetable fragments can roll into their lower airways. People may have no other symptoms except acute coughing as the foreign body enters their lower air- ways so they will not seek any diagnostic procedure to find the acute aspiration. They will be diagnosed as chronic aspiration when they have lung collapse or obstructive pneumonia.

In this study, the success rate of the one-step bronchoscopy to diagnose and remove a for- eign body in the lower airways is high (85/94, 90%) and does not differ between acute and chronic aspiration patients (90% vs. 91%). This may result from early intervention and the multiple modalities of bronchoscopy. Early intervention can lead to the immediate removal of the foreign body, preventing more granulation formation. Of the 54 chronic aspiration pa- tients, 37 (69%) had granulation, including eight (15%) who needed electromagnet or cryother- apy to eliminate the granulations before foreign body removal. Electromagnet and cryotherapy can increase the success rate in chronic aspiration patients. Four acute aspiration patients and four chronic aspiration patients had easy bleeding of the granulations that completely covered the foreign bodies. The foreign body was not removed by flexible bronchoscopy but by rigid bronchoscopy. It would be helpful to physicians to determine the number of times more than one or 2 more modalities required to manage airway foreign body. However, all foreign bodies in current study were successfully retrieved in one time procedure of flexible bronchoscopy. Difficult cases those could not be retrieved in one procedure would receive surgical manage- ment by surgeon. But the cases required surgical management were few (the numbers in the past 10 years).

Light sedation is commonly used for bronchoscopy to finish the procedure as soon as possi- ble. However, in recent years, more patients receive bronchoscopy with moderate to deep seda- tion for less irritable movements and longer time to perform electromagnet and cryotherapy.

In Taiwan, people believe that fish could help patients’ recovery of health from their dis- eases. Most patients may eat fish when they suffered from some diseases. Especially, people in

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Taiwan like to eat “Milkfish” which is full of fish bone. Therefore, it is not uncommon that pa- tients mis-swallow fish bone in Taiwan, which may cause airway aspiration, throat, or esopha- gus injury by fish bone! Such food like fish bone is usually not visible on chest X ray film.

There are multiple other case series in literature that highlight the same facts. This study is not novel and is descriptive. These are its major limitations! However, this current study is a cohort data during 10 years which included a large number of cases. In addition, we provided the different methods and tools to retrieve the foreign body such as forceps, basket, loop, coag- ulation forceps, coagulation knife, and probe for cryotherapy! We believed that this study would help the physicians to manage airway foreign body! Current definition of chronic aspi- ration in our study was defined as chocking history more than one month or no definite chock- ing history. This may not be adequate. However, We had searched references from midline, there were no any clear definitions of chronic aspiration.

In conclusion, flexible bronchoscopy with multiple modalities is effective for diagnosing and removing foreign bodies in the lower respiratory airways in adults, with a high success rate and no difference between acute and chronic aspirations.

Conclusion The most common foreign bodies in acute or chronic aspiration were teeth or bone in the lower airway of adult patients. Granulations were found in most patients with chronic aspira- tion and some foreign bodies were embedded in granulaton tissue. Flexible bronchoscopy with multiple modalities is a useful method to diagnose and remove the foreign bodies in these pa- tients. The successful rate was high (90%) and no difference between acute and chronic aspira- tion as we applied multiple modalities, included electromagnet and cryotherapy, in these patients.

Author Contributions Conceived and designed the experiments: YFF MHHHCL HPK. Performed the experiments: YFF MHH FTC YKH GYC SML HCL CHWHPK. Analyzed the data: YFF MHHHCL HPK. Contributed reagents/materials/analysis tools: YFF MHH FTC YKH GYC SML HCL CHW HPK. Wrote the paper: YFF MHHHCL HPK.

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journal.publications.chestnet.org 739

A Randomized Trial of 1% vs 2% Lignocaine by the Spray-as-You-Go Technique for Topical Anesthesia During Flexible Bronchoscopy Harpreet Kaur , MSc ; Sahajal Dhooria , MD , DM ; Ashutosh N. Aggarwal , MD , DM , FCCP ; Dheeraj Gupta , MD , DM , FCCP ; Digambar Behera , MD , FCCP ; and Ritesh Agarwal , MD , DM , FCCP

BACKGROUND: Th e optimal concentration of lignocaine to be used during fl exible bronchos- copy (FB) remains unknown. Th is randomized controlled trial compared the effi cacy and safety of 1% and 2% lignocaine solution for topical anesthesia during FB. METHODS: Consecutive patients were randomized to receive either 1% or 2% lignocaine solu- tion through the bronchoscope by the “spray-as-you-go” technique. Th e primary outcome of the study was the assessment of cough by the operator and the patient using the visual analog scale (VAS) and pain assessment using the faces pain rating scale. Th e secondary outcomes included total lignocaine dose, oxygenation status, adverse reactions related to lignocaine, and others. RESULTS: Five hundred patients were randomized (median age, 51 years; 71% men) 1:1 to either group. Th e median operator VAS score for cough was signifi cantly higher (25 vs 21, P 5 .015) in the 1% group; however, the patient VAS score was not significantly different (32 vs 27, P 5 .065). Th e pain rating was similar between the two groups. Th e median cumulative dose of lignocaine was signifi cantly higher in the 2% group (397 mg vs 312 mg, P 5 .0001; 7.1 mg/kg vs 5.7 mg/kg, P 5 .0001). About 28% of patients in the 2% group exceeded the maxi- mum recommended dose ( . 8.2 mg/kg) of lignocaine. No adverse event related to lignocaine overdose was seen in either group. CONCLUSIONS: One percent lignocaine was found to be as eff ective as 2% solution for topical anesthesia during FB, albeit at a signifi cantly lower dose as the latter. Th us, 1% lignocaine should be the preferred concentration for topical anesthesia during FB. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01955824; URL: www.clinicaltrials.gov CHEST 2015; 148 ( 3 ): 739 – 745

[ Original Research Pulmonary Procedures ]

Manuscript received January 5, 2015; revision accepted March 2, 2015; originally published Online First March 26, 2015. ABBREVIATIONS: EBB 5 endobronchial biopsy; FB 5 flexible bron- choscopy; RCT 5 randomized controlled trial; TBLB 5 transbronchial lung biopsy; TBNA 5 transbronchial needle aspiration; VAS 5 visual analog scale AFFILIATIONS: From the Department of Pulmonary Medicine, Post- graduate Institute of Medical Education and Research, Chandigarh, India. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

CORRESPONDENCE TO: Ritesh Agarwal, MD, DM, FCCP, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh-160012, India; e-mail: agarwal. ritesh@live.com © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.15-0022

740 Original Research [ 1 4 8 # 3 C H E S T S E PT E M B E R 2 0 1 5 ]

Flexible bronchoscopy (FB) is a widely used procedure for the diagnosis and treatment of a variety of broncho- pulmonary disorders because of patient comfort, low rate of complications, and lack of requirement of general anesthesia. 1 Most patients tolerate the procedure well although cough is reported to be an extremely distressing symptom. 2 It is likely that the acceptance of bronchoscopy would be signifi cantly improved with control of cough. A combination of midazolam and hydrocodone has been shown to signifi cantly reduce cough during FB, especially when invasive diagnostic procedures are performed. 3 However, in several centers including ours, due to logistics, sedation is not routinely used during basic diagnostic bronchoscopy; procedures such as BAL, endobronchial biopsy (EBB), and transbronchial lung biopsy (TBLB) are performed under topical anesthesia.

