Prognostic Factors for Successful Chemical Pleurodesis

In the past, it has been shown that if the pleural fluid pH or glucose levels are reduced, pleurodesis is
less likely to be successful (65,115). In one large series in which pleurodesis was attempted with talc
insufflation during thoracoscopy, pleurodesis failed in 6 of 14 patients (43%) if the pleural fluid pH level
was below 7.2 but only in 8 of 92 patients (9%) if the pleural fluid pH level was above 7.2 (115).
Comparable findings have been reported when the pleurodesis was attempted with intrapleural
tetracycline (65). Similar results are reported when a glucose measurement of less than 60 mg/dL was
used as a predictor of pleurodesis failure. One review of 433 patients undergoing pleurodesis found that
the pleural fluid pH level was the only independent predictor of pleurodesis failure (62). Interestingly,
the receiver operator curves (ROC) for the pleural fluid pH, pleural fluid glucose, and pleural fluid LDH
levels were virtually superimposable (62). Nevertheless, a low pleural fluid pH level should not be taken
as an absolute contraindication to chemical pleurodesis because 40% of patients with a pleural fluid pH
below 7 will still have a successful pleurodesis and 68% of the patients with pleural fluid pH below 7.3
will also have a successful pleurodesis (62). Interestingly, in this large series, there was no association
between pleurodesis success and the pleurodesis technique (thoracoscopy vs. tube thoracostomy),
pleurodesis agent (talc, bleomycin, or tetracycline derivative), or tumor type (62).
The success rate with pleurodesis is related to the changes in pleural pressure during thoracentesis. Lan
et al. (116) measured the change in pleural pressure after 500 mL of pleural fluid had been withdrawn
from 65 patients with a malignant pleural effusion. They then inserted a chest tube and continued to
drain the lung until (a) the drainage was less than 150 mL/day, (b) the drainage was less than 250
mL/day for 4 consecutive days, or (c) the drainage had continued for 10 days. At this time, they
attempted pleurodesis if the lung had expanded. They found that 14 patients had a pleural elastance
greater than 19 cm H2O, that is, the pleural pressure decreased by more than 9.5 cm H2O when the 500
mL of pleural fluid was withdrawn. They found that 11 of the 14 patients had a lung that had not
expanded. Pleurodesis was attempted in the remaining three patients with bleomycin and failed in all. In
contrast, only 3 of the 51 patients with pleural elastance less than 19 cm H2O had a trapped lung and
bleomycin pleurodesis was successful at 1 month in 42 of 43 (98%) of the patients who returned for
reevaluation.
The results of the study mentioned in the preceding text could have been anticipated because pleurodesis
will fail if the two pleural surfaces cannot be brought into approximation. The rapid fall in the pleural
pressure is an indication that the underlying lung is unlikely to expand with the removal of the pleural
fluid.
Mechanisms for Pleurodesis
Originally, antineoplastic agents such as nitrogen mustard (117) or radioisotopes (118) were injected
into the pleural space in the hope that these agents would kill the tumor cells and control the pleural
effusion. It was subsequently shown that the injection of these agents often controlled the pleural
effusion when tumor cells persisted and that the effectiveness of intrapleural therapy was related more to
the creation of a pleurodesis that prevented the accumulation of the pleural fluid than to any
antineoplastic effect of the agent administered (119,120). The effectiveness of intracavitary nitrogen
mustard is much greater when the instillation of this agent is combined with tube thoracostomy (4),
because the apposition of the two pleural surfaces allows the fibrotic process to obliterate the pleural
space.
Subsequent to the demonstration of the importance of the chemical pleuritis in controlling pleural
effusions, nonspecific irritants such as talc (121), tetracycline derivatives (122), silver nitrate, and
quinacrine (123) were combined with tube thoracostomy in an attempt to control malignant effusions.
The initial event in the production of a pleurodesis by these agents without question is an injury to the
pleura. An acute exudative pleural effusion develops within 12 hours of the instillation of essentially all
the agents that are currently used for pleurodesis including talc (124), tetracycline derivatives (125),
quinacrine (126), mitoxantrone (127), and bleomycin (126). The pleural fluid that accumulates after the
intrapleural injection of these agents is initially characterized by relatively high protein and LDH levels,
and neutrophil counts (128). However, injury to the pleura, as evidenced by the production of an acute
exudative pleural effusion, is not sufficient to induce a pleurodesis because many agents, when injected
intrapleurally, produce an acute exudative effusion but do not produce a pleurodesis (126).
