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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.

FLEXIBLE BRONCHOSCOPY IS SAFE WITH ECMO

RESPIRATORY CARE • MAY 2016 VOL 61 NO 5 647

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 underwent one FB, 48 (21.4%) had 2 FBs, 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

FLEXIBLE BRONCHOSCOPY IS SAFE WITH ECMO

648 RESPIRATORY CARE • MAY 2016 VOL 61 NO 5

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

FLEXIBLE BRONCHOSCOPY IS SAFE WITH ECMO

RESPIRATORY CARE • MAY 2016 VOL 61 NO 5 649

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

FLEXIBLE BRONCHOSCOPY IS SAFE WITH ECMO

650 RESPIRATORY CARE • MAY 2016 VOL 61 NO 5

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

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30. Vélez L, Correa LT, Maya MA, Mejı́a P, Ortega J, Bedoya V, Ortega
H. Diagnostic accuracy of bronchoalveolar lavage samples in immu-
nosuppressed patients with suspected pneumonia: analysis of a pro-
tocol. Respir Med 2007;101(10):2160-2167.

31. Karlson KH, Jr., Pickert CB, Schexnayder SM, Heulitt MJ. Flexible
fiberoptic bronchoscopy in children on extracorporeal membrane
oxygenation. Pediatr Pulmonol 1993;16(4):215-218.

32. Kamat PP, Popler J, Davis J, Leong T, Piland SC, Simon D, et al.
Use of flexible bronchoscopy in pediatric patients receiving extra-
corporeal membrane oxygenation (ECMO) support. Pediatr Pulmonol
2011;46(11):1108-1113.

33. Prentice E, Mastropietro CW. Flexible bronchoscopy for children on
extracorporeal membrane oxygenation for cardiac failure. Pediatr
Crit Care Med 2011;12(4):422-425.

FLEXIBLE BRONCHOSCOPY IS SAFE WITH ECMO

RESPIRATORY CARE • MAY 2016 VOL 61 NO 5 651

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

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

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

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

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

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

Key Words: bronchoalveolar lavage, flexible bronchoscopy,
children

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

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

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

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

MATERIALS AND METHODS

Study Setting and Data Sources

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

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

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

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

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

DOI: 10.1097/LBR.0000000000000287

ORIGINAL INVESTIGATION

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

mailto:c.rosas.salazar@vanderbilt.edu

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

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

Data Collection

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

Statistical Analyses

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

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

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

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

RESULTS

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

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

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

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

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

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

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

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

DISCUSSION

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

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

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

55 (10.6%)

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

299 (57.5%)

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

Flexible bronchoscope with a 2.0-mm suction
channel

106 (20.1%)

Flexible bronchoscopy through a laryngeal
mask airway

402 (79.9%)

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

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

Percentages were calculated for procedures with complete data.

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

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

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

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

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

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

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

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

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

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

Site of the BAL Percent of Fluid Return

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

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

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

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

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

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4. Wood RE. The diagnostic effectiveness of the flexible
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8. Rosell A, Xaubet A, Agusti C, et al. A new BAL fluid
instillation and aspiration technique: a multicenter
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9. Singletary ML, Phillippi-Falkenstein KM, Scanlon E,
et al. Modification of a common BAL technique to

enhance sample diagnostic value. J Am Assoc Lab Anim
Sci. 2008;47:47–51.

10. Rosas-Salazar C, Walczak SA, Winger DG, et al.
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11. Klech H, Haslam P, Turner-Warwick M. Worldwide
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12. Meyer KC, Raghu G, Baughman RP, et al. An official
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13. Meyer KC. Bronchoalveolar lavage as a diagnostic
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16. Olsen HH, Grunewald J, Tornling G, et al. Bronchoal-
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17. Riedler J, Grigg J, Robertson CF. Role of bronchoal-
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18. Shields MD, Riedler J. Bronchoalveolar lavage and
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19. Midulla F, Nenna R. Bronchoalveolar lavage: indica-
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Lobar pentamidine levels and Pneumocystis carinii
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http://www.cdc.gov/injury/wisqars/pdf/10LCID_All_Deaths_By_Age_Group_2010-a

Sub-Saharan Africa: Post-Independence

Starting in the late 1950s, Sub-Saharan Africans intensified the struggle for independence from their European colonizers, and the
white rulers. So came to Sub-Saharan Africa the process known as
decolonization. Following World War II, the region’s European rulers
came to realization that their control over the colonies could not
continue as usual. Two main forces emerged to challenge the
European domination of Africans. First, challenges came from
African nationalists who wanted something so simple yet so difficult
to realize: Africa for Africans. Second, after World War II, which was
framed as epic battle against undemocratic tyranny of
totalitarianism, Africans began to challenge why the allies could not
uphold the same democratic values in Africa. To many African
nationalists, it was an example of supreme irony that nations that
defeated Nazism and Fascism were doing something Hitler’s
Germany wanted to do in Europe, conquest and exploitation. (The
above is a picture of the founding members of the anti-apartheid
organization later became African National Congress.) They

obviously felt justified in resisting European colonization more aggressively after World War II, which, by the way, destroyed and
weakened European societies.

This decolonization process was relatively peaceful in countries like Kenya, Tanzania, and Ivory Coast. However, independence did
not come easily in southern part of Africa. In Rhodesia, a formal British colony, 250,000 white
residents who owned the country’s farmlands refused to let their power and domination pass away

peacefully. Instead of accepting the black majority rule, they
declared Rhodesia independent as a white-supremacist state.
The blacks in turn declared war against the white rulers and
the civil war continued until 1975 when the Rhodesian
government capitulated. So came the birth of Zimbabwe, but
at a heavy human and material cost.

Something similar happened in Angola and Mozambique,
both Portuguese colonies. When Lisbon refused to grant
independence to these countries, people of Angola and
Mozambique turned to guerrilla warfare. The war in Angola

became even more violent, when the U.S. and the Soviet Union turned that civil war into a theater
of their own superpower competition. The Marxist groups within guerrilla movement, supported by the Soviet Union and Cuba,

eventually succeeded in forcing Portugal to leave Angola and Mozambique, and setup leftist governments. The U.S. and South Africa
perceived the leftist governments in Angola and Mozambique as thereat to their interests and financed guerrilla forces seeking to

topple the Marxist government of Angola and Mozambique. The fighting continued
well into the 1980s. The war ended at least in Mozambique due in large part to the
Soviet Union and the U.S. losing interest in it following the end of the cold war. In
Angola, low intensity war drags on, however. In any event, as one geographer has
noted, “the countryside in both states is now so heavily riddled with landmines that it
can hardly be used.” Probably the most tragic aspect of Sub-Saharan Africa’s many
conflicts is wide use of the so-called “boy soldiers,” as shown in the above pictures.)

Another example of turbulent decolonization process took place in the Republic of
South Africa. In the 1960s, the black majority launched an organized opposition to
apartheid, system of racial segregation and discrimination that relegated the black

majority to the life in the impoverished and miserable ghettoes called townships. (As shown in the picture to your left, even the
bridges were segregated.) From there, blacks emerged in the morning to enter white residential areas to work there. They, of course,
came back to their shantytowns after work. The South African government met this challenge by throwing anti-Apartheid activists
into jail. The most popular among the imprisoned leaders of anti-
apartheid struggle was Nelson Mandela who had spent 27 years of his
life in incarceration. As it is said, all things come to pass, and apartheid
was no exception. This inhumane system of race control and
subjugation came under increasing criticism from other countries. Also
the angry young blacks who had, literally, nothing to live for therefore,
nothing to lose became increasing violent in their struggle against
apartheid. In 1994, the white minority rule finally ended when Nelson
Mandela, who was first released from his prison term, was elected
president of the Republic of South Africa. (Picture here shows president
Mandel in his old jail cell.) The presidency of Mandela and his successor,
Thabo Mbeki, have not shed all of the legacies of South Africa’s racist
past. With whites still dominating economic life of the country, and
blacks feeling the improvement in their lives too slow and insignificant,
South Africa has a long way to go in bridging the gap that still separates black and white life.

One of the legacies of the colonization of Sub-Saharan Africa by Europeans that has been a cause of underdevelopment is social
fragmentation. Sub-Saharan Africa, without European colonization, already is a multi-linguistic, ethnic, and cultural society. Just in
terms of language there are 1,000 different languages spoken in Africa. Also, in Africa, there has been a strong tradition clanocracy,
rule by clan (or tribal) authorities. European colonizer worsened this problem of fragmentation by imposing arbitrary division and
union of people. When European drew lines separating their colonies, Africa’s clan/ethnic Pandora’s box was opened. As one
geographer writes, “All over Africa, different ethnic groups found themselves forced into the same state with peoples of disparate,

linguistic and religious backgrounds, many of whom had
recently been their enemies. At the same time, a number of
the larger ethnic groups of the region found their territories
split between two or more countries.” The outcome of this
particular legacy of western colonization has been an
unending series of postcolonial conflicts that generated
millions of refugees and displaced persons, not to speak of
disruptions to the daily lives of people and economic
production.

This environment of division and conflict is exacerbated by the
tendency on the part off European rulers to pit competing
ethnic and religious groups against each other. This particular
method of colonial rule is commonly called “divide and
conquest (or rule).” One example is Rwanda. In this country,
there are two competing ethnic groups, Hutu and Tutsi, which

once constituted separate kingdoms. During Rwanda’s colonial rule under first Germans and later Belgians, Tutsis were favored
against Hutu. After independence, Hutus secured upper hand in Rwandan society and repressed Tutsi. In 1994, ethnic violence broke
out between the two groups, leading to waves of mass slaughter. The conflict also caused million of refugees (above) to flee to

neighboring countries that were destabilized by infusion of the refugees. Unity is a precious commodity in Africa. By late 1990s,
there were estimated 4 million refugees in Africa.

Sub-Saharan Africa’s poverty is also a product of mismanagement and
corruption. After their independence, Sub-Saharan African countries sought
to build their economy by exporting mineral and agricultural products. The
price of these products in international markets remained relatively high back
then, therefore, enabling African countries to earn foreign exchange and
attract foreign investment. The trouble came when “the relatively buoyant
economies of 1960s and early 1970s were to disappear in the 1980s as most
commodity prices began to decline.” Thereafter, “sizable foreign debt began
to weigh down many Sub-Saharan countries. By the end of the 1980s most of

the region entered a virtual
economic tailspin.”
Economic failures were also
engendered by the misguided developmental policy of focusing on heavy
industries, which made the country look industrially powerful and advanced, but
whose products were not competitive in the global market. In addition, many
countries that survived on agricultural export focused on cash crops that could be
sold in the international market while neglecting food production. When natural
calamities such as draught hit, people did not have enough to eat. (Here you are
looking at two faces of underdevelopment in Sub-Saharan Africa.) Then there is
the infamous problem of corruption, which is another deadly blow to Sub-Saharan
Africa’s developmental potential. One particularly harsh critic notes,

“In many cases inefficient and often corrupt government ministries took over large segments of the economy….With millions
of dollars in loans and aid pouring into the region, officials at various levels were tempted to skim from the top. African
states…were dubbed kleptocracies. A kleptocracy is a state where corruption is so institutionalized that politicians and
government bureaucrats siphon off a huge percentage of
the country’s wealth.”
(Les Rowntree, et al, Diversity Amid Globalization)

Corruption and mismanagement in African countries is in many
cases a product of what geographers call “Big Man” politics. In
other words, in many Sub-Saharan countries, “presidents, both
military and civilian, grabbed onto the reigns of power and
refused to let go. Military governments, one-party states, and
presidents-for-life became the norm” Some of these Big Man
leaders, literally and figuratively, are know for their use of
violence, and pilfering of national coffers. (One of the most well
known “Big Man” of Africa is Robert Mugabe of Zimbabwe whose
legacies are caricatured here to the right.)

Nigeria is a typical example of how a resource-rich country suffers from underdevelopment because of mismanagement, corruption,

dictatorship, and colonial imprints. (Nigeria by the way produces about three percent of the
worldwide petroleum production.) Yet Nigeria’s GNP per capita is $300. When has gone wrong?
This is what our textbook argues.

“But before long Nigeria’s oil wealth brought more bust than boom. Misguided development plans
now focused on grand, ill-founded industrial schemes and costly luxuries such as a national
airline;…the agriculture fell into neglect. Worse, poor management, corruption, outright theft of
oil revenues during military misrule, and excessive borrowing against future oil income led to
economic disaster. The country’s infrastructure collapsed….Basic [public] services broke down.”

As if these problems are not enough, Sub-Saharan Africa suffers from diseases that afflict and
claim the lives of a large number of people. (There are three types of disease, endemic, epidemic,
and pandemic, in the order of how large a population is afflicted.) Africa’s natural environment
characterized by high temperatures and humidity provides breeding grounds for organisms that

carry disease. Diseases that afflict a large number of Africans include trypanosomiasis, better known as African sleeping sickness and
malaria. Sub-Saharan Africa’s disease problem is exacerbated by wide use of untreated water for drinking and cooking. (Orphans of
Africa to your left.)

Recently, however, AIDS (Acquired Immune Deficiency Syndrome) has become the main epidemic
of Sub-Saharan Africa. According to a U.N. report, of the 32 million people worldwide who are
known to be infected by HIV that causes AIDS, 27 million live in 34 tropical African countries. In
several tropical African countries, between 20 to 25 percent of the entire population is inflicted
with HIV. There have been nearly 12 million AIDS deaths in Africa, quarter which are children.
There are 11 million children in Sub Saharan Africa orphaned by AIDS. Experts believe that the
reasons for such a rapid spread of the disease is due to lack of funding for education for safe sex
and medical treatment, as well as cultural resistance to using contraceptives among the male

population. (Mother and child victims
of AIDS is shown to the right.)