Lignocaine is the most common local anesthetic used during FB because of its quick onset, short duration of action, and lesser toxicity compared with other agents. 4 Th e use of topical lignocaine during FB has been shown to improve patient’s tolerance and satisfaction of

the procedure. 5,6 Furthermore, it has been demonstrated that nebulized lignocaine can reduce the need for sup- plemental topical anesthesia, administered as injection through the bronchoscope. 7,8 Th e optimal concentration of lignocaine as topical anesthesia, however, remains speculative, and 1% and 2% concentrations of lignocaine solutions are commonly used. The British Thoracic Society guidelines recommend the use of 1% lignocaine while the American College of Chest Physicians (CHEST) consensus statement endorses a wide range of lignocaine concentrations (1%-10%) that have been found to be eff ective without advocating any particular value. 9,10

Th ere is little data on the effi cacy of lower concentra- tions (1%-2%) of lignocaine. 11 It is important that the superiority of a particular concentration be ascertained, as eff ectiveness of lower concentrations would allow the use of higher volumes with lesser chances of complica- tions. In this randomized controlled trial (RCT), we report the effi cacy and safety of 1% vs 2% lignocaine for topical anesthesia in patients undergoing FB.

Materials and Methods Setting Th is was an investigator-initiated, single-center, randomized double- blind trial conducted in the bronchoscopy suite of this institute between May and November 2014. The study protocol was approved by the Ethics Review Committee (Ref. No. NK/1473/Res/687), and written informed consent was obtained from all the patients. As a protocol in our bronchoscopy suite, patients undergoing BAL, EBB, and TBLB are not routinely sedated, and bronchoscopy is performed under topical anesthesia. Patients undergoing other procedures such as conventional transbronchial needle aspiration (TBNA), endobronchial ultrasonography- guided TBNA, and other interventions are routinely sedated with mid- azolam and pentazocine.

Patients Patients were eligible for inclusion into the study if they met all of the following criteria: (1) indication for fl exible bronchoscopy, (2) age group of 12 to 90 years, and (3) hemodynamic stability (defi ned as systolic BP . 100 mm Hg and , 180 mm Hg). Patients with any of the following were excluded: (1) pregnancy, (2) hypoxemia (oxygen saturation [by pulse oximetry] , 92% with F io 2 of 0.3), (3) patients undergoing TBNA and other interventions, and (4) failure to provide informed consent.

Randomization Patients were randomized in 1:1 ratio to receive either 1% or 2% ligno- caine solution. Th e randomization sequence was computer-generated, and the assignments were placed in sealed opaque envelopes. Both the patient and the bronchoscopist were blinded to the concentration of lignocaine solution used for the procedure.

Study Protocol Demographic profi le including age, sex, height, weight, smoking history, BMI, and the type of procedure performed (airway inspection, BAL, EBB, TBLB) was recorded for all patients. Patients in both the groups were prepared in a similar fashion except for the concentration of lig- nocaine used. All patients were kept fasting overnight. The patients

were nebulized with 2.5 mL of 4% lignocaine (Lox, 42.7 mg/mL; Neon Laboratories Ltd) for 15 min prior to the procedure. Lignocaine spray (10%, Lox, 100 mg/mL; Neon Laboratories Ltd) was sprayed twice (10 mg/puff ) over the oropharynx. Approximately 5 mL of lignocaine gel (2%; Neon Laboratories Ltd), equivalent to 100 mg of lignocaine, was administered in the nasal cavity prior to the introduction of the broncho- scope. Patients thereaft er received 2-mL aliquots of 1% or 2% lignocaine solution (Wocaine; Wockhardt) delivered through the bronchoscope using the ‘‘spray-as-you-go’’ technique. Four aliquots of 2 mL of ligno- caine were administered: one each at the vocal cord, tracheal carina, and in the right and left main bronchus. Extra lignocaine aliquots were given as a ‘‘rescue’’ treatment to suppress cough, at the discretion of the oper- ator. Th e sum of the standard dose (2.5 mL of 4% nebulized lignocaine [106.75 mg] plus 5 mL of 2% lignocaine gel [100 mg] plus two puff s of 10% lignocaine spray [20 mg] plus 8 mL of 1% [85.2 mg] or 2% [170.4 mg] lignocaine) and rescue dose made up the total dose of lignocaine used. Patients were monitored for any adverse eff ects related to lignocaine use (like arrhythmia, involuntary movements, convulsions, anaphylaxis, and bronchospasm). Heart rate, respiratory rate, BP, and oxy gen satu- ration (by pulse oximetry) were monitored throughout the procedure.

Th e bronchoscopist was asked to assess the intensity of the patient’s cough during FB using a visual analog scale (VAS) immediately aft er the procedure. The VAS for cough was rated on a horizontal line, 100 mm in length anchored by “No cough” at one end and “Worst cough” at the other. 12 Once stable, the patients recorded their quantum of cough and pain using the VAS and the faces pain rating scale, respec- tively. Th e faces pain rating scale consists of six faces with brief word instructions provided with the scale representing increasing intensity of pain on an ordinal scale from 0 to 5. 13

Study Outcomes Th e primary outcome of the study was patient comfort during the pro- cedure measured by the intensity of cough rated on a VAS by both the operator and the patient and the pain assessment by the patient using the faces pain rating scale. The secondary outcomes included total lignocaine dose; changes in respiratory rate, heart rate and BP, and

journal.publications.chestnet.org 741

oxygenation status following the procedure; and adverse reactions related to lignocaine (arrhythmia, involuntary movements, convul- sions, anaphylaxis, and bronchospasm).

Statistical Analysis Statistical analysis was performed using the commercial statistical pack- age SPSS for MS-Windows, version 22 (IBM Corporation). P , .05

was considered as statistically significant. Data are presented in a descriptive fashion as number with percentage or median with interquar- tile range. x 2 (or the Fisher exact test) was used to analyze categorical variables and the Mann-Whitney U test was used for comparing the numerical data. The change in variables before, during, and after the procedure was analyzed with multiple repeated measure analysis of variance.

Results During the study period, 500 consecutive patients (250 in each group, 70.6% men) with a median (interquartile range) age of 51 years (40-60) were included in the study ( Fig 1 ). Th e baseline characteristics including the demographic characteristics, physiologic parameters, and the type of bronchoscopic procedures performed were similar in the two groups ( Table 1 ). Heart rate, respiratory rate, and BP increased aft er the procedure as compared with baseline in both the study groups. However, the change was not significantly different between the two groups ( Table 2 ).

Th e median operator VAS score for cough was signifi – cantly higher in the 1% group (1% group: 25 vs 2% group: 21; P 5 .015); however, the median patient VAS score for cough was similar between the two groups ( Table 3 ). Th e faces pain rating score was similar in the two groups ( Table 3 ). Th e median total dose of lignocaine used was

signifi cantly higher in the 2% group (2% group: 397 mg vs 1% group: 312 mg; P 5 .0001). Similarly, the ligno- caine dose adjusted for body weight was also signifi – cantly higher in the 2% group ( Table 3 ). Th e number of patients with total administered dose . 8.2 mg/kg lig- nocaine was also signifi cantly higher in the 2% group ( Table 3 ). Heart rate, respiratory rate, and BP aft er the procedure were similar in the two groups. No adverse events related to lignocaine such as bronchospasm, arrhythmias, involuntary movements, or convulsions were observed in any patient.

Discussion Th e result of this large RCT demonstrates that 1% and 2% concentrations of lignocaine solution are equally eff ective in anesthetizing the airway. Th e bronchoscopist- reported VAS scores for cough were higher in the 1% lignocaine group; the diff erence although statistically significant is unlikely to be clinically relevant as the

Figure 1 – CONSORT diagram demonstrating the fl ow of participants in the study. EBUS 5 endobronchial ultrasonography; TBNA 5 trans- bronchial needle aspiration.

742 Original Research [ 1 4 8 # 3 C H E S T S E PT E M B E R 2 0 1 5 ]

median diff erence of VAS score was merely four points on a scale ranging from 0 to 100. Moreover, the diff er- ence was not signifi cant in the patients’ own assessment of their cough in the two groups. Th e pain rating was also not diff erent in the two groups. Th e cumulative dose in the 1% arm was signifi cantly lower compared with the other group. Thus, 1% lignocaine could achieve topical anesthesia during bronchoscopy as eff ec- tively as 2% but at a much lower dose compared with 2% lignocaine.

