TRÀN DỊCH MÀNG PHỔI ÁC TÍNH

Management of a malignant pleural effusion: British
Thoracic Society pleural disease guideline 2010
Mark E Roberts,1
Edmund Neville,2
Richard G Berrisford,3
George Antunes,4
Nabeel J Ali1
, on behalf of the BTS Pleural Disease Guideline Group
INTRODUCTION
The discovery of malignant cells in pleural fluid
and/or parietal pleura signifies disseminated or
advanced disease and a reduced life expectancy in
patients with cancer.1
Median survival following
diagnosis ranges from 3 to 12 months and is
dependent on the stage and type of the underlying
malignancy. The shortest survival time is observed
in malignant effusions secondary to lung cancer
and the longest in ovarian cancer, while malignant
effusions due to an unknown primary have an
intermediate survival time.2e6
Historically, studies
showed that median survival times in effusions due
to carcinoma of the breast are 5e6 months.
However, more recent studies have suggested
longer survival times of up to 15 months.7e10
A
comparison of survival times in breast cancer
effusions in published studies to 1994 calculated
a median survival of 11 months.9
Currently, lung cancer is the most common
metastatic tumour to the pleura in men and breast
cancer in women.4 11
Together, both malignancies
account for 50e65% of all malignant effusions
(table 1). Lymphomas, tumours of the genito-
urinary tract and gastrointestinal tract account for
a further 25%.2 12e14
Pleural effusions from an
unknown primary are responsible for 7e15% of all
malignant pleural effusions.3 13 14
Few studies have
estimated the proportion of pleural effusions due to
mesothelioma: studies from 1975, 1985 and 1987
identified mesothelioma in 1/271, 3/472 and 22/592
patients, respectively, but there are no more recent
data to update this in light of the increasing inci-
dence of mesothelioma.4 13 14
Attempts have been made to predict survival
based on the clinical characteristics of pleural fluid.
None has shown a definite correlation: a recent
systematic review of studies including 433 patients
assessing the predictive value of pH concluded that
low pH does not reliably predict a survival of <3
months.15 16
In malignant mesothelioma, one
study has shown an association between increasing
pH and increasing survival.17
Burrows et al showed
that only performance status was significantly
associated with mortality: median survival was
1.1 months with a Karnofsky score <30 and
13.2 months with a score >70.18
An algorithm for the management of malignant
pleural effusions is shown in figure 1.
CLINICAL PRESENTATION
< The majority of malignant effusions are
symptomatic. (C)
< Massive pleural effusions are most
commonly due to malignancy. (C)
The majority of patients who present with
a malignant pleural effusion are symptomatic,
although up to 25% are asymptomatic with an
incidental finding of effusion on physical exami-
nation or by chest radiography.1
Dyspnoea is the
most common presenting symptom, reflecting
reduced compliance of the chest wall, depression of
the ipsilateral diaphragm, mediastinal shift and
reduction in lung volume.19
Chest pain is less
common and is usually related to malignant
involvement of the parietal pleura, ribs and other
intercostal structures. Constitutional symptoms
including weight loss, malaise and anorexia gener-
ally accompany respiratory symptoms.
A massive pleural effusion is defined as complete
or almost complete opacification of a hemithorax
on the chest x-ray. It is usually symptomatic and is
commonly associated with a malignant cause.20
The diagnosis of a malignant pleural effusion is
discussed in the guideline on the investigation of
a unilateral pleural effusion.
MANAGEMENT OPTIONS
Treatment options for malignant pleural effusions
are determined by several factors: symptoms and
performance status of the patient, the primary
tumour type and its response to systemic therapy,
and degree of lung re-expansion following pleural
fluid evacuation. Although small cell lung cancer,
lymphoma and breast cancer usually respond to
chemotherapy, associated secondary pleural effu-
sions may require intervention during the course of
treatment (figure 1). Malignant pleural effusions
are often most effectively managed by complete
drainage of the effusion and instillation of a scle-
rosant to promote pleurodesis and prevent recur-
rence of the effusion. Options for management
include observation, therapeutic pleural aspiration,
intercostal tube drainage and instillation of scle-
rosant, thoracoscopy and pleurodesis or placement
of an indwelling pleural catheter.