In conclusion, Sub-Saharan Africa is
still suffering from overwhelming array
of problems: environmental challenges,
historical exploitation by Europeans
including slave trade, postcolonial
conflicts exacerbated by superpower
rivalry in Africa, and mismanagement of natural resources by corrupt and
dictatorial leaders, just to mention the big ones. However, that does not
mean that it is hopeless. It still is the largest reservoir of natural
resources. Could you suggest ways in which Sub-Saharan African
countries could expedite their economic and social developments? In

other words, how could Africa smile as brightly as these children here? That question truly is the challenge of our time.

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.

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.

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

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

V O L U M E 3 3 � N U M B E R 5 � F E B R U A R Y 1 0 2 0 1 5

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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

http://www.jco.org

mailto:lillian.sung@sickkids.ca

http://dx.doi.org/10.1200/JCO.2014.58.0480

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 %

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).

Chellapandian et al

502

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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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.

Lung Procedures in Cancer and Stem-Cell Transplantation

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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.

Chellapandian et al

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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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.

Lung Procedures in Cancer and Stem-Cell Transplantation

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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.
Chellapandian et al

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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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295-301, 2007

■ ■ ■

Lung Procedures in Cancer and Stem-Cell Transplantation

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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

Chellapandian et al
© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

http://www.asco.org/rwc

http://jco.ascopubs.org/site/ifc

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”
Lung Procedures in Cancer and Stem-Cell Transplantation

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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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)

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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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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.

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-Hwa Wang1,2, 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.

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 1 / 9

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.

http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0118993&domain=pdf

http://creativecommons.org/licenses/by/4.0/

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

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 2 / 9

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%

doi:10.1371/journal.pone.0118993.t001

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 3 / 9

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).

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 4 / 9

Fig 1. The multiple 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.

doi:10.1371/journal.pone.0118993.t002

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 5 / 9

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.

doi:10.1371/journal.pone.0118993.g002

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 6 / 9

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

Flexible Bronchoscopy for Foreign Body

PLOS ONE | DOI:10.1371/journal.pone.0118993 March 13, 2015 7 / 9

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 MHH HCL HPK. Performed the experiments:
YFF MHH FTC YKH GYC SML HCL CHW HPK. Analyzed the data: YFF MHH HCL HPK.
Contributed reagents/materials/analysis tools: YFF MHH FTC YKH GYC SML HCL CHW
HPK. Wrote the paper: YFF MHH HCL 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 P T 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 P T 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 P T 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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O R I G I N A L R E S E A R C H

open access to scientific and medical research

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 (PtcCO

2
) change over the time course was similar in both groups, but both peak PtcCO

and time on PtcCO
2
�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; FEV

1
, 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; PtcCO

2
, transcutaneous carbon dioxide

tension; SO
2
, 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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International Journal of COPD 2017:12submit your manuscript | www.dovepress.com
Dovepress

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178

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 PtcCO

2
.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

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179

Flexible bronchoscopy with moderate sedation in COPD

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 (FEV

1
/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 (SO

2
),

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, SO

and PtcCO
2
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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180

Grendelmeier et al

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
SO

2
and PtcCO

2
during examination and at the initiation and

end of examination; 4) median and peak PtcCO
2
; 5) median

and nadir SO
2
; 6) time with PtcCO

2
�45 mmHg; 7) time with

SO
2
�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 FEV

1
% 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 PtcCO

2
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 FEV

1
% predicted, SO

2
, PtcCO

2
, and

cDL
CO

. 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 PtcCO
2
peak during bronchoscopy as

the dependent factor versus FEV
1
% predicted and DL

CO
. 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
FEV

1
and cDLCO, higher total lung capacity and residual

volume, and lower pO
2
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 FEV

1
% 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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181

Flexible bronchoscopy with moderate sedation in COPD

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 SO

2
and remained hypoxemic (SO

2
�88%)

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

correlation between time with an oxygen saturation �88%

or nadir SO
2
during the examination and FEV

1
% 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 58.5o14.9 66.5o10.2 61.6o15 �0.001
Male, gender 52.9% 66.6% 58.4% �0.001
Height, cm 168.3o9.4 168.5o8.7 160.3o9.1 0.596
Weight, kg 70.2o17.6 70.3o17.4 70.2o17.5 0.715
BMI, kg/m2 24.7o5.3 24.6o5.3 24.6o5.3 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 27.2o25.4 47.9o25.4 37.9o27.4 �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, % 86.4o20.3 86.5o20.0 88.1o42.68 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 263o126 286o132 273o129 0.003

Notes: Data are presented as mean o 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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182

Grendelmeier et al

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

FEV
1
, liters 2.25o0.92 1.51o0.69 1.96o0.91 �0.001

FEV
1
, % predicted 78.4o24.8 56.9o24.4 70.0o26.8 �0.001

FVC, liters 3.00o1.11 2.75o0.88 2.90o1.04 �0.001
FVC, % predicted 85.1o22.7 81.9o21.2 83.9o22.1 0.024
FEV

1
/FVC 70.3o12.3 49.2o15.8 63.0o17.2 �0.001

cDLCO, % 71.1o24.4 57.4o22.7 65.7o24.6 �0.001
RV, liters 2.17o0.66 3.36o1.27 2.63o1.11 �0.001
RV, % predicted 104.8o31.0 148.3o59.5 121.8o49.2 �0.001
TLC, liters 5.36o1.34 6.42o1.55 5.78o1.51 �0.001
TLC, % predicted 91.4o16.6 107.6o23.4 97.7o21.0 �0.001
RV/TLC 41.3o11.5 51.4o11.7 45.27o12.6 �0.001
Arterial blood gas analysis

paO
2
, mmHg 75.31o10.13 67.7o12.08 70.88o13.43 �0.001

paCO
2
, mmHg 36.45o5.25 38.78o6.68 37.73o6.23 0.196

pH 7.43o0.04 7.42o0.03 7.43o0.04 0.457
Bicarbonate, mmol/L 24.7o2.1 25.4o2.6 25.1o2.4 0.068

Notes: Data are presented as mean o SD. P-values represent the comparison between non-COPD and COPD groups.
Abbreviations: FEV

1
, 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; paO
2
, partial pressure of oxygen; paCO

2
, 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 229o143 234o158 231o149 0.544
Propofol (dose/kg), mg/kg 3.34o2.15 3.53o2.47 3.37o2.23 0.219
Propofol (dose/kg/min), mg 0.275o0.173 0.239o0.181 0.265o0.369 0.001
Hydrocodone, mg 4.23o2.27 4.08o2.62 4.11o2.38 0.477
Duration, minutes 12 (7–20) 15 (8–27) 12 (7–23) �0.001

Notes: Data are presented as number (%), mean o 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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183

Flexible bronchoscopy with moderate sedation in COPD

(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 PtcCO

2
levels. Hence, time on PtcCO

2
�45 mmHg

was found to be increased compared to non-COPD patients.
Conversely, the change in PtcCO

2
over the time course of

bronchoscopy was similar in patients with and without COPD
(P�0.571, Figure 3). PtcCO

2
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 PtcCO

2
correlated

both with the FEV
1
% predicted value and cDL

CO
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 FEV

1
% proved to

be independently associated with peak PtcCO
2
(beta coeffi-

cient �
0.393 [
0.358 to 0.0700], P�0.004) in a multivariate
linear regression model including both FEV

1
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 PtcCO

2
, 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 PtcCO

2
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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185

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

SO
2
, median, % 96 (94–97) 94 (93–95) �0.001

SO
2
time �88%, minutes 0.14 (0–1.16) 1.12 (0.04–4.4) �0.001

SO
2
nadir during bronchoscopy, % 87 (84–91) 86 (82–89) 0.002

PtcCO
2
at baseline, mmHg 35.2 (32.1–38.3) 36.7 (33.8–39.1) 0.036

PtcCO
2
median, mmHg 39.5 (36.5–44.7) 42.5 (38.7–46.2) �0.001

PtcCO
2
time �45 mmHg, minutes 12.0 (2.1–45.4) 32.9 (7.0–76.2) �0.001

PtcCO
2
peak, mmHg 51.9 (46.1–61.7) 57.9 (50.3–66.1) �0.001

PtcCO
2
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: PtcCO

2
, transcutaneous carbon dioxide tension; SO

2
, 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

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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; PtcCO

2
, transcutaneous carbon dioxide

ten sion.

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186

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 PtcCO

2
.6

Therefore, it is tempting to speculate that, despite the similar
increase in PtcCO

2
in patients with and without COPD

observed in our study, patients with COPD may be at higher
risk for complications due to the elevated PtcCO

2
baseline

levels. The question whether transcutaneous CO
2
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 FEV

1
/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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Flexible bronchoscopy with moderate sedation in COPD

Disclosure

The authors report no conflicts of interest in this work.

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Propofol sedation for flexible
bronchoscopy: a randomised,
noninferiority tri

Peter Grendelmeier, Michael Tamm, Eric Pflimlin and Daiana Stolz

Affiliation:
Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Basel, Switzerland.

Correspondence:
D. Stolz, Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgrabe

4, 4031 Basel, Switzerland.
E-mail: daiana.stolz@usb.ch

ABSTRACT Propofol has been established as a reliable method for sedation in flexible bronchoscopy.

There are no data comparing propofol administered as intravenous boluses versus continuous infusion.

702 consecutive patients undergoing flexible bronchoscopy were randomly allocated to receive

intravenous propofol using either an intermittent bolus technique or a continuous infusion. The primar

end-point was the number of adverse events assessed at the end of flexible bronchoscopy and at 24 h.

The number of any adverse event was similar in both randomised groups (219 versus 211, p50.810).

There were complications in eight cases (seven major bleedings, one respiratory failure). As compared with

the bolus group, the amount of propofol required was significantly higher in the infusion group (226

¡147 mg versus 308¡204.8 mg, p,0.0001). In a multivariate regression model, this difference remained

significant independent of the duration and the interventions performed during the procedure. The

duration of bronchoscopy was significantly longer in the infusion group (median 14 (interquartile range

9–24) versus 17 (12–27) min, p,0.0001).

Propofol continuous infusion is as safe as bolus administration; however, it is associated with higher

propofol requirements and a longer duration of the bronchoscopy.

@ERSpublications

Propofol continuous infusion is as safe as bolus administration, but has higher requirements and
longer bronchoscopy http://ow.ly/r4Uas

Received: Dec 12 2012 | Accepted after revision: July 02 2013 | First published online: July 30 2013

Clinical trial: This study is registered at www.controlled-trials.com with identifier number ISRCTN66129676.

Support statement: D. Stolz was supported by grants from the Swiss National Foundation (PP00P3_128412/1).
Additional funding was provided by the Clinic of Pulmonary Medicine and Respiratory Cell Research, University
Hospital Basel, Basel, Switzerland.

Conflict of interest: None declared.

ORIGINAL ARTICLE
BRONCHOSCOPY

Eur Respir J 2014; 43: 591–601 | DOI: 10.1183/09031936.00200412 591

www.controlled-trials.com

Introduction
The British Thoracic Society states that sedation for flexible bronchoscopy should be offered to patients

where there is no contraindication [1]. The aim of sedation is to facilitate patient comfort and satisfaction

and to alleviate patient anxiety, cough and dyspnoea while reducing complications of the procedure [2–4].

According to a survey of registered members of the British Thoracic Society, .95% of centres routinely

perform sedated bronchoscopy [5]. Optimal sedation for flexible bronchoscopy has been assessed in a

number of studies evaluating different sedative drug regimens using single agents or combinations thereof

[6–10]. Propofol (2,6-di-isopropylphenol), a sedative hypnotic, has recently proved to be a safe and

attractive alternative to combined sedation with midazolam and hydrocodone due to its rapid onset of

action and fast recovery time, particularly if timely discharge was a priority [11–18]. Additionally, as

compared with midazolam alone, propofol seems to provide a higher quality of sedation in terms of

neuropsychometric recovery and patient tolerance [18]. However, unlike the benzodiazepines, propofol

does not have a reversal agent. Many specialty bodies recommend its use only by those trained in the

administration of anaesthesia, and the license of whom propofol may be administered by also differs by

licensing agency.

The administration of propofol for conscious sedation in flexible bronchoscopy is usually performed by

repeated intravenous boluses. In contrast, the continuous infusion of propofol is an established method of

sedation in the intensive care unit (ICU), where its administration occurs over hours or days. Taking into

account the increasing complexity and, thus, duration of diagnostic and interventional flexible bronchoscopy,

continuous infusion of propofol seems to be an appealing approach to conscious sedation in this setting.

As yet, there are very limited data of propofol in gastrointestinal endoscopy [19, 20] and no data comparin

bolus administration versus continuous infusion of propofol in flexible bronchoscopy. Therefore, a large,

prospective, randomised, noninferiority trial was undertaken in order to determine whether propofol given

as a continuous infusion is as effective and safe as propofol applied by bolus administration in patients

undergoing flexible bronchoscopy.