Most guidelines currently recommend performance of FB under IV sedation. 9,10 However, in our center, due to high patient load and lower doctor-to-patient ratio, basic diagnostic procedures such as BAL, EBB, and TBLB are performed under topical anesthesia without any IV sedation. Although sedation should be used wherever possible, 3,14 local anesthesia can be achieved within 2 min of endotracheal lignocaine application, which blunts the cough refl ex eff ectively, 15 allowing for safe and comfortable performance of FB. 16

TABLE 1 ] Baseline Characteristics of the Study Population Characteristics 1% Lignocaine (n 5 250) 2% Lignocaine (n 5 250) Total (N 5 500) P Value

Demographic variables

Male, No. (%) 177 (70.4) 176 (70.8) 353 (70.6) .890

Age, y 50 (40-60) 52 (38-61) 51 (40-60) .710

Height, cm 165 (157-170) 165 (155-170) 165 (156-170) .873

Weight, kg 55 (49-64) 56 (48-65) 55 (49-65) .595

BMI, kg/m 2 20.5 (18-23) 20.9 (18-24) 20.8 (18-24) .540

Current smokers, No. (%) 106 (42.3) 104 (41.8) 210 (42) .926

Physiologic parameters

Heart rate, beats/min 98 (87-111) 98 (86-111) 98 (86-111) .804

Respiratory rate, breaths/min 20 (18-22) 20 (18-22) 20 (18-22) .340

Oxygen saturation, % 97 (95-98) 97 (95-98) 97 (95-98) .349

Systolic BP, mm Hg 120 (110-135) 122 (112-137) 121 (112-136) .136

Diastolic BP, mm Hg 76 (69-83) 76 (70-84) 76 (70-83) .662

Procedures performed, No. (%)

BAL 86 (34.4) 82 (32.8) 168 (33.6) .753

Endobronchial biopsy 90 (36) 86 (34.4) 176 (35.2) .758

Transbronchial lung biopsy 67 (26.8) 59 (23.6) 126 (25.2) .440

Airway inspection only 70 (28) 73 (29.2) 143 (28.6) .724

All values are expressed as median with interquartile range, unless otherwise stated.

TABLE 2 ] Serial Physiologic Parameters Measured Before, During, and After FB in the Two Groups

Parameters

1% Lignocaine 2% Lignocaine

Baseline During After Baseline During After

Heart rate, beats/min 99.0 (18.4) 113.4 (20.7) a 110.9 (18.8) b 98.6 (17.9) 112.4 (19.9) a 107.8 (17.9) b

Respiratory rate, breaths/min

19.9 (3.5) … 22.5 (3.3) b 20.2 (3.6) … 22.4 (3.3) b

Systolic BP, mm Hg 122.5 (17.8) … 124.5 (16.1) b 125.1 (16.6) … 126.6 (15.5) b

Diastolic BP, mm Hg 75.5 (10.9) … 76.1 (10.1) 76.4 (10.2) … 76.5 (9.8)

Oxygen saturation, % 96.2 (3.2) 96.7 (3.2) 96.3 (2.5) 96.5 (2.8) 96.5 (2.9) 96.3 (2.7)

All values are mean (SD) unless otherwise stated. P , .05 was taken as signifi cant. The diff erences between the means was analyzed using multiple repeated measure analysis of variance with Bonferroni adjustment for multiple comparisons; the within-groups factor was time (baseline, during, and after), and the between-groups factor was the lignocaine groups (1% vs 2%). FB 5 fl exible bronchoscopy. a Value during procedure signifi cantly diff erent from that at baseline within the groups. b Value after procedure signifi cantly diff erent from that at baseline within the groups.

journal.publications.chestnet.org 743

Few studies have evaluated the effective lignocaine concentration for topical anesthesia during FB ( Table 4 ). 11,17-19 Of the four, one has been published only as an abstract while three are peer reviewed. 19 Of the three peer-reviewed studies, only a single study was performed in the bronchoscopy suite, while the other two studies were conducted in the operating suite and are, thus, diff erent from the routine practice in the bronchoscopy suite. Th e results of these studies suggest that 2% is as effi cacious as 4% solution while 1% is as eff ective at 2% lignocaine. Th e limitation of these studies apart from diff ering methodologies is the small sample size. Th e results of our study supplement these studies and confi rm that 1% lignocaine solution is as efficacious as 2% but has the added advantage of effectiveness at signifi cantly lower cumulative dose.

Th ese fi ndings are important for routine practice as there are reported cases of death from presumed ligno- caine toxicity after FB. 20,21 In fact, 28% of patients in the 2% lignocaine arm of our study exceeded the dose of . 8.2 mg/kg, recommended as the maximum dose by the British Th oracic Society. 22 In another study, the anesthetists used doses of up to 14.8 mg/kg lignocaine by a spray-as-you-go method in a study involving volunteer subjects undergoing awake fi ber-optic intuba- tion; some volunteers were reported to have experi- enced involuntary movements, symptoms that may precede convulsions, which is a sign of lignocaine toxicity. 23 Th e pharmacokinetics of topical lignocaine during FB are complex and can be influenced by several factors, including the duration and frequency of suctioning. 24 This means that the plasma levels

TABLE 3 ] Primary and Secondary Outcomes of the Study Outcomes 1% Lignocaine (n 5 250) 2% Lignocaine (n 5 250) P Value

Primary

VAS score (cough) for operator 25 (12-51) 21 (9-38) .015

VAS score (cough) for patient 32 (11-60) 27 (10-50) .065

Faces pain rating scale 0 (0-2) 0 (0-2) .883

Secondary

Total dose of lignocaine, mg 312 (312-312) 397 (397-397) .0001

Lignocaine dose, mg/kg 5.7 (5.0-6.5) 7.1 (6.1-8.3) .0001

No. of patients with dose . 8.2 mg/kg, No. (%) 12 (4.8) 70 (28) .0001

Heart rate after procedure, beats/min 111 (98-123) 108 (96-118) .054

Respiratory rate after procedure, breaths/min 22 (20-24) 22 (20-24) .493

Systolic BP after procedure, mm Hg 122 (112-132) 126 (116-134) .075

All values in median (interquartile range), unless mentioned. VAS 5 visual analog scale.

TABLE 4 ] Studies Evaluating Different Lignocaine Concentrations for Topical Anesthesia During FB

Study/Year Nature of the

Study No. of

Patients Concentration of

Lignocaine End Points Outcome

Mainland et al 17 /2001

Double-blind RCT 96 1% (n 5 31) vs 1.5% (n 5 16) vs 2%

(n 5 48)

Nature and duration of cough; requirement of

additional supplements

All concentrations and dosages equally

eff ective

Hasmoni et al 11 /2008

Double-blind RCT 61 1% (n 5 32) vs 2% (n 5 29)

Cough frequency with digital voice recorder;

bronchoscopists overall satisfaction

No diff erence between the two groups

Xue et al 18 /2009

Double-blind RCT 52 2% (n 5 26) vs 4% (n 5 26)

Faces pain rating scale, 4-point cough severity

scale, 3-point tracheal intubation scale

No diff erence between the two groups

Bansal et al 19 /2011

Double-blind RCT 52 1% (n 5 26) vs 2% (n 5 26)

VAS, cough severity, and frequency score

No diff erence between the two groups

RCT 5 randomized controlled trial. See Table 2 and 3 legends for expansion of other abbreviations.