Observation
< Observation is recommended if the patient
is asymptomatic and the tumour type is
known. (C)
< Advice should be sought from the respira-
tory team and/or respiratory multidisci-
plinary team for symptomatic malignant
effusions. (U)
The majority of these patients will become symp-
tomatic in due course and require further interven-
tion. There is no evidence that initial thoracentesis
carried out according to standard techniques will
1
Sherwood Forest Hospitals
NHS Foundation Trust, UK
2
Portsmouth Hospitals NHS
Trust, UK
3
Royal Devon and Exeter NHS
Trust, UK
4
South Tees NHS Foundation
Trust, UK
Correspondence to
Dr Nabeel J Ali, Sherwood
Forest Hospitals NHS
Foundation Trust, Kingsmill
Hospital, Mansfield Road,
Sutton in Ashfield NG17 4JL,
UK;
nabeel.ali@sfh-tr.nhs.uk
Received 12 February 2010
Accepted 4 March 2010
ii32 Thorax 2010;65(Suppl 2):ii32eii40. doi:10.1136/thx.2010.136994
BTS guidelines

reduce the chances of subsequent effective pleurodesis after tube
drainage. However, repeated thoracentesis may limit the scope for
thoracoscopic intervention as it often leads to the formation of
adhesions between the parietal and visceral pleura.
Therapeutic pleural aspiration
< Pleural effusions treated by aspiration alone are asso-
ciated with a high rate of recurrence of effusion at
1 month so aspiration is not recommended if life
expectancy is >1 month. (A)
< Caution should be taken if removing >1.5 l on a single
occasion. (C)
Repeated therapeutic pleural aspiration provides transient relief
of symptoms and avoids hospitalisation for patients with
limited survival expectancy and poor performance status. It is
appropriate for frail or terminally ill patients. However, as small-
bore chest tubes are widely available, effective and may be
inserted with minimal discomfort,21e26
they may be preferable.
The amount of fluid evacuated by pleural aspiration will be
guided by patient symptoms (cough, chest discomfort)27
and
should be limited to 1.5 l on a single occasion. Pleural aspiration
alone and intercostal tube drainage without instillation of
a sclerosant are associated with a high recurrence rate and
a small risk of iatrogenic pneumothorax and empyema.28e36
Therapeutic pleural aspiration should take place under ultra-
sound guidance (see guideline on pleural procedures).
Intercostal tube drainage and intrapleural instillation of
sclerosant
< Other than in patients with a very short life expectancy,
small-bore chest tubes followed by pleurodesis are
preferable to recurrent aspiration. (U)
< Intercostal drainage should be followed by pleurodesis
to prevent recurrence unless lung is significantly
trapped. (A)
Pleurodesis is thought to occur through a diffuse inflammatory
reaction and local activation of the coagulation system with fibrin
deposition.37 38
Increased pleural fibrinolytic activity is associated
with failure of pleurodesis, as is extensive tumour involvement of
the pleura.39 40
Intercostal drainage without pleurodesis is asso-
ciated with a high rate of effusion recurrence and should be
avoided (see evidence table available on the BTS website at www.
brit-thoracic.org.uk). A suggested method for undertaking pleu-
rodesis is shown in box 1.
In animals the effectiveness of pleurodesis may be reduced by
concomitant use of corticosteroids. Recent evidence in rabbits
has shown reduced pleural inflammatory reaction and, in some
cases, prevention of pleurodesis with administration of cortico-
steroids at the time of talc pleurodesis.41
A subgroup analysis
comparing the efficacy of pleurodesis in the presence and
absence of non-randomised oral corticosteroid use also suggested
a negative effect of corticosteroids on efficacy.42
The adminis-
tration of non-steroidal anti-inflammatory drugs (NSAIDs) at
the time of pleurodesis is more contentious. Animal studies have
suggested that the use of NSAIDs may impair the action of
pleurodesis agents, but there is no evidence from human
studies.43
Size of intercostal tube
< Small-bore (10e14 F) intercostal catheters should be the
initial choice for effusion drainage and pleurodesis. (A)
Conventional large-bore intercostal tubes (24e32 F) have been
employed in most studies involving sclerosing agents.44
They
have traditionally been used because they are thought to be less
Table 1 Primary tumour site in patients with malignant pleural effusion
Primary
tumour site
Salyer14
(n[95)
Chernow1
(n[96)
Johnston13
(n[472)
Sears4
(n[592)
Hsu12
(n[785) Total (%)
Lung 42 32 168 112 410 764 (37.5)
Breast 11 20 70 141 101 343 (16.8)
Lymphoma 11 e 75 92 56 234 (11.5)
Gastrointestinal e 13 28 32 68 141 (6.9)
Genitourinary e 13 57 51 70 191 (9.4)
Other 14 5 26 88 15 148 (7.8)
Unknown
primary
17 13 48 76 65 219 (10.7)
Symptomatic?
Aspirate 500-1500ml to relieve symptoms
Prognosis >1
month
Aspirate as required to
control symptoms
Refer to respiratory medicine
Observe
No
Yes
Yes
No
No/don’t knowYes
Yes
No
Yes
No
either
No
Yes
* There is no evidence as to what proportion of unapposed
pleura prevents pleurodesis. We suggest that <50% pleural
apposition is unlikely to lead to successful pleurodesis
Known malignant pleural effusion
Trapped lung?