Methods
A total of 1223 consecutive patients were assessed for eligibility. 43% of screened patients did not meet

eligibility criteria for study inclusion (fig. 1). The main reasons for noninclusion were bronchoscopy at the

ICU and emergency bronchoscopy. Thus, 702 patients undergoing flexible bronchoscopy were randomly

allocated to receive intravenous propofol using either a continuous infusion or an intermittent bolus

technique. Patients aged o18 years were included between April 2011 and January 2012. Intubated or
isolated patients, patients with known allergy or intolerance to propofol, patients undergoing emergency

bronchoscopy, pregnant or breastfeeding females and patients with a mental disorder preventing

appropriate judgment concerning study participation were not included in the study. Informed consent was

obtained from each patient and the study was approved by the institutional review board, Ethikkommission

beider Basel. The trial was registered with the Current Controlled Trials Database (ISRCTN66129676).

All patients were assessed by a member of the nursing team trained in anaesthesiology and a chest physician

prior to the procedure, which included gradation of physical status in accordance with the American Society

of Anesthesiologists (ASA) criteria. Current medication such as anticoagulants, antiplatelet drugs, sedatives

and hypnotics were recorded. Comorbidities including chronic obstructive pulmonary disease, coronary

artery disease, congestive heart failure, cerebrovascular disease, renal failure, liver disease, malignant solid

tumour, haematological malignancy, rheumatic disease, diabetes mellitus, alcohol abuse and HIV infection

were noted and current blood work results were listed.

Bronchoscopy procedures were performed transnasally or transorally, with the patients in the semi-recumbent

position, by a total of five pulmonary fellows under close supervision of five pulmonary attending physicians.

Electrocardiographic and transcutaneous pulse oxymetric monitoring were recorded continuously during the

procedure. In addition, automated noninvasive blood pressure measurements were performed every 5 min.

Supplemental oxygen was given at 4 L

-1

via a nasal cannula to all patients. In the case of desaturation to

f90%, oxygen delivery was increased to 6 L?min-1 [21]. Patients were routinely given 4 mg i.v. hydrocodone
immediately prior to flexible bronchoscopy, as previously described [10]. Nasal anaesthesia was achieved by

2% lidocaine gel. Bronchoscopists were advised to instil 3-mL aliquots of 1% lidocaine over the vocal cords

and on the trachea and both right and left main bronchi. Instilled lidocaine doses were recorded for each

patient. All doses of supplemental local anaesthesia required, as judged by the bronchoscopist, were recorded

for each patient. No inhaled lidocaine was given prior to the procedure [7].

Patients were randomly assigned to either intravenous propofol using an intermittent bolus technique or as

continuous infusion for conscious sedation. Randomisation was through arbitrary allocation to one of the

two treatment groups based on a computer-generated random list (GraphPad Prism; GraphPad Software,

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412592

Inc., San Diego, CA, USA). Every patient’s assignment was carried out in the waiting room of the

bronchoscopy suite by a research nurse.

For patients assigned to the bolus administration of propofol (bolus group), the loading doses of propofol

were titrated in order to achieve adequate conscious sedation (onset of ptosis for bronchoscopy). Patients

received an initial 20 mg of i.v. propofol, followed by a carefully titrated dose. For ASA I and II patients, the

steps comprised 10–20 mg i.v. propofol, whereas for ASA III and IV, exactly 10 mg i.v. propofol was

administered based on the clinical response, as previously described [22]. Between each bolus, a pause

lasting o20 s had to be observed. Additional i.v. boluses of propofol were given, if the effect disappeared
during the examination, depending on the clinical effect, in order to maintain the required level of sedation.

Signs of pain or discomfort, agitation, persistent cough, and inadequate motor or verbal response to

manipulation 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.

Patients assigned to the continuous infusion of propofol (infusion group) received an initial bolus of 10 mg

i.v. propofol, immediately followed by the continuous infusion of propofol at an initial rate of

0.3 mg?kg
-1

in
-1

. The infusion rate was reduced to 0.2 mg?kg
-1

?min
-1

after 3 min and was further

diminished to 0.1 mg?kg
-1

?min
-1

and to 0.05 mg?kg
-1

?min
-1

after another 3 and 6 min, respectively, if

conscious sedation was achieved. In case of inadequate sedation, a bolus of 10–20 mg of propofol was given

and the infusion rate was increased in reversed order to a maximum rate of 0.5 mg?kg
-1

?min
-1

. In case of

apnoea, hypoxaemia or hypotension, the continuous infusion could be reduced in the above mentioned

manner or completely stopped at all times as judged by the bronchoscopist. Applied propofol infusion rates

were based on the analysis of previous data in a different patient population [17]. Propofol was

administered by the bronchoscopy nurse at the endoscopist’s discretion. The use of propofol in the

department was introduced almost 10 years ago under the supervision of a board-certified anaesthetist who

Assessed for eligibility
n=1223 Patients meeting exclusion criteria n=521

Outside bronchoscopy suite n=189

Unable to provide informed consent

(language barrier or neurological constraints) n=62

Emergency procedure n=

Single subject with repeated procedures n=

Refused n=44

Contact isolation n=31

Propofol intolerance n=1

Need for longer sedation for endobrachytherapy n=7

Combined endoscopic procedure n=17
Included in the study

n=702

Randomised
n=702

Allocated to bolus group
n=35

Allocated to infusion group
n=347

Analysed
n=347

Analysed
n=355

FIGURE 1 Study flow chart for patients included in the study.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412 593

was personally present during a 3-month initiation period. Since the introduction of this sedation method,

propofol has been administered by a bronchoscopy nurse with training in deep sedation. Currently all

endoscopy nurses are specially trained in the administration of propofol and the risks associated with its

use. They are proctored while administering propofol by an experienced nurse, until proficiency with

administration is demonstrated. All nurses are carefully instructed in the management of emergency

situations (e.g. mask ventilation, positioning of a nasopharyngeal tube). In every endoscopy procedure

room, equipment for emergency mask ventilation and appropriate drugs for use during emergency

situations were always immediately to hand.

Diagnostic procedures, i.e. brushing, washings, bronchoalveolar lavage (BAL), mediastinal as well as

peripheral transbronchial needle aspiration, endobronchial and transbronchial biopsy and endobronchial

ultrasound, were performed dependent upon the clinical indication. Additionally, interventions such as

stent or endobronchial valves implantation and laser therapy were carried out. Haemodynamic parameters,

sedation requirements, duration of bronchoscopy, bronchoscopic procedures and complications were noted

during the procedure on a form specifically designed for the study.

Adverse events were defined as oxygen desaturation f90%, need for nasopharyngeal or oropharyngeal
airway insertion, hypotension with a systolic blood pressure of ,90 mmHg, pneumothorax and minor

bleeding. Complications were defined as major bleeding, need to abort bronchoscopy, need for intubation,

need for ICU transfer post-bronchoscopy and death.

At the end of the procedure, bronchoscopists and nursing staff would chart their perception of cough

during the procedure on a 10-cm visual analogue scale (VAS). Similarly, 2 h after bronchoscopy, patients

were also asked to record their perception of cough related to the procedure on a 10-cm VAS. On this scale,

0 denoted no cough and 10 represented incessant cough. Patients were also asked to record anxiety and

discomfort associated with the procedure on a 10-cm VAS. On this scale, 0 denoted no fear or discomfort

and 10 represented the greatest imaginable fear or discomfort. Willingness to undergo repeat flexible

bronchoscopy was also documented 2 h after bronchoscopy.

Haemodynamic monitoring was performed immediately before, during and shortly after the procedure

(after removal of the bronchoscope), as well as before transfer from the bronchoscopy suite to the recovery

room. Moreover, the patient’s blood pressure, cardiac frequency and respiratory rate were monitored for up

to 3 h after bronchoscopy, until discharge.

The primary end-point was the number (percentage) of adverse events and complications (oxygen

desaturation f90%, need for nasopharyngeal or oropharyngeal airway insertion, need for intubation,
hypotension with a systolic blood pressure of ,90 mmHg, minor or major bleeding, ICU need post-

bronchoscopy, pneumothorax, need to abort bronchoscopy and death) assessed by the study physician

during and up to 24 h after the procedure.

Secondary pre-defined end-points included total dose of propofol, dose of propofol per kg body weight,

dose of propofol per kg body weight and per minute, total dose of hydrocodone, total amount of lidocaine

doses, duration of the procedure, mean lowest oxygen saturation during the procedure, mean lowest systolic

blood pressure during the procedure, haemodynamic parameters other than blood pressure during and

after the procedure, cough scores, as assessed by a VAS by patients, nurses and physicians 2 h after the

procedure, patient discomfort, median patient overall well-being (comfort) at 2 h after the procedure,

willingness to undergo a repeated procedure, assessed by a VAS 2 h after the procedure, and fear of

undergoing a repeated procedure, assessed by a VAS 2 h after the procedure.

Data analyses
Assuming an incidence of complications of 0.36 [11] in the arm treated with propofol as bolus and

incidence of complications of 0.31 in the arm treated with propofol in a continuous fashion, a total of 688

patients, 344 in each treatment arm, were considered to be needed to achieve a significance level of ,0.05

with a power of 0.8. Considering a 1% loss to follow-up, a total of 702 patients were aimed for inclusion.

Differences in dichotomous variables were evaluated using the Chi-squared test or Fischer’s Exact test, as

appropriate. Normally distributed parameters were analysed using the Student’s t-test for equality of means.

All other continuously non-normally distributed parameters were evaluated using the nonparametric

Mann–Whitney U-test or Kruskal–Wallis test, as appropriate.

The SSPS version 19 (SSPS Inc., Chicago, IL, USA) program was used. All tests were two-tailed; a p-value of

,0.05 was considered significant. Results are expressed as mean¡SD or median (interquartile range) unless

otherwise stated.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412594

Results
Demographic data are presented in table 1. There were no significant differences between the two

randomised groups in terms of age, sex, physical status, ASA class, presence of comorbidities or current

medication. However, there was a trend towards a higher number of patients with haematological

malignancy and hence immunosuppression in the bolus group. Of note, almost three-quarters of all patients

were classified as ASA class III (bolus and infusion groups 74.9% and 72.3%, respectively), defined as

patients with severe systemic disease.

Table 2

shows the indication, number and distribution of diagnostic and interventional procedures per

patient and randomisation group. The main reason for bronchoscopy was pulmonary infection, followed by

suspicion of malignancy and interstitial lung disease. Accordingly, the most common diagnostic procedures

TABLE 1 Demographic data of consecutive patients undergoing flexible bronchoscopy

Characteristics

Bolus Infusion Total p-value

Subjects n

355 347 702

Age years 61.2¡15 61.9¡14 61.5¡15 0.556
Males 207 (58.3) 197 (56.8) 404 (57.5) 0.6

Height cm 170¡10.2 170¡10.4 170¡10.3 0.762
Weight kg 71.5¡17.5 70.3¡17.7 70.8¡17.6 0.3

BMI kg?m-2 24.7¡5.3 24.3¡5.5 24.5¡5.4 0.3

Smoking status %

Never-smoker 104 (29.7) 106 (30.9) 210 (30.3)
Current smoker 79 (22.6) 70 (20.4) 149 (21.5) 0.782
Ex-smoker 167 (47.7) 167 (48.7) 334 (48.2)

Pack-years n 29¡30.5 27¡30 28¡30.1 0.587
ASA class %

I 7 (2.0) 4 (1.2) 11 (1.6)
II 66 (18.6) 77 (22.2) 143 (20.4) 0.514
III 255 (71.8) 241 (69.5) 496 (70.7)
IV or V 19 (5.4) 13 (3.7) 32 (4.6)

Comorbidities %
COPD 119 (33.5) 117 (33.7) 236 (33.6) 0.909
Coronary artery disease 52 (14.6) 45 (13.0) 97 (13.8) 0.519
Congestive heart failure 25 (7.0) 18 (5.2) 43 (6.1) 0.3

Cerebral vascular disease 12 (3.4) 9 (2.6) 21 (3.0) 0.541
Diabetes mellitus 47 (13.2) 37 (10.7) 84 (12.0) 0.280
Renal failure 45 (12.7) 42 (12.1) 87 (12.4) 0.807
Liver disease 8 (2.3) 10 (2.9) 18 (2.6) 0.598
Solid malignant tumour 142 (40.0) 149 (43.0) 291 (41.5) 0.429
Haematological malignancy 57 (16.1) 40 (11.5) 97 (13.8) 0.082
Immunosuppression 111 (31.3) 89 (25.6) 200 (28.5) 0.099
Rheumatological disease 22 (6.2) 17 (4.9) 39 (5.6) 0.447
HIV 9 (2.5) 6 (1.7) 15 (2.4) 0.457
Alcohol abuse 27 (7.6) 22 (6.3) 49 (7.0) 0.511
Intravenous drug use 5 (1.4) 6 (1.7) 11 (1.6) 0.736

Current medication %
Acetylsalicylic acid 68 (19.2) 56 (16.2) 124 (17.7) 0.311
Clopidogrel 8 (2.3) 11 (3.2) 19 (2.7) 0.454
Prasugrel 0 (0) 2 (0.6) 2 (0.3) 0.145
Oral anticoagulant 32 (9.0) 20 (5.8) 52 (7.4) 0.