744 Original Research [ 1 4 8 # 3 C H E S T S E PT E M B E R 2 0 1 5 ]

achieved in an individual patient are often unpre- dictable. 25-29 However, the propensity would increase with increasing doses of lignocaine used. By using 1% lignocaine, the risk of potential toxicity would be lower although it is still essential to carefully monitor the amount of lignocaine administered during FB. Another important benefit of a lower concentration would be the usage in patients with renal and hepatic dysfunction, as well as in patients with airway infl am- mation and pediatric age group, as the dose would be minimized.

Finally, our study is not without limitations. Th ere were several factors in our study that could aff ect the out- comes. Th ese were multiple operators (consultants, fellows), variable duration of bronchoscopy, wide range of indications, and concomitant procedures. However,

they were equally distributed between the two groups. Th e other limitation could be the lack of widespread generalization of our results given the fact that IV seda- tion was not used while a vast majority of bronchosco- pists use sedation. However, lack of sedation can also be regarded as a major strength of the study as it allowed a clear assessment of the cough severity by the patient in contrast to the previous study where the patients were sedated. 11 Th e other obvious strength of the study is the large sample size.

In conclusion, the results of this study suggest that 1% lignocaine is similar in effi cacy to 2% lignocaine for top- ical anesthesia during FB, at signifi cantly lower doses of lignocaine. Hence, 1% lignocaine should be the preferred concentration for topical anesthesia of the larynx and the tracheobronchial tree during FB.

Acknowledgments Author contributions: R. A. is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. H. K. contributed to data collection as well as drafting of the manuscript; S. D. and A. N. A. contributed to patient management, data collection, and revision of the manuscript for intellectual content; D. G. and D. B. contributed to patient management and revision of the manuscript; and R. A. conceived the idea and contributed to patient management as well as draft ing and revision of the manuscript for intellectual content. Financial/nonfi nancial disclosures: Th e authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Open Access Full Text Article

http://dx.doi.org/10.2147/COPD.S119575

Flexible bronchoscopy with moderate sedation in COPD: a case–control study

Peter Grendelmeier Michael Tamm Kathleen Jahn Eric Pflimlin Daiana Stolz Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, Basel, Switzerland

Background: Flexible bronchoscopy is increasingly used for diagnostic and therapeutic purposes. We aimed to examine the safety of flexible bronchoscopy with moderate sedation in patients with COPD. Methods: This study is a prospective, longitudinal, case–control, single-center study including 1,400 consecutive patients. After clinical and lung function assessments, patients were dichoto- mized in COPD or non-COPD groups. The primary end point was the combined incidence of complications. Results: The incidence of complications was similar in patients with and without COPD and independent of forced expiratory volume in the first second % predicted. Patients with COPD more frequently required insertion of a naso- or oropharyngeal airway; however, this differ- ence was no longer significant after adjustment for age, gender, and duration of the procedure. Hypotension was significantly more common among patients with COPD. The number of epi- sodes of hypoxemia 90% did not differ between the groups. However, patients with COPD had a lower mean and nadir transcutaneous oxygen saturation. Transcutaneous carbon dioxide tension (PtcCO2) change over the time course was similar in both groups, but both peak PtcCO2 and time on PtcCO2 45 mmHg were higher in the COPD group. There were no differences in patient-reported outcomes. Conclusion: The safety of flexible bronchoscopy is similar in patients with and without COPD. This finding confirms the suitability of the procedure for both clinical and research indications. Keywords: bronchoalveolar lavage, propofol, complication, risk, respiratory insufficiency

Abbreviations

FB, flexible bronchoscopy; BAL, bronchoalveolar lavage; ASA, American Society of Anesthesiologists; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; cDLCO, diffusion capacity for carbon monoxide, corrected for hemo- globin levels; EBUS, endobronchial ultrasound; PtcCO2, transcutaneous carbon dioxide tension; SO2, transcutaneous oxygen saturation; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IQR, interquartile range; ATS, American Thoracic Society; ERS, European Respiratory Journal.

Introduction

COPD is a leading cause of global morbidity and disability. COPD is predicted to become the third greatest cause of death worldwide by 2020.1

Patients with COPD are increasingly prone to undergo bronchoscopy for a variety of reasons. They have been typically exposed to cigarette smoking, thus sharing a major risk factor for malignancy and infection.2,3 In addition, interventional bronchoscopy has evolved as a treatment option for the disease itself (eg, bronchoscopic lung volume reduction) and its comorbidities (eg, laser and stenting placement).4 In addition, airway

Correspondence: Daiana Stolz Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland Tel 41 61 265 5193 Fax 41 61 265 4587 Email daiana.stolz@usb.ch

Journal name: International Journal of COPD Article Designation: Original Research Year: 2017 Volume: 12 Running head verso: Grendelmeier et al Running head recto: Flexible bronchoscopy with moderate sedation in COPD DOI: http://dx.doi.org/10.2147/COPD.S119575

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Grendelmeier et al

material gained by bronchoscopy is of paramount importance for translational research.

Up to now, there are scarce data examining the particulari- ties of FB in COPD. In a randomized, placebo-controlled trial, combined sedation using an opiate and a benzodiazepine has been shown to be effective and safe in high-risk patients suf- fering from COPD.4 Similarly, a trial investigating the safety of bronchoscopy with endobronchial biopsy and BAL under conscious sedation using midazolam in 57 patients concluded that bronchoscopy can be performed safely in this popula- tion.5 Conversely, bronchoscopy performed under moder- ate sedation in patients with severe COPD was frequently associated with significant hypoventilation as detected by transcutaneous PtcCO2.

6 While current guidelines advocate caution when sedating patients with COPD, they refrain from providing specific drug recommendations.7,8 Propofol (2.6 di-isopropylphenol) is a sedative hypnotic frequently used in the induction and maintenance of anesthesia. Sedation with propofol can be safely performed by a non-anesthesiologist during bronchoscopy.9–12 Minor adverse events including hypoxemia and hypotension are frequent and were noted in up to one-third of patients.9–14 In a large randomized trial including 702 patients comparing conscious sedation with propofol either as bolus or as a continuous infusion, one-third of all patients suffered from COPD, although no data about the severity of disease and the prevalence of partial or global respiratory failure have been reported.13,15

The growing number of indications for elaborated diagnostic and therapeutic procedures in advanced COPD raises the question of whether flexible bronchoscopy with moderate sedation is safe in this fragile population. In light

of the clinical relevance of this issue, we designed a pro- spective, case–control study, aiming to compare the safety of diagnostic and therapeutic flexible bronchoscopy in patients with and without COPD. The primary end point of the study was the overall incidence of complications related to the procedure.

Materials and methods

This is a prospective, longitudinal, case–control, single- center study performed at the Clinic of Respiratory Medicine, University Hospital Basel, a tertiary care hospital with 784 beds located in Basel, Switzerland. This study was approved by the Institutional Review Board, Ethikkommission beider Basel (EKNZ BASEC 01057).

Study population and procedure variables All patients aged 18 or older undergoing flexible bron- choscopy using moderate sedation according to the same sedation protocol, with propofol, between January 2013 and January 2014, were considered eligible. Intubated or tracheotomized patients, those unable or unwilling to provide informed consent, those with a known allergy to propofol or undergoing a procedure repeatedly, in a location other than the bronchoscopy suite, or as an emergency were excluded (Figure 1) from the study. All patients who fulfilled the inclu- sion criteria were included in the study. Written informed consent for the analysis of the data was obtained from each patient before undergoing bronchoscopy.

Patients were assessed for clinical history and under- went physical examination, which included gradation of physical status in accordance with the ASA by a physician

Figure 1 Study design.

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and a member of the nursing team trained in anesthesiology. Current medications and laboratory results including platelet counts and coagulation studies were listed. Patients were diagnosed with COPD in the presence of appropriate clinical history and physical examination, according to the GOLD recommendations. Patients presenting with an alternative, more probable diagnosis associated with the obstructive pattern (FEV1/FVC 0.7), such as asthma, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans in lung transplant recipients or in patients following stem cell transplantation, widespread bronchiectasis, organizing pneumonia or respiratory bronchiolitis-associated interstitial lung disease, were not classified as COPD. Body plethys- mography and diffusion capacity for carbon monoxide corrected for hemoglobin levels according to the ATS/ERS guidelines were performed within 72 hours before bron- choscopy. Moreover, blood gas analyses including partial pressure of oxygen, partial pressure of carbon dioxide, pH, and bicarbonate were performed.