Complete? *
Pleurodesis unlikely
to succeed –
consider indwelling
pleural catheter
Thoracoscopy and talc
poudrage
Intercostal tube
Effusion drainage
± pleurodesis
Pleurodesis
successful?
Consider indwelling
pleural catheter or
repeat pleurodesis
Trapped
lung? *
Talc slurry
Stop
Figure 1 Management algorithm for malignant pleural effusion.
Box 1 How to perform talc slurry chemical pleurodesis
< Insert small-bore intercostal tube (10e14 F).
< Controlled evacuation of pleural fluid.
< Confirm full lung re-expansion and position of intercostal tube
with chest x-ray. In cases where incomplete expansion
occurs, see text regarding trapped lung.
< Administer premedication prior to pleurodesis (see text).
< Instill lidocaine solution (3 mg/kg; maximum 250 mg) into
pleural space followed by 4-5 g sterile graded talc in 50 ml
0.9% saline.
< Clamp tube for 1-2 h.
< Remove intercostal tube within 24-48 h.
Thorax 2010;65(Suppl 2):ii32eii40. doi:10.1136/thx.2010.136994 ii33
BTS guidelines

prone to obstruction by fibrin plugs, but there is little published
evidence to confirm this. The placement of large-bore tubes is
perceived to be associated with significant discomfort45
and this
has led to the assessment of smaller bore tubes (10e14 F) for
drainage and administration of sclerosing agents.22 46 47
Three
randomised trials investigating the difference in efficacy
between small- and large-bore chest tubes all concluded that
they were equivalent (see evidence table available on the BTS
website at www.brit-thoracic.org.uk).21e23
Studies using small-
bore intercostal tubes with commonly used sclerosants have
reported similar success rates to large-bore tubes and appear to
cause less discomfort.24e26 48
The small-bore tubes in these
studies were inserted either at the patient’s bedside by a physi-
cian or under radiological guidance.
Small-bore tubes have been used for ambulatory or outpatient
pleurodesis. Patz and colleagues used a fluoroscopically-placed
tube (10 F) connected to a closed gravity drainage bag system for
this purpose.49
Bleomycin was the preferred sclerosing agent and
the pleurodesis success rate approached 80%. Ambulatory
drainage is discussed further in the section on indwelling pleural
catheters.
Fluid drainage, pleurodesis and trapped lung
< Large pleural effusions should be drained in a controlled
fashion to reduce the risk of re-expansion pulmonary
oedema. (C)
< In patients where only partial pleural apposition can be
achieved, chemical pleurodesis may still be attempted
and may provide symptomatic relief. (B)
< In symptomatic cases where pleural apposition cannot
be achieved (‘trapped lung’), indwelling pleural cathe-
ters offer a more attractive therapeutic approach than
recurrent aspiration. (U)
< Once effusion drainage and lung re-expansion have
been radiographically confirmed, pleurodesis should not
be delayed. (B)
< Suction to aid pleural drainage before and after
pleurodesis is usually unnecessary but, if applied,
a high-volume low-pressure system is recommended.
(C)
Large pleural effusions should be drained incrementally, draining
a maximum of 1.5 l on the first occasion. Any remaining fluid
should be drained 1.5 l at a time at 2 h intervals, stopping if the
patient develops chest discomfort, persistent cough or vasovagal
symptoms. Re-expansion pulmonary oedema is a well-described
serious but rare complication following rapid expansion of
a collapsed lung through evacuation of large amounts of pleural
fluid on a single occasion and the use of early and excessive
pleural suction.50 51
Putative pathophysiological mechanisms
include reperfusion injury of the underlying hypoxic lung,
increased capillary permeability and local production of
neutrophil chemotactic factors such as interleukin-8.52 53
The most important requirement for successful pleurodesis is
satisfactory apposition of the parietal and visceral pleura,
confirmed radiologically.44 54 55
Incomplete lung re-expansion
may be due to a thick visceral peel (‘trapped lung’), pleural
loculations, proximal large airway obstruction or a persistent air
leak. Most studies indicate that the lack of a response following
instillation of a sclerosant is associated with incomplete lung
expansion.56
Where complete lung re-expansion or pleural
apposition is not achieved, pleurodesis may still be attempted or
an indwelling pleural catheter may be inserted. Robinson and
colleagues reported a favourable response in 9 out of 10 patients
with partial re-expansion of the lung in a study using doxy-
cycline as a sclerosing agent.57
The amount of trapped lung
compatible with successful pleurodesis is unknown. Complete
lack of pleural apposition will prevent pleurodesis: consideration
of an indwelling pleural catheter is recommended in this situa-
tion. Where more than half the visceral pleura and parietal
pleura are apposed, pleurodesis may be attempted although
there are no studies to support this recommendation.