100

Heparin (therapeutic dose) 5 (1.4) 2 (0.6) 7 (1.0) 0.267
Heparin (prophylactic dose) 15 (4.2) 9 (2.6) 24 (3.4) 0.234
LMWH (therapeutic dose) 10 (2.8) 5 (1.4) 15 (2.1) 0.207
LMWH (prophylactic dose) 77 (21.8) 66 (19.0) 143 (20.4) 0.370

Sedatives 29 (8.2) 21 (6.1) 50 (7.1) 0.276
Hypnotics 18 (5.1) 15 (4.3) 33 (4.7) 0.640

Mean prothrombin time % 88.3¡23.6 90.5¡22.0 89.4¡22.8 0.211
INR 1.2¡0.7 1.2¡0.5 1.2¡0.6 0.209
Mean platelet count G?L-1 318¡149 338¡160 329¡156 0.095

Data are presented as mean¡ SD or n (%), unless otherwise stated. BMI: body mass index; ASA: American
Society of Anesthesiologists; COPD: chronic obstructive pulmonary disease; LMWH: low molecular weight
heparin; INR: international normalised ratio.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412 595

were BAL (60.8%) and bronchial washing (26.0%), followed by transbronchial and endobronchial biopsies

(17.1% and 14.8%, respectively). The majority of patients underwent one (53.9%) or two (23.0%)

diagnostic bronchoscopic procedures. There were more diagnostic bronchoscopies for infection in the bolus

group as compared with the infusion group, while more bronchoscopies for suspected interstitial lung

disease were performed in the infusion group. Accordingly, the number of transbronchial biopsies was

significantly higher in the infusion group (48 versus 72; p50.011).

Incidence of adverse events and complications
The number (rate) of any adverse event was similar in both randomised groups (219 (61.7%) patients in the

bolus group versus 211 (60.8%) patients in the infusion group; p50.810). There were complications in eight

(1.1%) cases (seven major bleedings (four in the bolus group and three in the infusion group), one

respiratory failure (in the infusion group)) leading to the termination of examination with subsequent

intubation and transfer to ICU in one patient in each group. Intubation was performed for major bleeding

in one patient (bolus group) and for respiratory failure in another (infusion group). There were no deaths.

Details of adverse events and complications are shown in table 3.

Secondary end-points
Medication requirements and duration of all interventions are shown in table 4. As compared with the

bolus group, the amount of propofol required was significantly higher in the infusion group (226¡147 mg

versus 308¡204.8 mg; p,0.0001). In a linear multivariate regression model, this difference remained

significant independently of duration and the interventions (e.g. transbronchial biopsy and endobronchial

ultrasound) performed during flexible bronchoscopy. Both lidocaine and hydrocodone requirements were

similar in both groups.

The duration of bronchoscopy (from beginning of sedation to removal of bronchoscope) was significantly

longer in the infusion group (14 (9–24) min versus 17 (12–27) min; p,0.0001). This difference was mainly

TABLE 2 Main indications for bronchoscopy per randomisation group

Indication for bronchoscopy Bolus Infusion Total p-value

Subjects n 355 347 702
Suspicion of malignancy 83 (23.4) 93 (26.8) 176 (25.1) 0.296
Interstitial lung disease 29 (8.2) 48 (13.8) 77 (10.7) 0.016
Infection 130 (36.6) 107 (30.8) 237 (33.8) 0.105
Chronic cough 17 (4.8) 9 (2.6) 26 (3.7) 0.124
Haemoptysis 5 (1.4) 10 (2.9) 15 (2.1) 0.201
Bronchial toilette 35 (9.9) 35 (10.1) 70 (10.0) 0.9

Stenting 10 (2.8) 9 (2.6) 19 (2.7) 0.855
Laser therapy 5 (1.4) 3 (0.9) 8 (1.1) 0.725
Miscellaneous 41 (11.5) 32 (9.2) 73 (10.4) 0.312
Diagnostic procedures

Inspection only 23 (6.5) 23 (6.6) 46 (6.6) 1.000
Bronchial washings 99 (28.0) 83 (23.9) 182 (26.0) 0.222
BAL 214 (60.3) 212 (61.3) 426 (60.8) 0.788
Bronchial brushing 40 (11.3) 46 (13.3) 86 (12.3) 0.430
Endobronchial biopsy 48 (13.5) 56 (16.1) 104 (14.8) 0.329
Transbronchial biopsy 48 (13.5) 72 (20.7) 120 (17.1) 0.011
Mediastinal TBNA 24 (6.8) 36 (10.4) 60 (8.5) 0.087
Peripheral TBNA 15 (4.2) 20 (5.8) 35 (5.0) 0.349
EBUS 24 (6.8) 29 (8.4) 53 (7.5) 0.423

Interventions
Laser therapy 6 (1.7) 7 (2) 13 (1.9) 0.748
Stenting 12 (3.4) 12 (3.5) 24 (3.4) 0.955
Calypso implantation 2 (0.6) 2 (0.6) 4 (0.6) 0.982
Valve implantation 3 (0.8) 4 (1.2) 7 (1.0) 0.682

Number of procedures
1 203 (57.5) 174 (50.3) 377 (53.9)
2 79 (22.4) 82 (23.7) 161 (23.0) 0.1

o3 48 (13.6) 67 (19.4) 115 (16.5)

Data are presented as n (%), unless otherwise stated. BAL: bronchoalveolar lavage; TBNA: transbronchial
needle aspiration; EBUS: endobronchial ultrasound.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412596

due to a significantly longer phase between beginning of sedation and insertion of the bronchoscope, while

no significant difference could be observed in terms of duration of the procedure itself (after insertion of the

bronchoscope).

Figure 2 presents the haemodynamic findings before, during and after bronchoscopy. There was no

significant difference in lowest oxygen saturation between the two groups, while lowest systolic and diastolic

blood pressure were significantly lower in the infusion group (105 versus 100 mmHg, p50.008 and 60

versus 58 mmHg, p50.014, respectively). Of note, all oxygen saturation assessments, as well as systolic and

diastolic blood pressure values, were significantly higher in the infusion group at the beginning of sedation.

The lowest respiratory rate was significantly higher in the bolus group (15 versus 13; p50.002) as compared

with the infusion group. There was no significant difference between the two groups in terms of lowest or

highest heart rate.

Cough scores, as judged by the bronchoscopists, nursing staff and patients themselves, did not differ

between patients randomised to the bolus and infusion group. Similarly, there were no differences in the

perception of discomfort, anxiety and fitness related to the procedure, as well as readiness for repeating

bronchoscopy across treatment groups. Interestingly, 96.3% of all patients would have agreed to undergo a

further bronchoscopic examination (table 5).

Table 6

presents the reasons for episodic change in the study arm receiving propofol continuous infusion.

Most changes (90%) occurred due to perceived discomfort and persistent cough at 3 or 6 min (57%)

following start of sedation.

TABLE 3 Adverse events and complications per randomisation group

Bolus Infusion Total p-value

Subjects n
Adverse events

355 347 702

Hypotension systolic pressure f90 mmHg 94 (26.5) 109 (31.4) 203 (28.9) 0.149
Hypoxaemia oxygen saturation f90% 133 (37.5) 133 (38.3) 266 (37.9) 0.814
Insertion of nasopharyngeal/oropharyngeal

airway
21 (5.9) 23 (6.6) 44 (6.3) 0.704

Pneumothorax 0 (0) 0 (0) 0 (0) 1.000
Minor bleeding 30 (8.5) 30 (8.6) 60 (8.6) 0.936

Complications
Major bleeding 4 (1.1) 3 (0.9) 7 (1.0) 0.724
Termination of examination 1 (0.3) 1 (0.3) 2 (0.3) 0.322
Intubation 1 (0.3) 1 (0.3) 2 (0.3) 0.989
Transfer to intensive care unit 1 (0.3) 1 (0.3) 2 (0.3) 0.322
Death 0 (0) 0 (0) 0 (0) 1.000

Data are presented as n (%), unless otherwise stated.

TABLE 4 Bronchoscopy characteristics per randomisation group

Characteristics Bolus Infusion Total p-value

Subjects n 355 347 702
Propofol total mg 226.6¡147.0 308.3¡204.8 267.0¡182.5 ,0.0001
Propofol mg?kg-1 3.25¡2.14 4.65¡4.73 3.94¡3.72 ,0.0001
Propofol mg?kg-1?min-1 0.217¡0.127 0.235¡0.137 0.226¡0.132 0.069
Propofol as bolus mg 226.6¡147.0 31.1¡33.1 128¡143.7 ,0.0001
Hydrocodone mg 4.4¡1.6 4.6¡1.6 4.5¡1.6 0.058
Lidocaine number of doses 4 (3–4) 4 (3–4) 4 (3–4) 0.479
Duration from beginning of sedation to

insertion of bronchoscope min
2 (2–4) 3 (3–5) 3 (2–5) ,0.0001

Duration from beginning of sedation to
removal of bronchoscope min

14 (9–24) 17 (12–27) 16 (10–27) ,0.0001

Duration from insertion to removal of
bronchoscope min

11 (7–22) 13 (7–24) 12 (7–22) 0.062

Data are presented as mean¡SD or as median (interquartile range), unless otherwise stated.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412 597

Discussion
The present study demonstrates that the number of adverse events and complications is similar in patients

receiving propofol using an intermittent bolus technique or continuous infusion for sedation in flexible

bronchoscopy. However, patients receiving propofol as a continuous infusion required higher doses of

propofol and presented a prolonged duration of bronchoscopy as compared with the intravenous bolus

application group.

To our knowledge, this is the first randomised, controlled trial comparing bolus and continuous

administration for conscious sedation with propofol in diagnostic and interventional bronchoscopy.

Propofol has proved to be an attractive option to combined sedation with midazolam and hydrocodone,

providing significantly faster recovery times and improved patient satisfaction scores [11, 18]. It has been

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oxygen per randomisation group.

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412598

also showed that the combination of propofol and hydrocodone is safe, has a better cough suppressing effect

and is associated with significantly lower propofol requirements as compared with propofol alone [10]. The

feasibility and safety of propofol sedation as administered by repeated bolus technique is also supported by

two large cohort studies reporting the performance of propofol sedation in flexible bronchoscopy [14, 17].

In the current study, the number of adverse events observed during and following flexible bronchoscopy

was similar for both sedation regimens, i.e. bolus and continuous infusion of propofol. Thereby, the most

frequently observed adverse event was hypoxaemia, followed by hypotension and minor bleeding. This

finding is in agreement with prior reports: we have previously described the incidence of hypoxaemia on at

least one occasion during bronchoscopy to range between 29% and 32% in two large randomised studies

[10, 11]. Similar figures were reported by another smaller trial [15]. The frequency of hypoxaemia and

hypotension as reported by CLARK et al. [18] were 34.9% and 4.7%, respectively. Interestingly, a significantly

lower incidence of hypoxaemia was reported by two cohort studies on propofol sedation in flexible

bronchoscopy. Herein, BOSSLET et al. [14] found hypoxaemia in only 3.8% and hypotension in only 1% of

all patients using a nurse administered propofol protocol [17]. Differences in the incidence of hypoxaemia

and hypotension across the studies can be tentatively explained by several factors. First, in contrast to

previous reports, we performed a large number of diagnostic and interventional procedures, which require

stable yet well-sedated patients with minimal coughing. Moreover, almost one-third of our patients were

severely immunocompromised, including several cases of HIV infection as well as active drug use. It is well

known that patients with advanced oncological and haematological disease, including solid organ and bone

marrow transplantation, intravenous drug users and HIV patients, have a higher incidence of complications

during bronchoscopy [23]. Some patients with HIV infection require higher doses of sedation [6]. However,

sedation requirements may depend on the anti-retrovirals being used and if they inhibit or augment the

hepatic metabolism of propofol [24, 25]. Accordingly, the amount of propofol given in the current study

(0.217 mg?kg
-1

?min
-1

in the bolus group and 0.235 mg?kg
-1

?min
-1

in the infusion group) was globally

higher than the amount described in previous reports (0.15 mg?kg
-1

?min
-1

) [10, 11, 17, 18] and particularly

by BOSSLET et al. [14]. Secondly, the distribution of patients within ASA classes may explain differences in

the incidence of hypoxaemia and hypotension across the studies. Only roughly one-fifth of the patients in

the current study were classified as ASA I or II, while the vast majority (84%) of the patients included in the

study by BOSSLET et al. [14] belonged to these two ASA classes, including normal healthy patients and

TABLE 5 Outcome parameters per randomisation group

Characteristics Bolus Infusion Total p-value

Subjects n 355 347 702
Cough score

Physician VAS 3.0 (1.0–5.0) 2.0 (1.0–5.0) 2.8 (1.0–5.0) 0.398
Nurse VAS 2.5 (1.8–4.0) 3.0 (1.0–4.0) 2.7 (1.0–4.0) 0.619
Patient VAS 3.0 (1.0–6.0) 3.0 (1.0–6.0) 3.0 (1.0–6.0) 0.917

Discomfort score 0.5 (0–1.0) 0.5 (0–1.5) 0.5 (0–1.0) 0.942
Anxiety score 0.5 (0–2.0) 0.5 (0–1.5) 0.5 (0–2.0) 0.737
Fitness score 3.75 (2–6) 3.5 (2–5) 3.5 (2–5.5) 0.644
Readiness for further bronchoscopic

procedure
277 (95.4) 271 (97.1) 543 (96.3) 0.288

Data are presented as as median (interquartile range) or n (%), unless otherwise stated. Data are presented
for 562 patients. VAS: visual analogue scale.

TABLE 6 Reasons for episodic change in infusion rate

Time Hypotension Hypoxaemia Discomfort Cough Other

Beginning of sedation 0 3 26 9 4
At 3 min 0 12 71 45 6
At 6 min 0 15 68 56 5
At 9 min 0 7 39 47 1
At .9 min 1 9 21 39 2

Data are presented as n.