Study procedure Bronchoscopy procedures were performed transnasally or transorally, with the patients in semi-recumbent position, by pulmonary fellow physicians under the close supervision of pulmonary attending physicians or by pulmonary attending physicians directly. Electrocardiogram, pulse oximetry (SO2), and respiratory rate were recorded continuously during the procedure and automated non-invasive blood pressure moni- toring was performed every 5 minutes. Supplemental oxygen was offered at 4 L min 1 via a nasal cannula to all patients. In the case of desaturation to 90%, oxygen delivery was increased to 6 L min 1.16 Nasal anesthesia was achieved by 2% lidocaine gel. Bronchoscopists were advised to instill 3 mL aliquots of 1% lidocaine over the vocal cords and on to the trachea and both right and left main bronchi.

Patients received propofol as repeated intravenous boluses. The loading dose of propofol was titrated in order to achieve adequate initial sedation (onset of ptosis). Initially, 20 mg of intravenous propofol, followed by a carefully titrated dose, was infused. For ASA I and II patients, the steps comprised 10–20 mg intravenous propofol, whereas for ASA III and IV, exactly 10 mg intravenous propofol was administered based on the clinical response, as previously described.17 Between each bolus, a pause lasting 60 seconds had to be observed. If the effect disappeared during the examination, additional intravenous boluses of 10–20 mg propofol were given, depending on the clinical effect, in order to maintain the required level of sedation. Signs of pain or discomfort, agitation, and persistent cough were considered

indicators of insufficient sedation, leading to administration of an additional dose of propofol (10–20 mg). The total dose of propofol was documented for each patient. A single dose of 4–8 mg of hydrocodone intravenously was given to all patients together with the initial bolus of propofol.14 Diagnostic procedures (ie, washings, bronchoalveolar lavage, brushing, mediastinal or peripheral transbronchial needle aspiration, endobronchial and transbronchial biopsy, EBUS) as well as therapeutic procedures (ie, laser therapy, insertion of stents, endo- or intrabronchial valves and coils) were performed upon clinical indication.

Hemodynamic monitoring, including systolic and dia- stolic blood pressure, heart rate, respiratory rate, oxygen satu- ration, and amount of oxygen supplementation required, was routinely carried out immediately before, during, and shortly after the procedure (after removal of the bronchoscope), and before transfer from the bronchoscopy suite to the recovery room, at predefined and standardized intervals. Hemodynamic parameters, including hypoxemia (any oxygen desaturation 90%) and hypotension (any systolic blood pressure 90 mmHg), procedural sedation, and duration of examination were recorded. Complications (chin lift, inser- tion of naso- or oropharyngeal airway, pneumothorax, minor bleeding, major bleeding, premature termination of examina- tion, intubation, transfer to the intensive care unit, and death) were predefined, retained in a standardized, specific study form and concomitantly documented. Additionally, SO2 and PtcCO2 were assessed by a digital continuous real time monitoring system (SenTec AG, Therwil, Switzerland) in a predefined, nested cohort of 220 consecutive patients. The combined cutaneous digital sensor was placed on the ear lobe of all patients at least for 20 minutes prior to the procedure and was removed 120 minutes after the patient left the bron- choscopy suite. Physicians and endoscopy personnel were blinded for the recording of transcutaneous measured carbon dioxide and oxygen during and after the examination.

Patients were asked to rate their cough, discomfort, anxiety, and overall well-being related to the procedure as well as the willingness to undergo a repeated procedure on a numerical visual analog scale (1 [minimum] to 10 [maxi- mum]) after full recovery, but at least 2 hours after comple- tion of endoscopy. Patient’s cough during the examination was also rated by the nursing team and the endoscopist on a similar numerical visual analog scale on completion of the procedure.

Study outcome The primary end point of the study was the combined incidence of all predefined complications in patients with and without

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COPD. Secondary end points included the following: 1) differ- ences in the incidence of each single complication; 2) hemody- namic parameters (systolic and diastolic blood pressure, heart rate, respiratory rate, oxygen saturation, and amount of oxygen supplementation required) on arrival at the bronchoscopy suite, initiation of sedation, 3, 6, and 9 minutes of examination, retraction of the bronchoscopy (end of the examination), and 5 minutes after the completion of the procedure; 3) course of SO2 and PtcCO2 during examination and at the initiation and end of examination; 4) median and peak PtcCO2; 5) median and nadir SO2; 6) time with PtcCO2 45 mmHg; 7) time with SO2 88%; and 8) cough during the procedure as rated by physicians and nurses, as well as patient-reported outcomes (cough, discomfort, anxiety, well-being, and readiness for a further bronchoscopic procedure).

Statistical analyses Descriptive statistics were computed for all variables to pro- vide means (SDs) or medians (interquartile ranges) for con- tinuous variables and frequencies for categorical variables. Normally distributed parameters were analyzed using the Student’s t-test for equality of means. All other continuously non-normally distributed parameters were evaluated using the non-parametric Mann–Whitney U test or Kruskal–Wallis test, as appropriate. Differences in dichotomous variables were evaluated using the chi-square test or Fisher’s exact test, as appropriate. The incidence of complications was analyzed as a combined end point and by single incident according to the presence and absence of COPD. Univariate and multivariate logistic regressions were used to examine the association between complications (dependent variables) and FEV1% predicted (independent variable) and COPD, age, gender, and duration of the procedure (independent variables). Mixed linear models were used to examine the association between hemodynamic parameters, including oxygen requirement, and transcutaneous PtcCO2 change over time course and the presence (model 1) and severity (model 2) of COPD. Dependent variables were parameter values and independent variables were time, COPD, parameter values at baseline, length of procedure, age, and the interaction “time and GOLD stage”. Subject was treated as a random factor. To achieve approximate normal distribution, parameters were log-transformed. Spearman’s test was used to examine the association between FEV1% predicted, SO2, PtcCO2, and cDLCO. In order to analyze the effect on different outcomes, linear regression models were performed. Dependent vari- ables were parameter values and the independent variable was COPD. Multivariate linear regression analysis was

performed to examine PtcCO2 peak during bronchoscopy as the dependent factor versus FEV1% predicted and DLCO. The Statistical Package for Social Sciences (SPSS Inc, version 21 for Windows) and R project (www.r-project.org) were used for analysis. All tests were two-tailed; a P-value 0.05 was considered significant.

Results

Demographic data are presented in Tables 1 and 2. There were significant differences between the two groups in terms of age, gender, smoking status, ASA class, and the presence of comorbidities. Similarly, patients with COPD had lower FEV1 and cDLCO, higher total lung capacity and residual volume, and lower pO2 as compared to patients without COPD. Indication, number, and distribution of diagnostic and interventional procedures per patient and group are given in Table 3. The main reason for bronchoscopy was pulmonary infection in patients without COPD in contrast to suspicion of malignancy in patients with COPD. Accord- ingly, the most commonly performed diagnostic procedures were BAL (67.5%) and bronchial washing (19.5%), followed by endobronchial and transbronchial biopsies (15.4 and 14.7%, respectively). Complex interventions, that is EBUS, stent-placement, laser application, and bronchoscopic lung volume reduction procedures, were performed in 202 cases. Almost one-third of the patients underwent two or more bronchoscopic procedures, with a similar distribution in both groups. Crude procedural sedation requirements were similar in patients with and without COPD. However, when adjusted for the duration of the examination and body weight, patients with COPD demanded significantly less propofol than patients without COPD.