The amount of pleural fluid drained per day before the
instillation of a sclerosant (<150 ml/day) is less relevant for
successful pleurodesis than radiographic confirmation of fluid
evacuation and lung re-expansion. In a randomised study,
a shorter period of intercostal tube drainage and hospital stay
was seen in the group in whom sclerotherapy was undertaken as
soon as complete lung re-expansion was documented (majority
<24 h) than in the group in whom pleurodesis was attempted
only when the fluid drainage was <150 ml/day. The success rate
in both groups approached 80%.55
After sclerosant instillation,
the duration of intercostal drainage appears not to affect the
chances of successful pleurodesis, although the only randomised
study to address this question was underpowered.58
Suction may rarely be required for incomplete lung expansion
and a persistent air leak. When suction is applied, the use of
high-volume low-pressure systems is recommended with
a gradual increment in pressure to about e20 cm H2O.
Analgesia and premedication
< Lidocaine (3 mg/kg; maximum 250 mg) should be
administered intrapleurally just prior to sclerosant
administration. (B)
< Premedication should be considered to alleviate anxiety
and pain associated with pleurodesis. (C)
Intrapleural administration of sclerosing agents may be painful;
significant pain is reported in 7% patients receiving talc to 60%
with historical agents such as doxycycline.57 59
Discomfort can be
reduced by administering local anaesthetic via the drain prior to
pleurodesis. Lidocaine is the most frequently studied local anaes-
thetic for intrapleural administration. The onset of action of
lidocaine is almost immediate and it should therefore be admin-
istered just before the sclerosant. The maximum dose of lidocaine
is 3 mg/kg (21 ml of a 1% lidocaine solution for a 70 kg male), with
a ceiling of 250 mg. The issue of safety has been highlighted in two
studies. Wooten et al60
showed that the mean peak serum
concentration of lidocaine following 150 mg of intrapleural lido-
caine was 1.3 mg/ml, well below the serum concentration associ-
ated with central nervous system side effects (ie, >3 mg/ml). In an
earlier study of 20 patients, larger doses of lidocaine were neces-
sary to achieve acceptable levels of local anaesthesia. The patients
receiving 250 mg lidocaine had more frequent pain-free episodes
than those given 200 mg, while serum levels remained within the
therapeutic range. Side effects were limited to transient para-
esthesiae in a single patient.61
The reason for the significant
difference in analgesia between the two groups with only a small
increment in the lidocaine dose was unclear.
There are no studies to inform a recommendation on the use
of premedication and sedation in non-thoracoscopic pleurodesis.
Pleurodesis is an uncomfortable procedure and is associated with
anxiety for the patient. The use of sedation may be helpful to
allay such fears and induce amnesia. The level of sedation should
be appropriate to relieve anxiety but sufficient to maintain
patient interaction. Sedation employed before pleurodesis should
be conducted with continuous monitoring with pulse oximetry
and in a setting where resuscitation equipment is available.62
Further research is underway to address this issue.
BTS guidelines

Sclerosant and complications
< Talc is the most effective sclerosant available for
pleurodesis. (A)
< Graded talc should always be used in preference to
ungraded talc as it reduces the risk of arterial hypo-
xaemia complicating talc pleurodesis. (B)
< Talc pleurodesis is equally effective when administered
as a slurry or by insufflation. (B)
< Bleomycin is an alternative sclerosant with a modest
efficacy rate. (B)
< Pleuritic chest pain and fever are the most common side
effects of sclerosant administration. (B)
An ideal sclerosing agent must possess several essential qualities:
a high molecular weight and chemical polarity, low regional
clearance, rapid systemic clearance, a steep dose-response curve
and be well tolerated with minimal or no side effects. The choice
of a sclerosing agent will be determined by the efficacy or success
rate of the agent, accessibility, safety, ease of administration,
number of administrations to achieve a complete response and
cost. Despite the evaluation of a wide variety of agents, to date
no ideal sclerosing agent exists.
Comparison of sclerosing agents is hampered by the lack of
comparative randomised trials, different eligibility criteria and
disparate criteria for measuring response and end points. A
complete response is usually defined as no reaccumulation of
pleural fluid after pleurodesis until death, and a partial response
as partial reaccumulation of fluid radiographically but not
requiring further pleural intervention such as aspiration.
However, some studies use a 30-day cut-off. A recent Cochrane
review concluded that thoracoscopic talc pleurodesis is probably
the optimal method for pleurodesis.63
This view is supported by
a systematic review.64
Studies are presently underway investi-
gating other agents including the profibrotic cytokine trans-
forming growth factor b.
Tetracycline
Until recently, tetracycline had been the most popular and
widely used sclerosing agent in the UK. Unfortunately, paren-
teral tetracycline is no longer available for this indication in
many countries as its production has ceased.65
Sterile talc
Talc (Mg3Si4O10(OH)2) is a trilayered magnesium silicate sheet
that is inert and was first used as a sclerosing agent in 1935.66
Talc used for intrapleural administration is asbestos-free and
sterilised effectively by dry heat exposure, ethylene oxide and
gamma radiation. It may be administered in two ways: at
thoracoscopy using an atomiser termed ‘talc poudrage’ or via an
intercostal tube in the form of a suspension termed ‘talc slurry’.