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DOI: 10.1183/09031936.00200412 599

patients with mild systemic disease. Finally, the definition of ‘‘hypoxaemia’’ varied in the above mentioned

studies (,90% versus f90%). Moreover, the term hypoxaemia was used independent of its duration in the
current paper, while other authors included duration of .1 or 2 min in the definition of hypoxaemia and

desaturation, respectively. Although we have previously demonstrated that the incidence of adverse events

observed with propofol is comparable with other sedation regimes, e.g. benzodiazepine and opiate or

benzodiazepine alone [10, 11], both hypoxaemia and hypotension are to be commonly expected in a

considerable amount of severely ill patients undergoing bronchoscopy under propofol.

The incidence of bleeding in this study is in accordance with previous reports of ours but higher than

reported by SCHLATTER et al. [10] and BOSSLET et al. [14], probably reflecting the widespread use of

transbronchial and endobronchial forceps biopsies in our institution. Indeed, from the severe complications

noted in eight patients (1.1%, four in each group), seven were major bleedings. It is noteworthy that the vast

majority of complications were ‘‘intervention’’ related and not sedation related. Overall, the number of

complications observed within this trial is consistent with previous results reported in the literature [10, 11, 17].

The difference of duration of 3 min, although statistically significant, is small. However, when considering

that, in several centres, many procedures are performed each day, we leave it up to the reader to judge

whether this difference is or is not significant for their setting.

The amount of propofol required for sedation was significantly higher in the infusion group (226 ¡147 mg

versus 308 ¡204.8 mg, p,0.0001). In a linear multivariate regression model, this difference remained

significant, independently of duration and the interventions performed during flexible bronchoscopy. One

could argue that the applied regimen itself lead to a higher dose of propofol in the infusion group. However,

sedation in the infusion group was much more often considered insufficient than too deep (table 6), leading

to an increase or failure to decrease the infusion rate or the application of additional propofol boluses. The

most plausible explanation for this observation is a failure to reach a blood concentration of propofol of

.1 mg?mL
-1

, usually leading to sedation, if propofol is given as an infusion as compared with bolus

application. Moreover, the initial bolus of 10 mg of propofol given to those patients was low. Application of

higher boluses usually leads to a rapid rise in plasma concentration above this critical level. Therefore, it

cannot be excluded that this initial low dose bolus has led to higher doses than expected being used and to

more adverse events in the continuous infusion rate arm. It is also a reason why it may have taken longer for

these patients to achieve adequate sedation. A change in protocol could therefore have led to a different

result and conclusion regarding the duration of the sedation.

Hydrocodone 4 mg was routinely given to all patients. We have previously shown in two randomised

studies that hydrocodone, both in combination with midazolam and propofol, markedly reduced cough

during flexible bronchoscopy without causing significant desaturation [8, 10]. Hydrocodone was used as it

is much cheaper than the newer opiates.

The present study has a few limitations. There was an imbalance in the distribution of indication for

bronchoscopy with more diagnostic bronchoscopies being performed for infection in the bolus group as

compared with the infusion group, while more bronchoscopies were performed for suspected interstitial

lung disease in the infusion group. Accordingly, the number of transbronchial biopsies was significantly

higher in the infusion group (48 versus 72; p50.011). However, assuming a higher rate of complications in

patients undergoing transbronchial biopsy as compared with patients undergoing BAL only, the incidence

of adverse events and complications in the infusion group was overestimated rather than underestimated.

Another factor to consider is that this was a monocentric study performed in an institution in which the

nursing staff has considerable expertise with propofol sedation for endoscopic procedures. Hence, caution

might be needed when introducing this sedative regimen in other institutions with less experienced nursing

staff. No sedation score was used to assess the level of sedation achieved, thereby following the

recommendations of the ASA [26], which suggest that no specific score other than the response of the

patient to verbal commands or tactile stimulation is required for monitoring sedation. As suggested by the

same society, we have provided the recommended monitoring of patients with pulseoxymetry, blood

pressure measurements at defined intervals as wells as electrocardiographic monitoring. Of note,

electroencephalogram-guided propofol administration for flexible bronchoscopy (where the goal was to

achieve and maintain a bispectral index between 70 and 85) was shown to be safe in a study by CLARK et al.

[18]. Moreover, this study was nonblinded and this may be a source of bias. Although blinding of the study

medication might have enhanced the robustness of our findings, it represented an insurmountable obstacle

for the study realisation. There are no data about the distribution of the procedures among pulmonary

fellows and attending physicians. Similarly, data about the distribution of the nurses administering the

sedation in each trial arm is not available. Finally, neither the nurse nor the physician was blinded to the

type of sedation received so that their VAS ratings of cough are limited. However, due to randomisation and

the fact that, if any, this bias can be considered a non-differential misclassification bias, i.e. meaning that the

BRONCHOSCOPY | P. GRENDELMEIER ET AL.

DOI: 10.1183/09031936.00200412600

error rate or probability of being misclassified is probably the same for all study subjects, it would have

produced a conservative bias. In the case of binary or dichotomous variables, this would probably result in

an underestimate of the hypothesised relationship between exposure and outcome. Finally, the severity of

chronic obstructive pulmonary disease was not systematically recorded within the study records and

capnography was not performed in the present study. Therefore, no statement can be made about the risk of

type II respiratory failure.

The strengths of the present study are the large number of patients with mixed, relevant comorbidities; the

diversity of diagnostic and interventional bronchoscopic procedures, the completeness of the evaluation

with no lost to follow-up and the original randomised non-inferiority design. Finally, well defined, ‘‘hard’’

end-points, such as need of ICU, intubation or death were chosen, which appears even more important in

the absence of blinding of the study.

In conclusion, our data suggest that propofol given as a continuous infusion for conscious sedation in

flexible bronchoscopy is as safe as bolus administration. However, with the current reported regimen, it is

associated with higher propofol requirements and a longer duration of the bronchoscopy.

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Table 3
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Table 6

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ORIGINAL ARTICLE

Target-controlled versus fractionated propofol sedation in flexible
bronchoscopy: A randomized noninferiority trial

DANIEL FRANZEN, DANIEL J. BRATTON, CHRISTIAN F. CLARENBACH, LUTZ FREITAG AND MALCOLM KOHLER

1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland

ABSTRACT

Background and objective: Fractionated propofol
administration (FPA) in flexible bronchoscopy (FB)
may lead to oversedation and an increased risk of
adverse events, because a stable plasma concentration
of propofol is not maintainable. The purpose of this
randomized noninferiority trial was to evaluate whether
target-controlled infusion (TCI) of propofol is non-
inferior to FPA in terms of safety in FB.
Methods: Coprimary outcomes were the mean lowest
arterial oxygen saturation (SpO2) during FB and the
number of propofol dose adjustments in relation to
procedure duration. Secondary outcomes were the
number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline, number of
occasions with systolic blood pressure < 90 mm Hg, cough frequency, cumulative propofol dose, recovery time, maximum transcutaneous CO2, mean SpO2 and O2 delivery during FB. Results: Seventy-seven patients were included. TCI was noninferior to FPA in terms of mean (standard deviation) lowest SpO2 during the procedure (88.3% (5.4%) vs 86.9% (7.3%)) and required fewer dose adjustments (0.04/min vs 0.28/min, P< 0.001) but a higher cumulative propofol dose (264 vs 194mg, P= 0.003). All other secondary outcomes were comparable between the groups. Conclusion: We suggest that TCI of propofol is a favourable sedation technique for FB with equal safety issues and fewer dose adjustments compared with FPA.

Clinical trial registration: NCT02246023 at ClinicalTrials.gov

Key words: flexible bronchoscopy, propofol, sedation.

Abbreviations: ASA, American Society of Anesthesiology; BAL,
bronchoalveolar lavage; BMI, body mass index; CI, confidence
interval; CV, collateral ventilation; EBUS, endobronchial ultrasound;
FB, flexible bronchoscopy; FPA, fractionated propofol administration;
GFR, glomerular filtration rate; NAAP, nonanaesthesiologist adminis-
tration of propofol; SBP, systolic blood pressure; SD, standard
deviation; SpO2, oxygen saturation; TBNA, transbronchial needle
aspiration; TCI, target-controlled infusion; tcpCO2, transcutaneous
carbon dioxide pressure value.

INTRODUCTION

Nonanaesthesiologist administration of propofol (NAAP)
has been shown to be a feasible and safe sedation
method for flexible bronchoscopy (FB).1,2 In daily
clinical practice, propofol sedation is given manually
in repeated doses (fractionated) by a specially trained
nurse in attendance of the bronchoscopist. However,
fractionated propofol administration (FPA) may lead
to oversedation and an increased risk of side effects
(i.e. oxygen desaturation or arterial hypotension), as
a stable plasma concentration of propofol is not
maintainable with this technique. For the purpose of
sedation during FB, continuous infusion of propofol
has recently been shown to be as safe as FPA,3 but
the continuous technique may be preferable to
minimize haemodynamic and respiratory side
effects.4 Propofol infusion devices can be manually
controlled or applied as target-controlled infusion
(TCI). In the latter, the physician sets a target blood
or effect site (i.e. brain) concentration, and the
computerized infusion device makes the necessary
changes to the infusion rate according to age, gender
and biometric parameters of the patient. The system
has been developed as a standardized infusion system
for the administration of propofol by TCI for the
purpose of general anaesthesia in surgery.5 Similarly,
TCI of propofol could be used for FB, and a target
effect site concentration of 2.5 μg/mL of brain tissue
has been proposed for this purpose.6 Because there
is no randomized study comparing propofol TCI
with FPA concerning patient safety and sedation
quality during bronchoscopy, we aimed to prove
noninferiority, assessed by oxygenation, ventilation
and blood pressure, and sedation quality assessed
by the number of dose adjustments and cough
frequency.

Correspondence: Daniel Franzen, Department of Pulmonology,
University Hospital Zurich, Raemistrasse 100, 8091 Zurich,
Switzerland. E-mail: daniel.franzen@usz.ch

Received 26 January 2016; invited to revise 17 March 2016;
revised 24 March 2016; accepted 22 April 2016 (Associate Editor:
Lonny Yarmus).

SUMMARY AT A GLANCE

In this randomized noninferiority trial, we evaluated
whether target-controlled infusion (TCI) of propofol
is noninferior to fractionated administration in
terms of safety in flexible bronchoscopy. TCI of
propofol is a favourable and safe sedation technique
for flexible bronchoscopy.

doi: 10.1111/resp.12830

METHODS

Study subjects
In this randomized, single-blinded, noninferiority trial,
we aimed to compare propofol TCI with FPA in FB,
where FPA served as control group. Four hundred
twenty-six patients underwent FB in NAAP sedation
between January 20 and 15 September 2015. Of these,
186 were eligible for the study (Fig. 1). Exclusion criteria
are listed in Table S1 in Supplementary Information.
Patients were randomized in a 1:1 ratio using sequen-
tially numbered sealed opaque envelopes to sedation
performed with either TCI of propofol (intervention
arm) or FPA applying NAAP (control arm). Blinding
of the patient to the assigned procedure was achieved
by hiding the device from the patients’ view. The
investigators were not blinded to the allocated seda-
tion technique.
The study was approved by the local ethics committee

(2014-0121/SNCTP000000706) and is registered at
ClinicalTrials.gov (identifier number: NCT02246023).

Written informed consent was obtained from all patients
before inclusion.

Study design
The purpose of study was planned and powered for
noninferiority to evaluate whether TCI of propofol is
noninferior to FPA in terms of safety in patients
undergoing FB. Coprimary outcomes were the mean
lowest arterial oxygen saturation (SpO2) during FB as
the noninferiority outcome measure and the number
of propofol dose adjustments or repeat doses, in
relation to procedure duration as the superiority
outcome measure. Secondary outcomes were the
number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline during FB, number
of occasions with systolic blood pressure< 90mmHg during FB, cough frequency, cumulative propofol dose, procedure and recovery time, maximum transcutaneous carbon dioxide pressure value (tcpCO2), mean SpO2 during the procedure, and otherwise complications that

Figure 1 Study flow chart.

2 D Franzen et al.

144

6 D Franzen et al.

make additional treatment necessary. Recovery time
was defined as time between termination of bron-
choscopy and first verbal contact or eye opening,
whereas procedure time was defined as time between
insertions until removal of the bronchoscope. Cough
frequency and unscheduled awakening during the
examination were measured manually by a study-
independent clinical nurse, where a cough-free
interval of at least 3s between two coughs was
considered to differentiate between two coughing
episodes. Transcutaneous SpO2 and tcpCO2 was
measured continuously using a TOSCA 500 instrument
(Radiometer, Basel, Switzerland), which has been
validated repeatedly for SpO2/tcpCO2 monitoring in
various circumstances.7–11

Sample size
Assuming a mean lowest arterial SpO2 of 94.8% with a
standard deviation of 2.7% in the arm treated with
FPA,12 a total of 78 patients (39 in each treatment
arm) were required to demonstrate that propofol TCI
is associated with a reduction in mean lowest
saturation of no more than 2% (noninferiority margin)
compared with FPA, with 90% power and a one-sided
significance level of 0.025.