The response of the pleura to an injury is a complex and incompletely understood multifactorial process
that can result in the development of fibrosis with the obliteration of the pleural space, or it can result in
restoration of the pleura to its normal state. The mechanisms of pleurodesis seem to differ from agent to
agent. The histologic appearance is much different with mitoxantrone (127) than it is with talc (124) or
tetracycline derivatives (125). The pleurodesis that follows talc, but not tetracycline, can be blocked if
corticosteroids are given systemically (129) or if tumor necrosis factor alpha–blocking antibodies
(130) are given intrapleurally immediately after talc is administered.
The balance between the procoagulant system and the fibrinolytic system is also important in
determining whether a pleurodesis will result after the intrapleural injection of a substance. If the
procoagulant system dominates, then pleurodesis will result, whereas if the fibrinolytic system
dominates, no pleurodesis will result. When rabbits are given tetracycline intrapleurally, the number of
pleural adhesions that occur is reduced if the rabbits are given either heparin or urokinase intrapleurally
(131). In humans, pleurodesis occurs after talc insufflation only if the intrapleural fibrinolytic activity
decreases (132).
Transforming Growth Factor β
Without a doubt, cytokines are involved in the production of a pleurodesis, but the importance of various
cytokines in inducing either fibrosis or repair remains to be determined. In the future, it is likely that
pleurodesis will be produced by the intrapleural injection of cytokines. One cytokine that is an excellent
candidate as an effective pleurodesis-producing agent is transforming growth factor (TGF-β). TGF-β
has several characteristics that would be important for a pleurodesis agent: (a) TGF-β is a potent
fibrogenic cytokine that regulates extracellular matrix production. In situations in which there is too
much TGF-β, fibrosis results (133). The transient overexpression of TGF-β in the rat lung leads to
marked pleural and interstitial fibrosis (134). (b) Once present, TGF-β can induce its own transcription
(135), which suggests that a single injection may be sufficient. (c) Mesothelial cells express and secrete
TGF-β; therefore, one intrapleural injection of TGF-β might result in prolonged secretion of TGF-β,
which could result in pleurodesis. (d) The incubation of human pleural mesothelial cells with TGF-β
results in secretion of increased levels of plasminogen activator inhibitor 1 (PAI-1) (136). This could
facilitate pleurodesis because inhibition of the fibrinolytic system is thought to be necessary for the
production of a pleurodesis (132).
Our preliminary studies in both rabbits (128) and sheep (137,138) demonstrate that the intrapleural
injection of small amounts of TGF-β results in a better pleurodesis than does the intrapleural injection of
either doxycycline or talc slurry. The pleurodesis after TGF-β occurs faster than after talc (139).
Moreover, the pleural fluid that results from the intrapleural injection of TGF-β is characterized by a
much lower WBC count and LDH level than the fluid that results from the intrapleural injection of
doxycycline or talc slurry (128). The pleurodesis following intrapleural TGF-β is not inhibited by
corticosteroids (140). We believe that TGF-β produces a fibrotic reaction in the pleural space without
the necessity for a pleural injury. If indeed this is the situation, TGF-β will be an ideal agent for
pleurodesis. Presently, the effectiveness and safety of TGF-β as an agent for pleurodesis in humans is
being investigated in clinical trials.
Vascular Endothelial Growth Factor
When mesothelial cells are incubated with TGF-β, the mesothelial cells produce increased amounts of
VEGF (141). In addition, the pleural fluid levels of VEGF are significantly correlated with the levels of
TGF-β in patients with pleural effusions (142). We noted that when pleurodesis was induced in rabbits
by the intrapleural administration of TGF-β, there was much more pleural fluid than when pleurodesis
was induced with doxycycline or talc slurry (96). We therefore hypothesized that the increased amounts
of pleural fluid with TGF-β were due to increased amounts of VEGF. However, when we administered
anti-VEGF antibodies to the rabbits, the amount of pleural fluid was just slightly diminished, but no
pleurodesis occurred (97). When the pleural tissues were assessed for the amount of vasculature, there
was a close correlation between the amount of vasculature and the pleurodesis scores (97). This study
demonstrated that angiogenesis is very important in the production of a pleurodesis and pleurodesis
should not be attempted in patients who are receiving anti-VEGF regimens.

Choice of Sclerosing Agent

Currently, the agents that are most commonly recommended are talc (either insufflated or as a slurry),
the tetracycline derivatives (minocycline or doxycycline), the antineoplastic agents (bleomycin or
mitoxantrone), silver nitrate and iodopovidone. A brief discussion of the various agents proposed as
sclerosing agents follows.