Success rates (complete and partial response) for talc slurry
range from 81% to 100%.30 54 56 67e70
The majority of studies
have used talc slurry alone and only a limited number of
comparative studies have been published (see evidence table
available on the BTS website at www.brit-thoracic.org.uk). A
truncated randomised study by Lynch and colleagues71
compared talc slurry (5 g) with bleomycin (60 000 units) and
tetracycline (750 mg). Although the study was terminated early
because of the removal of tetracycline from the US market,
analysis of the data to that point revealed no differences
between the three treatment groups 1 month after pleurodesis.
In a randomised trial between talc slurry (5 g) and bleomycin
(60 000 units), 90% of the talc group achieved a complete
response at 2 weeks compared with 79% of the bleomycin
group, which was statistically insignificant.72
Three studies have
directly compared talc slurry with talc poudrage (see evidence
table available on the BTS website at www.brit-thoracic.org.
uk).73e75
For one randomised study the data are available only in
abstract form.73
It suggests superiority of poudrage over slurry,
but limited data are available to validate this conclusion. Of the
other two studies, Stefani et al compared medical thoracoscopy
and talc poudrage with talc slurry in a non-randomised way.75
Their results suggest superiority of poudrage over slurry, but the
two groups were not equal with respect to performance status.
In the largest study, Dresler et al compared a surgical approach to
talc poudrage with talc slurry.74
They concluded equivalence,
but 44% of patients dropped out of the study before the 30-day
end point due to deaths and a requirement of 90% lung re-
expansion radiologically after intervention to be included in the
analysis.
Three studies have compared talc poudrage with other agents
administered via an intercostal tube. One compared bleomycin
(see below) and the other two tetracyclines (see evidence table
available on the BTS website at www.brit-thoracic.org.uk).76e78
Diacon et al concluded that talc insufflation at medical thoraco-
scopy was superior to bleomycin instillation on efficacy and cost
grounds.76
Kuzdzal et al and Fentiman et al both showed an
advantage of talc insufflation over tetracyclines.77 78
Each of the
three studies analysed fewer than 40 patients.
Talc slurry is usually well tolerated and pleuritic chest pain
and mild fever are the most common side effects observed. A
serious complication associated with the use of talc is adult
respiratory distress syndrome or acute pneumonitis leading to
acute respiratory failure. There have been many reports of
pneumonitis associated with talc pleurodesis, although
predominantly from the UK and the USA where historically
non-graded talc has been used.56 79e87
The mechanism of acute
talc pneumonitis is unclear and has been reported with both talc
poudrage and slurry.56 80
This complication is related to the
grade of talc used. Maskell and colleagues undertook two studies
to determine this association. In the first study they randomised
20 patients to pleurodesis using either mixed talc or tetracycline
and compared DTPA clearance in the contralateral lung with
that undergoing pleurodesis at 48 h after pleurodesis.88
DTPA
clearance half time decreased by more in the talc group, which is
a marker of increased lung inflammation. There was also
a greater arterial desaturation in those patients exposed to talc.
In the second part of the study, graded (particle size >15 mm)
and non-graded (50% particle size <15 mm) talc were compared.
There was a greater alveolarearterial oxygen gradient in the
group exposed to non-graded talc at 48 h after pleurodesis. In
a subsequent cohort study of 558 patients who underwent
thoracoscopic pleurodesis using graded talc, there were no
episodes of pneumonitis.89
Two studies have investigated the systemic distribution of talc
particles in rats after talc pleurodesis. The earlier study using
uncalibrated talc found widespread organ deposition of talc
particles in the lungs, heart, brain, spleen and kidneys at 48 h.
The later study used calibrated talc and found liver and spleen
deposition (but no lung deposition) at 72 h, but no evidence of
pleurodesis in the treated lungs.90 91
A further study in rabbits
found greater systemic distribution of talc with ‘normal’ (small
particle talc).92
This supports the evidence from clinical studies
that large particle talc is preferable to small particle talc.