Procedure-related details and sedation
Bronchoscopy procedures were performed transna-
sally or transorally, with the patients in the recumbent
position, by supervised fellows (who had in the past
performed at least 50 bronchoscopies) or consultants
assisted by experienced nurses who also adjusted the
infusion pumps and recorded all events. Electro-
cardiographic and transcutaneous pulse oxymetric
monitoring were recorded continuously during the
procedure. In addition, automated noninvasive
blood pressure measurements were performed every
3min. Supplemental oxygen was given at a rate of
4L/min via a nasal cannula to all patients. In the
case of desaturation to <90%, oxygen delivery was increased to 6–10 L/min. Patients were routinely given 5mg of hydrocodone and 0.2mg of glyco- pyrrolate intravenously immediately prior to FB. Nasal anaesthesia was achieved by 2% lidocaine gel. Bronchoscopists were advised to instil 10mL of aliquots of 1% lidocaine over the vocal cords, on the trachea, and on both right and left main bronchi. Instilled lidocaine doses were recorded for each patient. All doses of supplemental local anaesthesia required, as judged by the bronchoscopist, were recorded for each patient. In both treatment arms, additional medication (i.e. analgesics) or doses other than those mentioned earlier were not allowed during FB. For TCI propofol delivery, the Perfusor Space

infusion pump was used (B. Braun Melsungen AG,
Melsungen, Germany). Bronchoscopy was started after
reaching the initial targeted effect site concentration
(Ce) of 2.5μg/mL using the Schnider pharmacokinetic
model described elsewhere, which is based on certain
biometric values as total weight, lean body mass and
height.6,13–16 Thereafter, Ce could be adjusted depending

on the clinical effect by increments of 0.2 μg/mL, in
order to maintain the required level of sedation. The
adequate level of sedation for starting the bron-
choscopy was considered after loss of reaction to
verbal and tactile stimuli, corresponding to a target
sedation level between 3 and 4 (moderate to deep
sedation) according to the American Society of
Anesthesiology (ASA).17 Signs of pain or discomfort,
agitation, extensive cough and inadequate motor or
verbal response to manipulation were considered
indicators of insufficient sedation, leading to Ce
increment of 0.2 μg/mL.
For patients assigned to FPA, the loading doses of

propofol were titrated in order to achieve the adequate
sedation level (onset of ptosis). Patients received an
initial bolus of 30–40mg of propofol, followed by a
carefully titrated dose of 10–20mg of propofol based
on the clinical response. Between each bolus, a pause
lasting more than 20s had to be observed. Additional
intravenous boluses of propofol were given if the
patient showed signs of discomfort during the
examination in order to maintain the required level of
sedation. The adequate level of sedation for starting
the bronchoscopy was identical to the TCI group
(ASA 3–4). In case of the aforementioned indicators of
insufficient sedation, an additional dose of propofol
(10–20mg) was administered. If adverse events
happened and patients desaturated, chin-lift and jaw-
thrust manoeuvers or nasopharyngeal airway insertion
were performed by a bronchoscopy nurse. In case of
an ongoing hypoxaemia despite the aforementioned
measures, anaesthesiology support was called with
placement of a laryngeal mask or endotracheal tube.
Both procedures were defined as serious adverse
events.

Statistical analysis
The coprimary noninferiority outcome was assessed
by calculating the absolute difference in mean lowest
SpO2 between treatment arms using a multiple linear
regression model adjusting for treatment allocation,
smoking status (current/former vs never), body mass
index (BMI), collar size, age and maximum O2 delivery.
TCI was considered to be noninferior to FPA in terms
of safety if the lower bound of the 95% confidence
interval (CI) for the treatment difference was greater
than �2%. Continuous outcomes were analysed using
multiple linear regression, and binary outcomes were
analysed using binomial regression with a log link
function to obtain the risk ratio between treatment
arms. Count data (e.g. number of dose adjustments)
were compared between treatment arms using inci-
dence rate ratios estimated using negative binomial
regression, offsetting the model for the length of the
FB procedure. Each outcome was analysed under the
intention-to-treat principle including all randomized
patients with complete data, except for the non-
inferiority outcome, which was also analysed in a per-
protocol sample excluding patients who received a
maximum of more than 10L/min of oxygen or an
intervention via a nasopharyngeal airway insertion
during the procedure. All superiority outcomes were
performed at the two-sided 5% significance level.

TCI of propofol in bronchoscopy 3

TCI of propofol in bronchoscopy 1447

RESULTS

In total, 77 patients could be included in the study
(Fig. 1). As a result of randomization, baseline
characteristics of patients including intervention type
were similar between treatment groups (Table 1). The
majority of patients were in ASA class I or II and had
a Mallampati classification (distance from the tongue
base to the roof of the mouth) of 1 or 2. The main
indication for bronchoscopy was suspected malig-
nancy. Therefore, the leading bronchoscopic pro-
cedures were endobronchial ultrasound (EBUS) with
the convex and/or radial probe. Due to the frequent
use of the convex EBUS probe in this study,
bronchoscopes were mainly introduced via the oral
rather than the nasal route.

Primary outcomes
In the intention-to-treat analysis, the mean (standard
deviation) lowest SpO2 was 86.9% (7.3%) in the FPA
group compared with 88.3% (5.4%) in the TCI group
(Fig. 2). After adjusting for possible risk factors of oxygen
desaturations including age, BMI, neck circumference
and cigarette smoking, and the given maximum O2
delivery, the absolute mean difference in lowest
SpO2 between arms was 1.2% (95% CI: �1.7%, 4.2%;
Table 2). Sixteen patients were excluded from the
per-protocol analysis, which estimated a similar
difference of 1.6% (95% CI: �1.6%, 4.9%; Fig. 2 and
Table 2). Notably, there was no life-threatening oxy-
gen desaturation.

The mean procedure duration was similar between
treatment arms with 26.1min in the FPA group
compared with 26.5min in the TCI group. The mean
number of dose adjustments or repeat doses in the
FPA arm was 0.28/min compared with 0.04/min in
the TCI arm, leading to an incidence rate ratio of 0.17
(95% CI: 0.12, 0.23; P< 0.001) after adjusting for smoking, BMI, neck circumference, age and maximum O2 delivery (Table 3).

Secondary outcomes
All but one of the secondary outcome measures were
comparable between the groups (Tables 4 and 5).
Cumulative propofol dose was significantly higher in
the TCI compared with the FPA group (264 vs 194mg;
P=0.003). However, the mean recovery time after FB
was not influenced by the mode of sedation (Figure S1
in Supplementary Information and Table 5). There
were no serious adverse events that made additional
treatment necessary or deaths in either treatment arms.

Table 1 Baseline characteristics

Characteristics
FPA

(n = 38)
TCI

(n = 39)

Age (years) 64.0 (11.6) 65.6 (11.3)
Gender, male 24 (63) 23 (59)
BMI (kg/m2) 24.5 (3.7) 25.0 (4.5)
Smoker 25 (66) 32 (82)
Collar size (cm) 39.0 (4.3) 39.5 (4.1)
Mallampati classification
1 13 (34) 11 (28)
2 16 (42) 15 (38)
3 8 (21) 13 (33)
4 1 (3) 0 (0)

GFR (mL/min) 83.4 (15.2) 90.0 (16.7)
ASA classification
I 8 (21) 3 (8)
II 19 (50) 24 (62)
III 10 (26) 12 (31)
IV 1 (3) 0 (0)

Comorbidities
Chronic lung disease 11 (29) 9 (23)
Chronic heart disease 10 (26) 7 (18)
Arterial hypertension 13 (34) 12 (31)
History of malignancy 8 (21) 8 (21)

Indication for FB
Suspected malignancy 27 (71) 29 (74)
Cancer staging 5 (13) 1 (3)
Interstitial lung disease 2 (5) 2 (5)
Infection

1 (3) 1 (3)

Suspected sarcoidosis 4 (10) 3 (8)

Bronchoscopic procedures
EBUS-TBNA 25 (66) 24 (62)
Radial EBUS mini probe 8 (21) 17 (44)
BAL 6 (16) 10 (26)
Measurement of CV Chartis
(Pulmonx International Sarl,
Neuchatel, Switzerland)

1 (3) 1 (3)

FB by oral route 31 (82) 26 (67)

Values are presented as mean (standard deviation) or n (%) as
appropriate.

ASA, American Society of Anaesthesiology; BAL, bronchoalveolar
lavage; BMI, body mass index; CV, collateral ventilation; EBUS,
endobronchial ultrasound; FB, flexible bronchoscopy; FPA, fractionated
propofol administration; GFR, glomerular filtration rate; TBNA, trans-
bronchial needle aspiration; TCI, target-controlled infusion.

Figure 2 Results of the intention-to-treat and per-protocol analyses
on lowest oxygen saturation (SpO2). Forest plot of the treatment
differences on mean lowest SpO2 showing noninferiority of propofol
target-controlled infusion compared with fractionated propofol
administration for flexible bronchoscopy in nonanaesthesiologist
administration of propofol sedation in the intention-to-treat (P = 0.42)
and per-protocol (P = 0.31) analyses. Filled circles indicate the position
of the point estimates for between-group differences, and vertical lines
indicate the 95% confidence interval.

4 D Franzen et al.

1448 D Franzen et al.

Basic measures to maintain an appropriate oxygena-
tion of the patient, as increase of oxygen delivery (53%
vs 56%, P =0.8), chin-lift and jaw-thrust manoeuver
(49% vs 53%, P=0.7) or insertion of a nasopharyngeal

airway (18% in both groups, P=0.9), did not differ
between the groups. No serious adverse events (i.e.
need for advanced airway support) occurred in any of
the study groups.

Table 2 Mean lowest oxygen saturation—noninferiority outcome with noninferiority margin Δ = �2%

Treatment n Mean (SD) (%)
Unadjusted treatment

effect (95% CI)

Adjusted† treatment

effect (95% CI)

Intention to treat
FPA 38 86.9 (7.3) 1.4% (�1.5, 4.3) 1.2% (�1.7, 4.2)
TCI 39 88.3 (5.4)

Per protocol‡

FPA 30 87.4 (7.6) 1.6% (�1.7, 4.9) 1.6% (�1.6, 4.9)
TCI 31 89.0 (4.9)

CI, confidence interval; FPA, fractionated propofol administration (control group); TCI, target-controlled infusion of propofol (intervention
arm); SD, standard deviation.

†Adjusted for smoking, body mass index, neck circumference, age and O2 delivery.
‡Sixteen patients excluded from the per-protocol analysis (two received more than a maximum of 10 L/min of oxygen, and 14 received an

intervention via a Wendel tube).

Table 3 Number of dose adjustments—superiority outcome

Treatment n
Mean number of dose

adjustments (SD)
Mean length of

procedure (SD) (min)
Adjusted incidence rate
ratio† (95% CI), P-value

FPA 38 7.4 (4.6) 26.1 (13.2) 0.17 (0.12, 0.23), P < 0.001 TCI 39 1.2 (1.3) 26.5 (11.6)

CI, confidence interval; FPA, fractionated propofol administration; SD, standard deviation; TCI, target-controlled infusion.
†Adjusted for smoking, body mass index, neck circumference, age and O2 delivery.

Table 4 Count variables (number of occasions with oxygen saturation < 90% and/or oxygen desaturations of >4% from
baseline during flexible bronchoscopy, number of occasions with systolic blood pressure < 90 during flexible bronchoscopy, cough frequency)

Outcome

Mean number of events/min (SD)
Incidence rate
ratio (95% CI) P-valueFPA (n = 38) TCI (n = 39)

Oxygen desaturations 0.17 (0.14) 0.13 (0.10) 0.84 (0.59, 1.20) 0.35
SBP < 90 0.01 (0.03) 0.02 (0.05) 1.86 (0.62, 5.61) 0.27 Cough 0.84 (0.66) 0.74 (0.70) 0.88 (0.62, 1.26) 0.50

CI, confidence interval; FPA, fractionated propofol administration; SBP, systolic blood pressure; SD, standard deviation; TCI, target-controlled
infusion.

Table 5 Continuous outcomes (cumulative propofol dose, recovery time, maximum transcutaneous carbon dioxide pressure
value, mean oxygen saturation, maximum O2 delivery)

Outcome

Mean (SD)
Absolute mean

difference (95% CI) P-valueFPA (n = 38) TCI (n = 39)

Cumulative propofol dose (mg) 193.7 (95.0) 264.1 (105.8) 70.4 (24.7, 116.1) 0.003
Recovery time (min) 5.0 (2.5) 4.6 (2.0) �0.3 (�1.4, 0.7) 0.52
Max. tcpCO2 (kPa) 6.1 (1.0) 6.3 (1.4) 0.2 (�0.4, 0.7) 0.51
Mean SpO2 (%) 96.1 (2.1) 96.6 (1.1) 0.6 (�0.2, 1.3) 0.16
Maximum O2 delivery (L/min) 7.3 (2.2) 6.9 (2.4) �0.4 (�1.4, 0.7) 0.46

CI, confidence interval; FPA, fractionated propofol administration; SpO2, oxygen saturation; SD, standard deviation; TCI, target-controlled
infusion; tcpCO2, transcutaneous carbon dioxide pressure value.