Complications in patients with and without COPD The combined incidence of complications was similar in patients with and without COPD (P 0.301) and indepen- dent of FEV1% predicted (P 0.789, Table 4). Individually, the need for insertion of a naso- or oropharyngeal airway was more common in the group of patients with COPD. However, this difference was no longer significant after adjustment for age, gender, and duration of the procedure. The risk for any complication (P 0.142) and the number of complications (P 0.113) observed during the procedure were similar across GOLD stages. However, patients with severe and very severe disease had an increased number of complications as compared to those with mild or moderate disease (P 0.037).

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Hemodynamic parameters and amount of oxygen requirement Patients with and without COPD depicted distinctive hemodynamic responses to sedation and required diverging amounts of oxygen supplementation during the procedure (Figure 2). Herein, hypotension (20.7% [n 135] vs 29.8% [n 131], P 0.001) was significantly more common among patients with COPD, but this association was again dependent

on age, gender, and the duration of bronchoscopy (P 0.124).

While the number of episodes of hypoxemia 90% did not

differ between COPD and non-COPD (36.2% [n 236] vs

40.9% [n 180], P 0.125), patients with COPD had a lower

median and nadir SO2 and remained hypoxemic (SO2 88%)

longer than patients without COPD (Table 5). There was no

correlation between time with an oxygen saturation 88%

or nadir SO2 during the examination and FEV1% predicted

Table 1 Demographic data of 1,092 patients undergoing flexible bronchoscopy based on the presence or absence of COPD

Characteristics No COPD (n 652) COPD (n 440) Total (n 1,092) P-value

Age, years 58.5 14.9 66.5 10.2 61.6 15 0.001 Male, gender 52.9% 66.6% 58.4% 0.001 Height, cm 168.3 9.4 168.5 8.7 160.3 9.1 0.596 Weight, kg 70.2 17.6 70.3 17.4 70.2 17.5 0.715 BMI, kg/m2 24.7 5.3 24.6 5.3 24.6 5.3 0.478 Smoking status

Current smoker, % 76 (11.7%) 109 (24.8%) 185 (17.0%) 0.001 Ex-smoker, % 312 (47.9%) 294 (66.8%) 606 (55.5%)

Pack-years, n 27.2 25.4 47.9 25.4 37.9 27.4 0.001 ASA class, %

I 16 (2.5%) 4 (0.9%) 20 (1.8%) 0.001 II 179 (27.5%) 70 (15.9%) 249 (22.8%) III 413 (63.3%) 307 (69.8%) 720 (66.0%) IV or V 44 (6.8%) 60 (13.6%) 104 (9.5%)

Comorbidities, % Coronary artery disease 84 (12.9%) 84 (19.1%) 168 (15.4%) 0.009 Congestive heart failure 41 (6.3%) 50 (11.4%) 91 (8.3%) 0.007 Cerebral vascular disease 21 (3.2%) 19 (4.3%) 40 (3.7%) 0.371 Diabetes mellitus 63 (9.7%) 54 (12.3%) 117 (10.7%) 0.209 Renal failure 106 (16.3%) 44 (10.0%) 150 (13.7%) 0.006 Liver disease 9 (1.4%) 10 (2.3%) 19 (1.7%) 0.345 Solid malignant tumor 139 (21.4%) 187 (42.5%) 326 (29.9%) 0.001 Hematological malignancy 139 (21.4%) 19 (4.3%) 158 (14.5%) 0.001 Immunosuppression 275 (42.2%) 55 (12.5%) 330 (30.2%) 0.001 Rheumatologic disease 62 (9.5%) 16 (3.6%) 78 (7.1%) 0.001 HIV 3 (0.5%) 11 (2.5%) 14 (1.3%) 0.004 Alcohol abuse 14 (2.2%) 25 (5.7%) 39 (3.6%) 0.005 Intravenous drug use 3 (0.5%) 4 (0.9%) 7 (0.6%) 0.205

Current medication, % Acetylsalicylic acid 104 (16.0%) 129 (29.4%) 233 (21.3%) 0.001 Clopidogrel 16 (2.5%) 10 (2.3%) 26 (2.4%) 0.850 Prasugrel 3 (0.5%) 1 (0.2%) 4 (0.4%) 0.513 Oral anticoagulant 45 (6.9%) 27 (6.1%) 72 (6.6%) 0.699 Heparin (therapeutic dose) 6 (0.9%) 2 (0.5%) 8 (0.7%) 0.501 Heparin (prophylactic dose) 16 (2.5%) 14 (32%) 30 (2.7%) 0.474 LMWH (therapeutic dose) 7 (1.1%) 7 (1.6%) 14 (1.3%) 0.526 LMWH (prophylactic dose) 74 (11.4%) 66 (15.0%) 140 (12.9%) 0.099 Sedatives 20 (3.1%) 25 (5.7%) 45 (4.1%) 0.042 Hypnotics 14 (2.2%) 19 (4.3%) 33 (3.0%) 0.079

Mean prothrombin time, % 86.4 20.3 86.5 20.0 88.1 42.68 0.942 INR 1.1 (1.0–1.1) 1.1 (1.0–1.1) 1.1 (1.0–1.1) 0.583 Mean platelet count, g/L 263 126 286 132 273 129 0.003

Notes: Data are presented as mean SD, n (%), or median (IQR). P-values represent the comparison between non-COPD and COPD groups. Abbreviations: BMI, body mass index; ASA, American Society of Anesthesiologists; HIV, human immunodeficiency virus; LMWH, low-molecular-weight heparin; INR, international normalized ratio; IQR, interquartile range.

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Table 2 Lung function and arterial blood gas analysis data of 1,092 patients undergoing flexible bronchoscopy based on the presence or absence of COPD

Characteristics No COPD (n 652) COPD (n 440) Total (n 1,092) P-value

FEV1, liters 2.25 0.92 1.51 0.69 1.96 0.91 0.001 FEV1, % predicted 78.4 24.8 56.9 24.4 70.0 26.8 0.001 FVC, liters 3.00 1.11 2.75 0.88 2.90 1.04 0.001 FVC, % predicted 85.1 22.7 81.9 21.2 83.9 22.1 0.024 FEV1/FVC 70.3 12.3 49.2 15.8 63.0 17.2 0.001 cDLCO, % 71.1 24.4 57.4 22.7 65.7 24.6 0.001 RV, liters 2.17 0.66 3.36 1.27 2.63 1.11 0.001 RV, % predicted 104.8 31.0 148.3 59.5 121.8 49.2 0.001 TLC, liters 5.36 1.34 6.42 1.55 5.78 1.51 0.001 TLC, % predicted 91.4 16.6 107.6 23.4 97.7 21.0 0.001 RV/TLC 41.3 11.5 51.4 11.7 45.27 12.6 0.001 Arterial blood gas analysis

paO2, mmHg 75.31 10.13 67.7 12.08 70.88 13.43 0.001 paCO2, mmHg 36.45 5.25 38.78 6.68 37.73 6.23 0.196 pH 7.43 0.04 7.42 0.03 7.43 0.04 0.457 Bicarbonate, mmol/L 24.7 2.1 25.4 2.6 25.1 2.4 0.068

Notes: Data are presented as mean SD. P-values represent the comparison between non-COPD and COPD groups. Abbreviations: FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; cDLCO, diffusion capacity for carbon monoxide, corrected for hemoglobin levels; RV, residual volume; TLC, total lung capacity; paO2, partial pressure of oxygen; paCO2, partial pressure of carbon dioxide.