Bleomycin
Bleomycin is the most widely used antineoplastic agent for the
management of malignant pleural effusions. Its mechanism of
action is predominantly as a chemical sclerosant similar to talc
BTS guidelines

and tetracycline. Although 45% of the administered bleomycin
is absorbed systemically, it has been shown to cause minimal or
no myelosuppression.93
Bleomycin is an effective sclerosant
with success rates after a single administration ranging from
58% to 85% with a mean of 61%. No studies have demonstrated
superiority over talc.42 71 72 94e102
It has an acceptable side effect
profile with fever, chest pain and cough the most common
adverse effects.99 102
The recommended dose is 60 000 units
mixed in normal saline. Bleomycin has also been used in studies
evaluating small-bore intercostal tubes placed under radiological
guidance with similar efficacy rates.46 48 49 103
In the USA,
bleomycin is a more expensive sclerosant than talc, but this is
not the case in Europe where non-proprietary formulations are
available.42 72 104
Rotation following pleurodesis
< Patient rotation is not necessary after intrapleural
instillation of sclerosant. (A)
Rotation of the patient to achieve adequate distribution of the
agent over the pleura has been described in many studies.
However, rotating the patient is time consuming, inconvenient
and uncomfortable. A study using radiolabelled tetracycline
showed that tetracycline is dispersed throughout the pleural
space within seconds and rotation of the patient did not influ-
ence distribution.105
A subsequent randomised trial using
tetracycline, minocycline and doxycycline revealed no significant
difference in the success rate of the procedure or duration of fluid
drainage between the rotation and non-rotation groups.106
A
similar study using talc showed no difference in distribution of
talc after 1 min or 1 h and no difference in the success rate of
pleurodesis at 1 month.107
Clamping and removal of intercostal tube
< The intercostal tube should be clamped for 1 h after
sclerosant administration. (C)
< In the absence of excessive fluid drainage (>250 ml/ day)
the intercostal tube should be removed within 24e48 h
of sclerosant administration. (C)
Clamping of the intercostal tube following intrapleural admin-
istration of the sclerosant should be brief (1 h) to prevent the
sclerosant from immediately draining back out of the pleural
space, although there are no studies to prove that this is
necessary.105
Intercostal tube removal has been recommended
when fluid drainage is <150 ml/day, but there is little evidence
to support this action.58 68 108 109
In the only randomised study
that has addressed the issue, Goodman and Davies randomised
patients to 24 h versus 72 h drainage following talc slurry
pleurodesis regardless of volume of fluid drainage. They found no
difference in pleurodesis success, although they did not reach the
recruitment target based upon the power calculation. In the
absence of any evidence that protracted drainage is beneficial,
and given the discomfort associated with prolonged drainage, we
recommend removal of the intercostal tube within 24e48 h
after the instillation of the sclerosant, provided the lung remains
fully re-expanded and there is satisfactory evacuation of pleural
fluid on the chest x-ray.
Pleurodesis failure
The most likely cause of pleurodesis failure is the presence of
trapped lung. There is no reliable way to predict pleurodesis
failure: a recent systematic review found that an arbitrary cut-
off of pH <7.20 did not predict pleurodesis failure.15
Where
pleurodesis fails, there is no evidence available as to the most
effective secondary procedure. We recommend that further
evacuation of pleural fluid should be attempted with either
a repeat pleurodesis or insertion of indwelling pleural catheter,
depending upon the presence of trapped lung. Surgical pleur-
ectomy has been described as an alternative option for patients
with mesothelioma (see later).
Malignant seeding at intercostal tube or port site
< Patients with proven or suspected mesothelioma should
receive prophylactic radiotherapy to the site of thor-
acoscopy, surgery or large-bore chest drain insertion,
but there is little evidence to support this for pleural
aspirations or pleural biopsy. (B)
Local tumour recurrence or seeding following diagnostic and
therapeutic pleural aspiration, pleural biopsy, intercostal tube
insertion and thoracoscopy is uncommon in non-mesothelioma
malignant effusions.110e113
However, in mesothelioma up to
40% of patients may develop malignant seeding at the site of
pleural procedures. Three randomised studies have addressed the
efficacy of procedure site radiotherapy to prevent tract metas-
tasis (see evidence table available on the BTS website at www.
brit-thoracic.org.uk).114e116
Boutin and colleagues114
found that
local metastases were prevented in patients who received
radiotherapy (21 Gy in three fractions) to the site of thoraco-
scopy. All the patients received radiotherapy within 2 weeks of
thoracoscopy. The incidence of tract metastases in the control
group in this study was 40%. This study was followed by
a longitudinal study that supported its conclusions.117
In two
later studies including sites from a wider range of procedures
such as needle biopsy and chest drain, the incidence of tract
metastases was not significantly different. Bydder and colleagues
showed no benefit of a single 10 Gy radiotherapy fraction to the
intervention site in preventing recurrence.116
All the patients
received radiotherapy within 15 days of the procedure, but 46%
of procedures were fine needle aspirations. O’Rourke and
colleagues used the same radiotherapy dose as Boutin but to
smaller fields. They found no benefit of radiotherapy, but again
included a range of procedures including needle biopsy. The
study included 60 patients but only 16 thoracoscopies, 7 in the
radiotherapy group and 9 in the best supportive care group.