TCI of propofol in bronchoscopy 5

TCI of propofol in bronchoscopy 1449

DISCUSSION

In this randomized noninferiority trial, we compared
propofol TCI with FPA for FB in NAAP sedation, with
the latter serving as control group. TCI was noninferior
to FPA in terms of mean lowest SpO2 during the
procedure and was shown to require fewer dose
adjustments but a higher cumulative propofol dose.
Furthermore, the number of occasions with SpO2 < 90%, oxygen desaturations of >4% from baseline, hypotensive
episodes, cough frequency, procedure and recovery
time, maximum tcpCO2 and mean SpO2 during the
procedure were not significantly different between the
treatment arms.
In a study published by Grendelmeier et al.,3 a

conventional continuous infusion device was used,
where the infusion rate of propofol was changed
manually according to a fixed protocol: the infusion
rate was set at 0.3mg/kg/min after an initial bolus of
10 mg of propofol. Thereafter, the infusion rate was
reduced to 0.2mg/kg/min after 3min and was further
reduced to 0.1 and 0.05mg/kg/min after another 3
and 6min, respectively.3 In their study, continuous
propofol infusion was shown to be as safe as FPA,
although conclusions for their noninferiority endpoint
were based on a P-value rather than a CI, and thus, the
conclusions by the authors are questionable. Con-
tinuous infusion was associated with a higher cumu-
lative propofol dose and a longer procedure duration.3

Compared with the conventional infusion pump used
in their study, TCI devices change the infusion rate
automatically according to a programmed algorithm,
which is based on pharmacokinetic–pharmacodynamic
modelling studies.13,14,16 The main advantage of
propofol administration using TCI is the achievement
of a stable plasma (and effect site) concentration by
satisfying the physiological circumstances of biodis-
tribution and elimination of the drug. Thus, the risk
of oversedation and, consequently, potentially life-
threatening side effects may be reduced. Furthermore,
safety concerns of NAAP and the burden for the staff
can be minimized. According to our results, propofol
TCI is at least noninferior compared with FPA in terms
of patient safety. Although there was a significantly higher
cumulative propofol dose in the TCI arm, procedure and
recovery times were similar in both treatment arms.
Thus, cumulative propofol dose does not seem to be
a relevant argument against the use of TCI.
For the purpose of general anaesthesia, a recently

published systematic review does not provide suffi-
cient evidence to make firm recommendations about
the use of TCI versus manually controlled infusion
of propofol.18 However, fewer interventions were
required by the anaesthesiologist, and the time course
of propofol effects was shown to improve during the
use of TCI compared with the manually controlled
infusion, whereas no clinically significant differences
were demonstrated in terms of quality of anaesthesia
or adverse events.18 In nonintubated but noninvasively
ventilated patients with acute respiratory failure who
were treated in the intensive care unit, TCI with
propofol for FB has been shown to be feasible and safe.19

Furthermore, subjects sedated with propofol TCI had
fewer movements at insertion of the laryngoscope,

improved haemodynamic stability, fewer episodes of
apnoea and less respiratory acidosis after endoscopy,
and the recovery was also shorter compared with
manual administration.20

Our study has some limitations. First, we have
chosen an initial target effect site concentration of
2.5μL/mL of propofol as proposed by Lin et al.6 We
do not know the treatment effect with other initial
effect site concentrations. Ce was not reduced in
phases during FB, in which excitatory stimuli were less
intense (e.g. bronchoalveolar lavage compared with
EBUS–transbronchial needle aspiration). This could
be addressed in a future trial and may be associated
with a reduced cumulative propofol dose. Moreover,
we cannot determine if fixed dose premedication with
midazolam and hydrocodone used in both treatment
arms of this study has a relevant influence on the
results. However, previous studies showed that patient
discomfort and cough are reduced in patients given a
premedication with midazolam and hydrocodone, and
thus, this has become standard in many centres.21,22

Second, bronchoscopist and staff were not blinded for
the sedation technique. Therefore, cough frequency
could be confounded. Third, sedation quality was not
assessed, neither by the bronchoscopist nor by the
patient. We have rather chosen to focus on objectively
measurable outcomes. Moreover, the value of self-
referred sedation quality is highly questionable,
because patients have anterograde amnesia after
premedication with midazolam. Fourth, most of the
patients were in ASA class I or II or had a Mallampati
classification 1 or 2, which should be taken into
consideration when interpreting the results of the
study, especially when TCI is used.

In conclusion, we suggest that TCI of propofol is a
favourable sedation technique for FB. Safety issues
(oxygenation, ventilation and blood pressure), cough
frequency and procedure times are comparable with
FPA. Using TCI, fewer interventions are needed to
induce and maintain sedation. However, the cumu-
lative dose of propofol is higher with the use of TCI,
which is maybe negligible, particularly when Ce is
adapted to different stages of FB.

REFERENCES

1 Bosslet GT, Devito ML, Lahm T, Sheski FD, Mathur PN. Nurse-
administered propofol sedation: feasibility and safety in
bronchoscopy. Respiration 2010; 79: 315–21.

2 Carmi U, Kramer MR, Zemtzov D, Rosengarten D, Fruchter O.
Propofol safety in bronchoscopy: prospective randomized trial
using transcutaneous carbon dioxide tension monitoring.
Respiration 2011; 82: 515–21.

3 Grendelmeier P, Tamm M, Pflimlin E, Stolz D. Propofol sedation
for flexible bronchoscopy: a randomised, noninferiority trial. Eur.
Respir. J. 2014; 43: 591–601.

4 Jose RJ, Shaefi S, Navani N. Sedation for flexible bronchoscopy:
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5 Glen JB. The development of ‘diprifusor’: a TCI system for
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6 Lin TY, Lo YL, Hsieh CH, Ni YL, Wang TY, Lin HC, Wang CH, Yu CT,
Kuo HP. The potential regimen of target-controlled infusion of
propofol in flexible bronchoscopy sedation: a randomized
controlled trial. PLoS One 2013; 8: e62744.

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a single earlobe monitor (TOSCA). Br. J. Anaesth. 2007; 99: 567–71.

9 Stege G, van den Elshout FJ, Heijdra YF, van de Ven MJ,
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Respiration 2009; 78: 147–53.

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Respiration 2010; 80: 139–45.

11 Hazenberg A, Zijlstra JG, Kerstjens HA, Wijkstra PJ. Validation of a
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bronchoscopy: a randomised non-inferiority trial. Eur. Respir. J.
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13 Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C,
Goodale DB, Youngs EJ. The influence of age on propofol
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14 Absalom AR, Mani V, De Smet T, Struys MM. Pharmacokinetic
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Shafer SL, Youngs EJ. The influence of method of administration

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Saghi T, Pillot J, Filloux B, Coz S, Boyer A et al. Fiberoptic
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Supplementary Information
Additional Supplementary Information can be accessed via the html
version of this article at the publisher’s website:

Figure S1 Kaplan-Meier plot of recovery times.

Table S1 Exclusion criteria.

TCI of propofol in bronchoscopy 7

TCI of propofol in bronchoscopy 1451

Alpha-1-Antitrypsin Deficiency: Emphysema Without Smoking.

Christin Nott

Table of Contents

Introduction……………………………………………………3

History……………………………………………………………………………3

Alpha-1-antitrypsin therapies………………………………….4

Risk factors of acquiring emphysema………………………….6

Knowledge in the medical community…………………………7

Medical treatments for emphysema……………………………9

Summary………………………………………………………………………..14

References cited…………………………………………………………..15

INTRODUCTION

Alpha-1-Antitrypsin Deficiency (AATD) is a devastating genetic disease that literally steals the breath away from people, silently destroying lung tissue, then revealing itself in the prime of one’s life, leaving that person unable to do anything about what has already been lost. Although smoking is the usual cause of emphysema, AATD can also cause emphysema, and not only can it cause emphysema without a prior smoking history, it does so in people in their 30’s and 40’s rather than in later life. One would think that something this significant would require knowledge in the medical community so that steps could be taken to prevent the destruction, but there has not been a great deal of research on this issue until recently. Even now, many respiratory therapists are unaware of what AATD is, what causes it, and what it means to care for someone with this affliction.

HISTORY

Knowing what causes a disease is an important first step in finding a way to help the patients who have the disease. AATD is an autosomal co-dominant genetic disease that predisposes a person to develop COPD. The protease inhibitor, Alpha-1-Antitrypsin (AAT), helps inhibit the neutrophil elastase from damaging the lung.1 In AATD, the AAT is very low and therefore unable to keep elastase from doing damage. Every time a person has an allergic reaction, a cold, or any kind of foreign object within the lungs, elastase is recruited to the lungs to inhibit the damage from inflammatory or infectious assaults. Unfortunately, without AAT, elastase does not know when to quit. Instead of just taking care of the infiltrates and stopping, elastase will destroy healthy lung tissue as well.1

Although there is not a cure for AATD, there are ways to halt the destruction of the lungs. One such method is genetic testing at the newborn level so the parents and affected child will know about the disease. They can avoid smoke and other irritants that could cause the lungs to become emphysematous. Another approach, if there is already damage to lungs, is augmentation therapy, which will replace the AAT in the deficient patient.2 Augmentation therapy has been very helpful to those afflicted with AATD, although it will not repair damage already acquired, it will prevent further damage.2 However, that should not give anyone the notion that with augmentation therapy a person with AATD will be able to smoke and not have to worry about emphysema worsening. Anyone with emphysema, whether AATD or not, should quit smoking or they will risk damaging the lungs further.

ALPHA-1-ANTITRYPSIN THERAPIES

Because it is a disease with a respiratory component, respiratory therapists are going to be involved in therapies concerning this disease. For now, IV is the route chosen for augmentation therapy; therefore, the respiratory therapists are not involved in this form of the therapy. However, although the augmentation is an important part of therapy, if a patient already has emphysema due to AATD, they will need other therapies such as bronchodilators and oxygen therapy.3 Also, a new form of augmentation is emerging, AAT inhalation therapy.3 In that case, therapists will have an opportunity to be even more involved with the AATD treatment plan.

Since augmentation is the front line defense in keeping the lungs from sustaining further damage, safety for the patient is a concern. There have been many studies on augmentation in AATD patients to include survival rate, side effects, FEV1 decline, lung disease progression, and cost effectiveness of the treatment. Once such study by National Heart, Lung, and Blood Institute (NLBI) showed the rate of decline was significantly slower during the treatment in comparison to pre-treatment.4 Furthermore, the study showed that augmentation was “particularly effective in patients with baseline FEV1 >65% of predicted.”4 (p 197) In another study conducted by the Canadian AIR Registry, “the results of this study, reported as an abstract, suggested a slower decline in FEV1 in patients receiving augmentation therapy compared with the subjects who did not.”4(p 197) It is a general belief in the medical community that augmentation therapy is safe and is tolerated quite well by patients. There are a few reported side effects, mainly nausea, vomiting, and fatigue. Localized swelling at the IV site and bruising can be troublesome and unsightly, but not life threatening. However, since the augmentation therapy is made from human plasma, there is a small chance that one could acquire HIV or hepatitis. With advances in screening, the risk is slight, but it is still a possibility.4

Another option for an advanced case of emphysema caused by AATD is LVRS (lung volume reduction surgery). Although a person with AATD acquired emphysema genetically rather than by smoking, the premise and end result is the same, lung damage. Generally, smoking generated emphysema is in all lung lobes and scattered throughout, thus called diffuse centrilobular emphysema. AATD presents differently; it is predominately in the lower part of the lobes, or panlobular emphysema.5 Certain criteria must be met before LVRS will be considered, such as, severe obstruction (FEV1 < 40%), hyperinflation, severe dyspnea, and CT scan evidence of advanced emphysema with some degree of heterogeneity in the distribution of the emphysema.5 There is also exclusion for those > 75 years of age, or with the presence of giant bulla, severe left ventricular dysfunction, or BMI (body mass index) of < 18 kg.5 There was significant improvement in the FEV1 of the patients after surgery, a significant gain in PaO2, and a significant decrease in dyspnea.5 Although the surgery seems to benefit patients with smoking related emphysema more than AATD patients due to the location of the damage, there is still improvement and therefore surgery is beneficial to use on an end-stage AATD patients.5

RISK FACTORS OF AQUIRING EMPHYSEMA

There are several risk factors for someone with AATD to end up with emphysema including occupational exposures, dust, allergens, and lower respiratory infections.6 Since smoking causes emphysema in a smoker with normal AAT levels, imagine the increase of damage to the lungs for someone with a severe deficiency of AAT if they are exposed to smoke. This is why those who have AATD will show up with emphysema in their 30’s and 40’s rather than in their late 50’s and 60’s as is the norm with emphysema. Smoking need not be direct to cause damage; it may be indirect by passive or second hand smoke.

National Jewish Hospital in Denver, Colorado studied AATD patients exposed to second hand smoke as children and those who had smoked themselves. In those who had childhood exposure, chronic cough, wheezing, as well as continuous respiratory infections were a common denominator amongst AATD patients.6 Although childhood respiratory infections were associated with earlier symptoms in both never-smokers and smokers, the onset of cough and wheeze were earlier in those who smoked.6

The best thing a person can do for their lungs is to not have any exposure to smoke of any kind, and to quit if they do smoke. This is even more important for those with AATD. “Complete smoking cessation continues to be the best nonpharmacological approach to deter the relentless decline of lung function in COPD and, polymorphisms in antioxidant,A1AT, and MMPs genes, seem associated with fast FEV1 decline.”7 (p 118) It was found that just cutting down on smoking, even up to 50%, would not change the decline in lung function of an AATD patient. Only those that totally abstained and remained abstinent for a year saw any significant improvement in FEV1, although lung function steadily declined in a fashion comparable to never-smokers.7 Prevention of acute exacerbations of COPD and combined treatment with long-acting bronchodilators and inhaled corticosteroids is also important as exacerbations can cause a more rapid decline of FEV1 over time.7 The amount one smokes directly correlates with the rate at which lung function declines: heavy smokers are going to have a rapid decline and once the damage is done there is no way to repair it short of a lung transplant. Therefore, it is imperative to direct smokers with AATD towards smoking cessation.