Table 3 Main indication, bronchoscopic procedures, and procedural sedation in 1,092 patients undergoing flexible bronchoscopy based on the presence or absence of COPD

Indication for

bronchoscopy

No COPD (n 652) COPD (n 440) Total (n 1,092) P-value

Suspicion of malignancy 113 (17.3%) 126 (28.6%) 239 (21.9%) 0.001 Interstitial lung disease 93 (14.3%) 8 (1.8%) 101 (9.3%) Infection 299 (45.9%) 95 (21.6%) 394 (36.0%) Chronic cough 30 (4.6%) 5 (1.1%) 35 (3.2%) Hemoptysis 11 (1.7%) 15 (3.4%) 26 (2.4%) Bronchial toilette 40 (6.1%) 67 (15.2%) 107 (9.8%) Stenting 5 (0.8%) 11 (2.5%) 16 (1.5%) Laser therapy 9 (1.4%) 9 (2.0%) 18 (1.6%) Miscellaneous 53 (8.1%) 102 (23.2%) 155 (14.2%) Diagnostic procedures

Bronchial washings 90 (13.8%) 122 (27.7%) 212 (19.4%) 0.001 Bronchoalveolar lavage 513 (78.7%) 226 (51.4%) 739 (67.7%) 0.001 Bronchial brushing 44 (6.8%) 63 (14.3%) 107 (9.8%) 0.001 Endobronchial biopsy 89 (13.7%) 80 (18.2%) 169 (15.5%) 0.054 Transbronchial biopsy 110 (16.9%) 51 (11.6%) 161 (14.7%) 0.022 Mediastinal TBNA 32 (4.9%) 19 (4.3%) 51 (4.7%) 0.664 Peripheral TBNA 25 (3.8%) 32 (7.3%) 57 (5.2%) 0.017 EBUS 66 (10.1%) 38 (8.6%) 104 (9.5%) 0.420

Interventions Laser therapy 10 (1.56%) 9 (2.0%) 19 (1.78%) 0.638 Stenting 5 (0.8%) 9 (2.0%) 14 (1.3%) 0.096 Valve implantation 1 (0.2%) 23 (5.2%) 24 (2.2%) 0.001 Coils implantation 0 (0%) 9 (2.0%) 9 (0.8%) 0.001

Number of procedures 0–1 433 (66.4%) 287 (65.2%) 720 (65.9%) 0.204 2–3 193 (29.6%) 125 (28.4%) 318 (29.1%)

4 26 (4.0%) 28 (6.4%) 54 (4.9%) Propofol (total dose), mg 229 143 234 158 231 149 0.544 Propofol (dose/kg), mg/kg 3.34 2.15 3.53 2.47 3.37 2.23 0.219 Propofol (dose/kg/min), mg 0.275 0.173 0.239 0.181 0.265 0.369 0.001 Hydrocodone, mg 4.23 2.27 4.08 2.62 4.11 2.38 0.477 Duration, minutes 12 (7–20) 15 (8–27) 12 (7–23) 0.001

Notes: Data are presented as number (%), mean standard deviation, or median (IQR). P-values represent the comparison between non-COPD and COPD groups. Abbreviations: TBNA, transbronchial needle aspiration; EBUS, endobronchial ultrasound; IQR, interquartile range.

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(rho 0.058, P 0.543 and rho 0.054, P 0.565, respec- tively) or cDLCO% (rho 0.110, P 0.093 and rho 0.040, P 0.219, respectively). The risk for hypoxemia (P 0.117) and hypotension (P 0.104) did not differ across GOLD stages. Collapsing GOLD stages 3 and 4 together depicted a trend toward a higher risk of hypoxemia in patients with severe or very severe disease (P 0.055).

Patients with COPD had higher baseline and median and peak PtcCO2 levels. Hence, time on PtcCO2 45 mmHg was found to be increased compared to non-COPD patients. Conversely, the change in PtcCO2 over the time course of bronchoscopy was similar in patients with and without COPD (P 0.571, Figure 3). PtcCO2 peak increased linearly across the COPD stages (median [interquartile range]: GOLD I, 51.9 [48.6–60.1] mmHg; GOLD II, 56.9 [48.4–65.8] mmHg; GOLD III, 60.3 [52.6–66.3] mmHg; and GOLD IV, 66 [52.8–79.7] mmHg; P 0.031). Peak PtcCO2 correlated both with the FEV1% predicted value and cDLCO in COPD (rho 0.336, P 0.001 and rho 0.285, P 0.004) but not in non-COPD (P 0.05 for both). Only FEV1% proved to be independently associated with peak PtcCO2 (beta coeffi- cient 0.393 [ 0.358 to 0.0700], P 0.004) in a multivariate linear regression model including both FEV1 and cDLCO.

Cough scores and patient-reported outcomes Cough scores reported by patients, nurses, and physicians did not differ for patients with and without COPD (P 0.176, P 0.619, and P 0.639) and correlated significantly with each other (patient/nurses: rho 0.278, P 0.028; patient/physician: rho 0.261, P 0.039; nurses/physicians: rho 0.839, P 0.01). Likewise, patients with and without COPD had similar discomfort (0.5 [0–1.5] vs 1.0 [0–1.5], P 0.430), anxiety (0.5 [0–1.8] vs 1.0 [0–2.0], P 0.192), and well-being scores (4.0 [2–5] vs 3.8 [2–6.1], P 0.162). The readiness to

undergo a further bronchoscopy was similar in both patient groups (98.5% vs 95.7%, P 0.309).

Discussion

The present study suggests that the safety of FB with mod- erate sedation with propofol is comparable in patients with and without COPD. However, patients with COPD exhibit distinctive hemodynamic responses to sedation. Patients with COPD commonly developed hypotension in addition to more severe and persistent hypoxemia. Moreover, despite a similar peri-procedural increase in PtcCO2, COPD patients were exposed to more pronounced hypercapnia, mainly due to higher baseline levels as compared to their non-COPD counterparts. Thus, monitoring of the PtcCO2 levels might be warranted in patients with COPD with basal hypercapnia, severe airway obstruction, and in those requiring prolonged interventions. Other interesting findings of this study are that both operating conditions for the endoscopy team, cough scores assessed by physicians and nurses, as well as patient- reported outcomes seem not to be negatively influenced by the presence of COPD. The side-effect profile of the exami- nation confirms the suitability of flexible bronchoscopy for research sampling and supports the realization of system biol- ogy studies in matrices such as bronchoalveolar lavage and/ or endobronchial biopsies, even in patients with advanced disease. Taken together, these results strongly suggest that patients with COPD, despite their frailty, can safely benefit from complex interventions performed through flexible bronchoscopy with moderate sedation.

To our knowledge, this is by far the largest study exam- ining the safety of flexible bronchoscopy and the only one including complex procedures in patients with COPD. We observed a similar number of peri-procedural complications in patients with and without the disease, supporting a similar safety profile of propofol in this population.9,10,14 Propofol

Table 4 Complications of flexible bronchoscopy in 1,092 patients undergoing flexible bronchoscopy according to the present or absence of COPD

Incident No COPD (n 652) COPD (n 440) Total (n 1,092) P-value

Chin lift 449 (68.9%) 326 (74.1%) 775 (71.0%) 0.080 Insertion of nasopharyngeal/ oropharyngeal airway

48 (7.4%) 52 (11.8%) 100 (9.2%) 0.021

Pneumothorax 0 (0%) 1 (0.2%) 1 (0.1%) 0.234 Minor bleeding 46 (7.1%) 18 (4.1%) 64 (5.9%) 0.068 Major bleeding 5 (0.8%) 1 (0.2%) 6 (0.6%) 0.307 Termination of examination 0 (0.0%) 1 (0.2%) 1 (0.1%) 0.234 Intubation 3 (0.5%) 0 (0.0%) 3 (0.3%) 0.235 Transfer to intensive care unit 6 (0.9%) 1 (0.2%) 7 (0.6%) 0.218 Death 0 (0%) 0 (0%) 0 (0%) 1.000

Notes: Data are presented as number (%). P-values represent the comparison between non-COPD and COPD groups.