Tetracycline Derivatives
Tetracycline derivatives are now the second most common agents used for sclerosis (143). In the survey
by Lee et al. (143), tetracycline derivatives were the sclerosing agent of choice for 25.8% of the
respondents. During the 1980s, tetracycline was probably the most commonly used agent for creating a
pleurodesis. Tetracycline, 35 mg/kg, is effective in creating a pleurodesis in rabbits (126). Tetracycline
is also effective in treating malignant pleural effusions. Sherman et al. (165) reported that tetracycline,
1,500 mg, effectively controlled 94.4% of 108 malignant pleural effusions. In a review of 11 reports
involving 359 patients, the success rate with tetracycline was 67% (166).
Parenteral tetracycline is no longer available in the United States, although it remains available in some
countries such as Germany (167). It has recently been shown that oral forms of tetracycline and its
derivatives can be used for pleurodesis if they are dissolved in saline and then passed through a 0.2-µm
sterile and nonpyrogenic polyethersulfone membrane to remove infectious materials and other
particulate particles (168).
Because parenteral tetracycline is no longer available, the tetracycline derivatives minocycline and
doxycycline have been evaluated for their effectiveness in producing a pleurodesis. In the rabbit,
minocycline, 7 mg/kg (169), or doxycycline, 10 mg/kg (125), produces a pleurodesis that is comparable
to that produced by tetracycline, 35 mg/kg. One disturbing aspect of the intrapleural administration of
tetracycline derivatives in animals is that it is associated with a high incidence of hemothorax, which is
frequently fatal (169). The hemothoraces and the mortality, however, are prevented if chest tubes are
inserted into the animals (125).
Doxycycline and minocycline are effective in producing pleurodesis in patients with malignant pleural
effusion. When five reports (170,171,172,173,174) with a total of 110 patients are combined, there was
control of the effusion at 30 days in 91 of the patients (83%). The usual dose of doxycycline is 500 mg.
There has also been one report in which the administration of minocycline, 300 to 500 mg, produced a
complete response at 30 days in 62.5% of patients and a partial response (no need for further
thoracentesis) in an additional 25% (175). The primary side effect when pleurodesis is performed with a
tetracycline derivative is severe chest pain (176). Although the chest pain tends to be worse in patients
who receive the tetracycline derivative for a pneumothorax, it is sometimes very severe in patients with
malignant pleural effusions. It is recommended that patients who receive a tetracycline derivative for
pleurodesis be given lorazepam or midazolam in addition to systemic pain medications before the
injection.
It is possible that pleurodesis can be induced by using combinations of sclerosing compounds at less
than their usual doses. Dikensoy et al. (177) demonstrated that administration of one half (5 mg/kg
doxycycline plus 200 mg/kg talc) or one fourth (2.5 mg/kg doxycycline plus 100 mg/kg talc) of both the
usual doses of doxycycline (10 mg/kg) and talc (400 mg/kg) in rabbits resulted in a mean pleurodesis
score that was better than the mean pleurodesis score with full-dose talc and similar to the mean
pleurodesis score with full-dose doxycycline.

Intrapleural Injection of Sclerosing Agent

Pleurodesis should be performed by injecting the sclerosant through a chest tube. The reason to use a
chest tube rather than just injecting the sclerosing agent into the pleural effusion is that fusion of the
visceral and the parietal pleura to create a pleurodesis requires that the two pleural surfaces be next to
each other. If they are not in close apposition, pleurodesis is unlikely to occur.
The first question in performing a pleurodesis is on the size of chest tube to be used. There is no
evidence that the use of a large tube provides better results than does the use of a small tube
(200,201,202). Clementsen et al. (200) randomized 18 patients to either a 10-F or a 24-F catheter and
reported that there was no difference in the response rates. Patients accepted the small catheter more
readily (200). Marom et al. (201) treated 32 patients using a 14-F self-retaining van Sonnenberg
catheter, which was inserted with the Seldinger technique. They reported that 23 of 32 (72%) patients
had a complete response, 4 (12%) had a partial response, and pleurodesis failed in 5 (16%) with the
intrapleural injection of talc slurry (201). Parulekar et al. (202) reviewed the records of 58 cases of
malignant pleural effusion in which small-bore chest tubes were used in 44 and large-bore chest tubes
were used in 14. The recurrence rates were virtually the same in both groups and multivariate analyses
failed to demonstrate that tube size had any influence on the rate of recurrence (202).
The chest tube is connected to a water-sealed drainage system, and the effusion is allowed to drain
(182). It is recommended that negative pressure not be applied initially to the chest tube in this situation
because the combination of a chronic pleural effusion and the application of negative pleural pressure
can cause reexpansion pulmonary edema (see Chapter 24). If the lung has not expanded within 24 hours,
then negative pressure should be applied to the chest tube.