At one time it was thought that AATD was strictly a European descent disease because gene-mapping studies indicated that the PiZ allele, the cause of AATD, probably arose in Northern Europe.8 However, further studies revealed that AATD is more of an equal opportunity disease like cystic fibrosis rather than a disease like Tay Sachs which afflict those of Jewish descent, or sickle cell which strikes those of African descent. There is not a racial or ethnic group that is immune from acquiring this genetic defect, it is considered one of the most common and serious hereditary disorders in the world.8

KNOWLEDGE IN THE MEDICAL COMMUNITY

It is amazing that something so common worldwide, and serious is still relatively an unknown disorder amongst the medical community, especially among respiratory therapists and physicians. To show that AATD is under-recognized by those that needs to be knowledgeable, a web-based test with 30 multiple choice answers was given to internal medicine house officers and respiratory therapists at Cleveland Clinic main campus hospital to test their knowledge of AATD.9 The test scores were assessed according to years of training and experience, as well as personal knowledge of AATD. The results were shocking. Out of the 99 respiratory therapists and 66 physicians, the scores were 54% for physicians and 52% for RT’s.9 It did not matter if the physician was a pulmonologist or if the RT had a 4 year degree, the only participants that scored better were those who claimed they had personal knowledge of AATD. These results are an indicator that the people who should be most knowledgeable about this disease are not very knowledgeable.9 This is a grave disservice to a group in need of informed caregivers.

Although the medical community is still somewhat in the dark where AATD is concerned, a patient advocacy group, the Alpha-1 Foundation, is committed to helping those affected by this disease. Because the Alpha-1 Foundation has business partners from all occupations including physicians, pharmaceuticals, the government, and scientific communities; they are able to promote awareness and research.10 AATD is an expensive disorder. Augmentation costs approximately $76,500 per year and this is a lifetime maintenance therapy. The Alpha-1 Foundation collaborating with pharmaceutical companies helps fund augmentation therapy for patients who are unable to afford it.10 Patient advocacy groups are very influential when it comes to initiating interest in research of unknown conditions. The Alpha-1 Foundation is particularly interested in providing resources to increase research, improve health, promote worldwide detection of the disease, and to find a cure.10 Early detection, access to augmentation and other maintenance drugs such as bronchodilators and inhaled steroids, in addition to educating medical personnel will go a long way in helping those with this disorder.10 Fortunately, the Alpha-1 Foundation is paving the way for this to become a reality. Perhaps there will come a day when all newborns are routinely screened for this disorder in the same way cystic fibrosis is, early detection is always the best way to prevent damage from occurring.

Unfortunately, the word emphysema brings to mind a smoker who has caused damage to their lungs themselves. Those with AATD may never have smoked a day in their life, but they are condemned because they have a “smoker’s disease” and they are judged even by the medical community who are unaware of what AATD is. At this time, there is not a cure for AATD, but there are ways to keep from losing lung function and creating more damage in the lungs. Not smoking and keeping away from smoke will go a long way in keeping the lungs from deteriorating faster. Also, getting flu vaccinations yearly, augmentation therapy, avoiding those with illnesses, and exercising will help keep lung function up. The best thing that could happen for AATD patients is for the medical community to become aware of this disorder on a worldwide basis. The Alpha-1 Foundation is working on getting the word out and doing all it possibly can to shine a light on a devastating disease that debilitates and kills people in the prime of their life.

MEDICAL TREATMENTS FOR EMPHYSEMA

Although Alpha-1-antitrypsin is a genetic form of emphysema, it is still a chronic obstructive pulmonary disease (COPD), and medically must be treated as such. Several treatments are beneficial for maintenance of this disease. Advair (salmeterol and fluticasone propionate) is on the front line of maintenance pharmaceuticals for COPD. Although there is not a pharmaceutical agent out there right now that will cure COPD, Advair is beneficial in that it reduces inflammation in the airways. Reducing the inflammation will help to prevent exacerbations.11

So does Advair have an effect on survival for those with COPD patients? Glaxo-SmithKline, makers of Advair, conducted a TORCH (Towards a Revolution in COPD Health) study in order to see for themselves. In this randomized double-blind trial, they compared a twice-daily dose of 50 µg of salmeterol with 500 µg fluticasone propionate alongside a placebo.11 It was found that although Advair did not significantly reduce the mortality rate in its users, it was beneficial in other areas such as keeping them from having to use systemic corticosteroids, and keeping them from severe exacerbations that would require hospitalization.11 Another benefit to using Advair, is that although it only modestly increased FEV1, it did slow the FEV1 decline rate.11

In those with mild COPD, a short-acting bronchodilator such as albuterol, or a bronchodilator with an added anticholinergic such as albuterol with ipratropium, can be used for treatment. For those with moderate to severe COPD, these medications are used more for rescue purposes rather than a maintenance regimen.12 Fast acting β2-adrenergic agonists such as albuterol are essential when there is reversible bronchospasm during an exacerbation. A long-acting bronchodilator is added to a maintenance regimen when symptoms are poorly controlled or when someone is using more than one canister of their rescue inhaler per month. Studies have shown that using albuterol with ipratropium lessened the amount of acute exacerbations, helped with the overall quality of life, helped with exercise tolerance, and helped the person in pulmonary rehabilitation get the most out of their program. Although there can be side effects to using albuterol or albuterol with ipratropium, such as tachycardia, in general, side effects are mild and not life threatening.12

For those patients categorized in the moderate to severe range, adding tiotropium to the regimen gave added benefits. Using tiotropium lessened emergency room visits and hospital admissions when compared to a patient using Serevent alone. Not only was there the added benefit of having less breathing problems, this also helped with costs due to hospitalizations.13 When comparing tiotropium to ipratropium, once again, tiotropium users were less likely to have hospitalizations when compared to ipratropium users. As a side note, patients must be careful when using several different maintenance pharmaceuticals, using Duo-Neb (albuterol and ipratropium) or Atrovent (ipratropium) is contradicted when using Spiriva (tiotropium) because of an unintended increase in the dose of anti-cholinergic bronchodilator. However, Advair and Spiriva may be used together along with albuterol.13

Possibly the most beneficial treatment in COPD, is oxygen therapy. Although pharmaceutical agents help with inflammation, oxygen therapy is the only treatment available to a COPD patient shown to help prolong life.14 Giving a patient supplemental oxygen helps to lower pulmonary hypertension as well as improve the patient’s dyspnea.14 Not all COPD patients need supplemental oxygen, but for those that do, it is important that they use it as prescribed. Tests which guide the prescription of supplemental oxygen are arterial blood gas studies, 6 minute walk tests, and pulse oximetry. If a patient is hypoxemic at rest, that patient may need supplemental oxygen both at rest and during activity.14

While every precaution is taken to keep a patient with COPD out of the hospital, exacerbations happen, sometimes this is due to a viral or bacterial infection within the lungs. A patient with COPD, may not have the cardiopulmonary reserve to overcome an acute exacerbation, and hospitalization in this case will happen more often than not. When hospitalization does occur, every effort is made to keep the patient off mechanical ventilation. It was found that the use of 2 consecutive days of an antibiotic for acute exacerbations of COPD started on hospital day 1 or 2, meant less use of invasive treatment such as mechanical ventilation.15

Another approach to manage acute exacerbations in the hospital is with the use of intravenous or oral corticosteroids. Intravenous and oral corticosteroid use resulted in a measurable FEV1 improvement that continued over the course of 10 days in comparison to the group that was not given intravenous or oral corticosteroids.16 However, the improvement comes with a price. Systemic steroid use has been linked to some devastating side effects, side effects that can last a lifetime. Glucose intolerance which can cause diabetes, increased risk of infection due to the immunosuppressive quality of the drug, osteoporosis, obesity, psychosis, hypokalemia, and metabolic alkalosis just to name a few.16 Because of the severity of the side effects, one must balance the need and the outcome before considering this option. A patient starting on this medication must be watched closely for side effects.16 It is a miracle drug, but not something to take lightly.

Depression and anxiety may also lead to hospitalization for a COPD patient.17 Although depression and anxiety do not directly cause exacerbations, they do appear to cause a worse health-related quality of life with a statistically significant increased risk of mortality.17 When one is faced with a debilitating disease and is unable to breathe, depression would make sense. When a person is depressed, they give up. It is somewhat of a vicious cycle, the effects of the disease cause depression, the depression makes the effects of the disease worse, and on it goes in a never-ending cycle.

Anxiety is a vicious cycle. Not being able to breathe causes anxiety, when one is anxious he breathes faster, However breathing faster does not improve their disease process. In this case, the anxiety could cause an acute exacerbation that could end in a hospitalization. It was also found that those with depression and anxiety not only end up in the hospital more often, but there were significantly more deaths after discharge.18

Those with COPD need specific care in order to maximize the outcome of their lives. In answer to this, several different organizations came up with practice guidelines in order to improve health outcomes and decrease practice variation.19 In theory this could contain costs and standardize care. However in treating COPD, it is not a one size fits all scenario. Each person is different and each person responds differently to treatment. One may need lung reduction surgery in order to survive, while another may only need pharmaceuticals in order to have a good quality of life. Therefore, although there must be guidelines to follow, one must not feel like they are boxed into a particular path they must follow with every patient.19

So what is the best way for a patient to be proactive rather than just following guidelines and hoping for the best? Self-care management puts the patient in the driver’s seat alongside the medical team rather than in the backseat. Patients who take a more active role in their day-to-day care are less likely to end up in the hospital. Self-care management is formalized patient education that teaches the skills to manage medications, guides behavior changes, and provides emotional support so patients can live full and active lives.20 There is a saying, knowledge is power, and this is true for those with COPD.

The more a person knows about their disease, the more they are empowered. Anxiety may come from fear, and fear often comes from the unknown. If a person is aware of what is causing their symptoms and the ways to combat those symptoms, the anxiety may lessen. Classes taught patients about breathing techniques, nutrition, coughing techniques, conserving energy, and gave them an action plan (in case of an exacerbation). These all helped empower the patient.20 Activity increased for these patients, health-related quality of life improved, and there were far less hospitalizations for those who took self-management classes. 20 Pulmonary rehabilitation for the COPD patient is also beneficial, whether in the beginning stages of COPD or at the end. Pulmonary rehabilitation will help patients utilize their oxygen more efficiently as well as slowing FEV1 decline.20

SUMMARY

It does not matter what has caused the emphysema, AATD or smoking, the bottom line is there is destruction of lung tissue with both situations. This damage will produce symptoms that may with pulmonary rehabilitation, medications, surgery, self-help groups, oxygen, or all of the above. Depression and/or anxiety need to be taken into consideration, and every effort must be made to avoid exacerbations in order to preserve lung function.

REFERENCES

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2. Stolk J, Seersholm N, Kalsheker N. Alpha-1-antitrypsin deficiency: current perspective on research, diagnosis, and management. Int J Chron Obstruct Pulmon Dis. 2006;1(2):151-160.

3. Stoller J. Alpha-1-antitrysin deficiency; an under-recognized but important issue for respiratory therapists. Respir Care. 2003;48(12):1022-1024.

4. Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biol.: Targets Ther. 2009;3:193-204.

5. Dauriat G, Mal H, Jebrak G, Brugiere O, Castier y, Camuset J, et al. Functional results of unilateral lung volume reduction surgery in alph-1-antitrypsin deficient patients. Int J Chron Obstruct Pulmon Dis. 2006;1(2):201-206.

6. Mayer A, Stoller J, Vedal S, Ruttenber A, Strand M, Sandhaus R, et al. Risk factors for

symptom onset in PI*Z alph-1-antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2007;1(4):485-492.

7. Molfino N. Genetic predisposition to accelerated decline of lung function in COPD. Int J Chron Obstruct Pulmon Dis. 2007;2(2):117-119.

8. Serres F. Worldwide racial and ethnic distribution of alpha-1-antitrypsin deficiency. Chest. 2002;122:1818-1829.

9. Taliercio R, Chatburn R, Stoller J. Knowledge of alpha-1-antitrypsin deficiency among internal medicine house officers and respiratory therapists: results of a survey. Respir Care. 2010;55(3):322-327.

10. Walsh J, Snider G, Stoller J. A review of the alph-1-antitrypsin foundation: its formation, impact, and critical success factors. Respir Care. 2006;51(5):526-531.

11. Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C, Jones P, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.

12. Gross N. Chronic obstructive pulmonary disease: an evidence-based approach to treatment with a focus on anticholinergic brochodilation. Mayo Clin Proc. 2008;83(11):1241-1250.

13. Oba Y. Cost-effectiveness of long-acting bronchodilators for chronic obstructive pulmonary disease. Mayo Clin Proc. 2007;82(5):575-582.

14. Sin D, McAlister F, Man S, Anthonisen N. Contemporary management of chronic obstructive pulmonary disease. JAMA. 2010;303(20):2035-2042.

15. Rothber M, Pekow P, Lahiti M, Brody O, Skiest D, Lindenauer P. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. 2003;290(17):2301-2312.

16. Singh J, Palda V, Stanbrook M, Chapman K. Corticosteroid therapy for patients with acute exacerbation of chronic obstructive pulmonary disease. Arch Intern Med. 2002;162:2527-2536.

17. Fan V, Ramsey S, Giardino N, Make B, Emery C, Diaz P, et al. Sex, depression, and risk of hospitalization and mortality in chronic obstructive pulmonary disease. Arch Intern Med. 2001;167(21):2345-2353.

18. Ng T, Niti M, Tan W, Cao Z, Ong K, Eng P. Depressive symptoms and chronic obstructive pulmonary disease effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med. 2007;167;60-67.

19. Lacasse Y, Ferreira I, Brooks D, Newman T, Goldstein R. Critical appraisal of clinical practice guidelines targeting chronic obstructive pulmonary disease. Arch Intern Med. 2001;161:69-74.

20. Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin R, et al. Reduction in hospital utilization in patients with chronic obstructive pulmonary disease a disease-specific self-management intervention. Arch Intern Med. 2003;163:585-591.

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