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Flexible bronchoscopy with moderate sedation in COPD

Table 5 Results of the transcutaneous, real time, continuous monitoring of the oxygen saturation and carbon dioxide tension in a nested cohort of 220 patients undergoing flexible bronchoscopy according to the presence or absence of COPD

Characteristics No COPD (n 118) COPD (n 102) P-value

SO2, median, % 96 (94–97) 94 (93–95) 0.001 SO2 time 88%, minutes 0.14 (0–1.16) 1.12 (0.04–4.4) 0.001 SO2 nadir during bronchoscopy, % 87 (84–91) 86 (82–89) 0.002 PtcCO2 at baseline, mmHg 35.2 (32.1–38.3) 36.7 (33.8–39.1) 0.036 PtcCO2 median, mmHg 39.5 (36.5–44.7) 42.5 (38.7–46.2) 0.001 PtcCO2 time 45 mmHg, minutes 12.0 (2.1–45.4) 32.9 (7.0–76.2) 0.001 PtcCO2 peak, mmHg 51.9 (46.1–61.7) 57.9 (50.3–66.1) 0.001 PtcCO2 at end of intervention, mmHg 49.2 (42.0–57.0) 54.5 (47.0–63.0) 0.003

Notes: Data are presented as median (interquartile range). P-values represent the comparison between non-COPD and COPD groups. Abbreviations: PtcCO2, transcutaneous carbon dioxide tension; SO2, transcutaneous oxygen saturation.

has proved to be an attractive option to combined sedation with midazolam and hydrocodone, providing significantly faster recovery times and improved patient satisfaction scores.9,10 It has also been shown that the combination of propofol and hydrocodone is safe, has a better cough suppressing effect, and is associated with significantly lower propofol requirements compared to propofol alone.14 The feasibility and safety of propofol sedation as administered by repeated bolus or continuous infusion is also supported by a large randomized trial.13 Remarkably, the main factor responsible for complications during FB is sedation, which is usually associated with an obstruction at oropharynx level. This concept has been translated in our study into a higher requirement for insertion of a naso- or oropharyngeal airway

in patients with COPD, which was, however, dependent on the age and duration of the procedure. Accordingly, the incidence of sedation-associated complications is likely to be influenced by different variables other than airflow obstruction. It is well known, for instance, that patients with advanced oncologic and hematological disease – including solid organ and bone marrow transplantation – have a higher incidence of complications during bronchoscopy.18 In addi- tion, the most frequently encountered severe complication was major bleeding which is clearly associated with more invasive bronchoscopy procedures but unrelated to the extent of airflow obstruction.

Hypotension is a well-known side effect of propofol dur- ing induction of anesthesia, with an incidence ranging from 25% to 67.5% irrespective of the presence of cardiovascular conditions.19 Similar hypotensive effects have been reported in sedation related to bronchoscopy.12,13 Hypotension follow- ing propofol is suggested to be caused by a decrease in sym- pathetic activity comprising a reduction in systemic vascular resistance and decline in cardiac output linked to vasodilation, diminished baroreflex mechanism, and decreased myocardial contractility.20 It is conceivable that the higher incidence of hypotension observed in this study might be related to the advanced age and cardiovascular comorbidities more com- monly present in the group of patients with COPD.

The incidence of hypoxemia on at least one occasion dur- ing bronchoscopy has been reported to range between 29% and 35%.9,10,14 While the incidence of hypoxemia, defined as oxygen desaturation 90% of any duration, was similar in both groups in the current study, patients with COPD had a longer time with an oxygen saturation below 88% and a lower nadir oxygen saturation during examination. These findings are not surprising as patients with COPD had lower baseline saturation. Indeed, as pulmonary function deteriorates, and

Figure 3 Transcutaneous carbon dioxide tension in a nested-cohort of 220 patients undergoing flexible bronchoscopy based on the presence or absence of COPD. Black boxes represent patients without COPD and gray boxes represent patients with COPD. Abbreviations: FB, flexible bronchoscopy; PtcCO2, transcutaneous carbon dioxide ten sion.

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Grendelmeier et al

as the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia increases.1 Accordingly, over 80% of the patients with advanced disease enrolled in the National Emphysema Treatment Trial were using some form of oxygen therapy.21 Of note, COPD was an independent factor associated with the need of invasive ventilator support in critically ill patients with acute respiratory failure undergoing flexible bronchoscopy in a previous study.22

While propofol sedation did not cause excessive respira- tory drive depression in patients without COPD,23 bronchos- copy performed under moderate sedation in patients with severe COPD was frequently associated with significant hypoventilation as detected by transcutaneous PtcCO2.

6 Therefore, it is tempting to speculate that, despite the similar increase in PtcCO2 in patients with and without COPD observed in our study, patients with COPD may be at higher risk for complications due to the elevated PtcCO2 baseline levels. The question whether transcutaneous CO2 monitoring can improve patient safety in patients with severe airflow obstruction may warrant further evaluation.

We acknowledge several limitations of the present study. This was a monocentric study performed in an institution in which the endoscopy nursing staff have considerable expertise on propofol sedation. Hence, caution might be needed when introducing this sedative regimen in other institutions. The study was not non-blinded and, potentially, this may represent a source of bias. However, outcomes of interest were objective and predefined. Although both patient groups presented distinct baseline characteristics, differences between the two groups in terms of demographics as well as lung function reflect the inhered characteristics of the disease rather than a real imbalance between the groups. We have applied the GOLD definition of COPD to categorize patients in both diagnostic groups. Importantly, 242 (37%) of the patients categorized as non-COPD due to the presence of an alternative, more probable diagnosis for the obstructive pattern in lung function had FEV1/FVC 70. This figure highlights the fact that there are many different pathological entities associated with an obstructive pattern in the lung function test. While the GOLD definition is far from ideal, it remains the most commonly used to diagnose the disease, having, therefore, the greatest generalizability. It is possible, however, that the use of more refined diagnostic criteria could have led to different results. Nevertheless, in this study, the risk of complications and the number of complications were similar in patients with and without obstruction, irrespective of the COPD diagnosis. The investigation of the pathophysi- ological mechanisms associated with hypoxemia during FB

in patients with COPD was out of the scope of the current study. As previously described, the principal contributor to hypoxemia in COPD patients seems to be ventilation/ perfusion (V/Q) mismatch resulting from progressive airflow limitation and emphysematous destruction of the pulmonary capillary bed. Increased tissue consumption of oxygen, with resultant decreased mixed venous oxygen tension also appears to contribute to increased hypoxemia during exacerbations. The risk of sleep-disordered breathing and consequent nocturnal hypoxemia, potentially exacerbated during sedation, correlates with the degree of obesity, which is increasingly reported in patients with COPD. Dysregulated ventilatory control is another factor contributing to the occur- rence and persistence of hypoxemia in COPD. In addition, alveolar hypoxia is associated with the development of pulmonary hypertension in patients with COPD. Skeletal muscle dysfunction is another relevant extrapulmonary con- sequence of COPD and might also be linked to hypoxemia.1 The strengths of study are its originality, the case–control design with a large sample size, and the objective assessment of the disease and its severity, including the complexity of bronchoscopic procedures.

Conclusion

In conclusion, our data suggest a similar safety profile of flexible bronchoscopy using moderate propofol sedation in patients with and without COPD. This finding confirms the suitability of the procedure for both clinical and research indications.

Acknowledgments

We thank the endoscopy staff, particularly EP, and Anja Meyer RN for the support during the trial. We also thank Andy Schötzau and Christian Müller (Eudox AG) for statistical analyses. Daiana Stolz was supported by grants from the Swiss National Foundation (PP00P3_128412/1). Additional funding was provided by the Clinic of Pulmo- nary Medicine and Respiratory Cell Research, University Hospital Basel.

Some of the data of this manuscript have been honored with an oral presentation at the Chest Conference 2015, Montreal, Canada.

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the ver- sion to be published, and agree to be accountable for all aspects of the work.

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