Tract metastases occurred in 4 patients in the best supportive
care group (a rate of 44%) and none in the radiotherapy
group.115
This is very similar to the incidence of tract metastasis
in the study by Boutin et al (40%). The other procedures were
pleural biopsies (45%) and chest tubes (25%). A longitudinal
study by Agarwal et al found the highest rate of pleural tract
metastases in association with thoracoscopy (16%), thora-
cotomy (24%) and chest tube (9%), but a much lower rate in
association with pleural aspiration (3.6%) and image-guided
biopsy (4.5%).118
Careful analysis of the available data therefore
supports the use of radiotherapy to reduce tract metastasis after
significant pleural instrumentation (thoracoscopy, surgery or
large-bore chest drain), but not for less invasive procedures such
as pleural biopsy or pleural aspiration. A larger study to specif-
ically address this question would be of use.
A cohort of 38 patients described by West et al reported an
incidence of pleural tract metastasis after radiotherapy of 5%,
but in these cases the metastasis occurred at the edge of the
radiotherapy field. Of six patients who received radiotherapy
after an indwelling pleural catheter, one subsequently developed
pleural tract metastasis.119
There are, at present, insufficient
data on which to make a recommendation about the use of
radiotherapy in the presence of indwelling pleural catheters.
The role of prophylactic radiotherapy following pleural
procedures in non-mesothelioma malignant effusions has not
been established and therefore cannot be recommended.
BTS guidelines

Intrapleural fibrinolytics
< Intrapleural instillation of fibrinolytic drugs is recom-
mended for the relief of distressing dyspnoea due to
multiloculated malignant effusion resistant to simple
drainage. (C)
The use of fibrinolytic agents to ameliorate symptoms related to
complex pleural effusions has been described in several studies
although there are no randomised controlled trials.
Davies et al found that intrapleural streptokinase increased
pleural fluid drainage and led to radiographic improvement and
amelioration of symptoms in 10 patients with multiloculated or
septated malignant effusions. Intrapleural streptokinase was
well tolerated and no allergic or haemorrhagic complications
were reported.120
Gilkeson et al121
preferred urokinase in their
prospective but non-randomised study. Twenty-two malignant
pleural effusions were treated with urokinase resulting in
a substantial increase in pleural fluid output in patients both
with and without radiographic evidence of loculations. The
majority then underwent pleurodesis with doxycycline resulting
in a complete response rate of 56%. Similarly, no allergic or
haemorrhagic complications were encountered. In the largest
series, 48 patients unfit for surgical release of trapped lung after
incomplete lung re-expansion following tube drainage were
given intrapleural urokinase.122
Breathlessness was improved in
29 patients, 27 of whom eventually successfully achieved
pleurodesis. This study compared cases with historical controls
treated solely with saline flushes and in whom breathlessness
was not assessed.
None of these studies is large enough to accurately describe
the safety profile of fibrinolytic drugs in this setting. Immune-
mediated or haemorrhagic complications have rarely been
described with the administration of intrapleural fibrinolytics in
contrast to systemic administration of these agents.123 124
A
chest physician should be involved in the care of all patients
receiving this treatment.
Thoracoscopy
< In patients with good performance status, thoracoscopy
is recommended for diagnosis of suspected malignant
pleural effusion and for drainage and pleurodesis of
a known malignant pleural effusion. (B)
< Thoracoscopic talc poudrage should be considered for
the control of recurrent malignant pleural effusion. (B)
< Thoracoscopy is a safe procedure with low complica-
tion rates. (B)
Thoracoscopy (under sedation or general anaesthesia) has grown
in popularity as a diagnostic and therapeutic tool for malignant
effusions. Under sedation, it is now widely used by respiratory
physicians in the diagnosis and management of pleural effusions
in patients with good performance status.125e128
Patient selec-
tion for thoracoscopy and talc poudrage is important in view of
the invasive nature of the procedure and cost.129
A significant
benefit of thoracoscopy is the ability to obtain a diagnosis, drain
the effusion and perform a pleurodesis during the same
procedure.
The diagnostic yield and accuracy of thoracoscopy for
malignant effusions is >90%.99 125 127 130 131
Talc poudrage
performed during thoracoscopy is an effective method for
controlling malignant effusions with a pleurodesis success rate
of 77e100%.6 68 97 132e138
Randomised studies have established
the superiority of talc poudrage over both bleomycin and
tetracyclines (see evidence table available on the BTS website at
www.brit-thoracic.org.uk).73 76e78
One large randomised study
comparing talc poudrage with talc slurry failed to establish
a difference in efficacy between the two techniques.74
A further
small non-randomised study comparing these two techniques
also established equivalence.133
A large study has established the
safety of talc poudrage using large particle talc; no cases of
respiratory failure were seen in this cohort of 558 patients.89
Talc
poudrage is known particularly to be effective in the presence of
effusions due to carcinoma of the breast.139
Thoracoscopy has less to offer in patients with a known
malignant pleural effusion and a clearly trapped lung on the
chest x-ray. However, under general anaesthesia, reinflation of
the lung under thoracoscopic vision will inform whether the
lung is indeed trapped and therefore guide the decision to
perform talc poudrage or insert a pleural catheter. The procedure
can facilitate breaking up of loculations or blood clot in
haemorrhagic malignant pleural effusion and can allow the
release of adhesions and thereby aid lung re-expansion and
apposition of the pleura for talc poudrage.140 141
Thoracoscopy is a safe and well-tolerated procedure with
a low perioperative mortality rate (<0.5%).6 126 129 142
The most
common major complications are empyema and acute respira-
tory failure secondary to infection or re-expansion pulmonary
oedema, although the latter may be avoided by staged evacua-
tion of pleural fluid and allowing air to replace the fluid.127 129 143
Long-term ambulatory indwelling pleural catheter drainage
< Ambulatory indwelling pleural catheters are effective in
controlling recurrent and symptomatic malignant effu-
sions in selected patents. (B)
Insertion of a tunnelled pleural catheter is an alternative method
for controlling recurrent and symptomatic malignant effusions
including patients with trapped lung. Several catheters have
been developed for this purpose and the published studies
employing them have reported encouraging results.140 144e147
The presence of foreign material (silastic catheter) within the
pleural space stimulates an inflammatory reaction, and vacuum
drainage bottles connected to the catheter every few days
encourage re-expansion and obliteration of the pleural space.
Most catheters can be removed after a relatively short period.
In the only randomised and controlled study to date, Putnam
and colleagues145
compared a long-term indwelling pleural
catheter with doxycycline pleurodesis via a standard intercostal
tube. The length of hospitalisation for the indwelling catheter
group was significantly shorter (1 day) than that of the doxy-
cycline pleurodesis group (6 days). Spontaneous pleurodesis was
achieved in 42 of the 91 patients in the indwelling catheter
group. A late failure rate (defined as reaccumulation of pleural
fluid after initial successful control) of 13% was reported
compared with 21% for the doxycycline pleurodesis group.
There was a modest improvement in the quality of life and
dyspnoea scores in both groups. The complication rate was
higher (14%) in the indwelling catheter group and included local
cellulitis (most common) and, rarely, tumour seeding of the
catheter tract.
The largest series to date reported on 250 patients, with at
least partial symptom control achieved in 88.8%. Spontaneous
pleurodesis occurred in 42.9% while catheters remained until
death in 45.8%.148
A more recent series of 231 patients treated
with an indwelling catheter to drain pleural effusion reported
a removal rate of 58% after spontaneous cessation of drainage,
with only 3.8% reaccumulation and 2.2% infection.147
This
group included those with trapped lung (12.5% of all patients) or
who had failed other therapy. A further series of 48 patients
reported a spontaneous pleurodesis rate of 48%.149
Pien et al
studied a group of 11 patients in whom an indwelling catheter
BTS guidelines

was placed specifically for a malignant effusion in the presence
of trapped lung; 10 patients reported symptomatic
improvement.144
A recent series of 45 patients reported by Janes et al described
three cases of catheter tract metastasis associated with
indwelling pleural catheters occurring between 3 weeks and
9 months after insertion. Metastases occurred in 2 of 15 patients
with mesothelioma but in only 1 of 30 patients with other
metastatic malignancy.150
An indwelling pleural catheter is therefore an effective option
for controlling recurrent malignant effusions when length of
hospitalisation is to be kept to a minimum (reduced life expec-
tancy) or where patients are known or are suspected to have
trapped lung and where expertise and facilities exist for out-
patient management of these catheters. Although there is
a significant cost associated with the disposable vacuum
drainage bottles that connect to indwelling pleural catheters,
there may be a cost reduction associated with reduced length of
hospital stay or avoidance of hospital admission.
Pleurectomy
Pleurectomy has been described as a treatment for malignant
pleural effusions. Open pleurectomy is an invasive procedure
with significant morbidity. Complications may include
empyema, haemorrhage and cardiorespiratory failure (operative
mortality rates of 10e19% have been described).151e153
Pleur-
ectomy performed by video-assisted thoracic surgery has been
described in a small series of patients with mesothelioma. There
is not sufficient evidence to recommend this as an alternative to
pleurodesis or indwelling pleural catheter in recurrent effusions
or trapped lung.154
Competing interests No member of the Guideline Group is aware of any competing
interests.
Provenance and peer review The draft guideline was available for online public
consultation (July/August 2009) and presented to the BTS Winter Meeting (December
2009). Feedback was invited from a range of stakeholder institutions (see
Introduction). The draft guideline was reviewed by the BTS Standards of Care
Committee (September 2009).
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