The pleurodesis is less likely to be successful if the patient is on corticosteroids or nonsteroidal anti-
inflammatory drugs (NSAIDs). The induction of a pleurodesis usually involves the creation of intense
intrapleural inflammation, which then leads to fibrosis. Therefore, it is not surprising that
antiinflammatory drugs decrease the efficacy of pleurodesis. In animal studies, the efficacy of
pleurodesis is decreased in rabbits given doxycycline and corticosteroids (203) or diclofenac (204), an
NSAID, in rabbits given talc slurry and corticosteroids (205), and in pigs treated with mechanical
abrasion and diclofenac (206). Accordingly, it is recommended that corticosteroids and NSAIDs not be
administered to patients undergoing pleurodesis.
Once the chest tube has been inserted, how long should one wait before injecting the sclerosing agent? It
is important to make certain that the underlying lung has fully expanded before the injection is made. If
the underlying lung has not expanded, then the injection of a sclerosing agent will lead only to additional
thickening of the visceral pleura, which will further compromise the function of the underlying lung.
Some authors have advocated that the sclerosing agent not be injected until the drainage from the chest
tube is less than 150 mL/day (178). However, there is no supporting data for this practice. Villanueva et
al. (207) randomly assigned patients to a group in which tetracycline was not instilled until the drainage
was less than 150 mL/day and a group in which 1500 mg of tetracycline was instilled as soon as the lung
had reexpanded. The rate of success was the same in each group (80%), but the duration of the chest
tube drainage was much less in the latter group (2 days) than in the former group (7 days). In view of
this study, it is recommended that the sclerosant be injected as soon as the lung has reexpanded.
If successful reexpansion of the lung cannot be accomplished with pleural drainage, as shown in Fig.
10.4B, sclerosing agents should not be injected into the pleural space. Their injection can only thicken
the visceral pleura and allow lesser lung expansion. If the lung does not expand with tube thoracostomy,
the pleural fluid can be drained on a chronic basis with the PleurX catheter or with a pleuroperitoneal
shunt (see the discussion of pleuroperitoneal shunt later in this chapter). One of these options should
definitely be performed if the mediastinum is shifted away from the side of the effusion (Fig. 10.4A).
The injection of any of the tetracycline derivatives produces an intense pleuritis that can be very painful.
Accordingly, patients should be given systemic medication to control the pain. We currently use
lorazepam or midazolam to produce conscious sedation. Sherman et al. (208) have suggested that the
patient should be given local anesthesia such as lidocaine hydrochloride intrapleurally. There are no
controlled studies evaluating the efficacy of intrapleural lidocaine, and currently, no intrapleural
anesthetic is recommended because the patient remembers no pain due to the conscious sedation.
After the sclerosant is injected, the catheter is flushed with an additional 50 to 100 mL of saline and the
chest tube is clamped for at least 1 hour. Although in the past it has been recommended that the patient
be moved into different positions so that the sclerosant contacts all the pleural surfaces, this does not
appear to be necessary. In animals, the dispersal of radioisotopes injected intrapleurally is similar
whether the animals are rotated or not (209). In humans, the dispersal of the injected radioisotopes is
similar whether the patients are rotated (210). Rotation did not have a statistically significant effect on
the results of pleurodesis in one randomized study with tetracycline derivatives (211). The rate of
success with rotation was 73.7% whereas that with no rotation was 61.9% (211). However, because
rotating the patient certainly does not decrease the likelihood of pleurodesis and because the patient has
much less pain with rotation if the small catheters are used, it is recommended that all patients be rotated
unless it is particularly uncomfortable for the patient.
After 1 to 2 hours, the chest tube is unclamped and negative pressure (-15 to -20 cm H2O) is applied to
the chest tube. Suction is maintained for at least 24 hours and until the pleural drainage is less than 150
mL/day. The chest tube is removed after 96 hours regardless of the volume of pleural fluid. The keys to
the success of this procedure are the pleuritis produced by the sclerosant and the approximation of the
visceral and the parietal pleura by the chest tubes so that a pleural symphysis can occur. There appears to
be no advantage if the sclerosant is injected twice. In one study, 25 patients received one injection of
tetracycline, 20 mg/kg, and 25 patients received instillations of tetracycline, 20 mg/kg, on 2 consecutive
days. Effusions recurred in four patients in each group (212).
Pleurodesis can be performed with the patient as an outpatient. Pleurodesis accomplished on an
outpatient basis has two advantages. First, the patient is not hospitalized. Because the mean
hospitalization time of patients treated in hospital is approximately 6.5 days (107) and the patient has a
life expectancy of only approximately 90 days, this hospitalization represents 5% of and probably the
best days of the patient's remaining life. Second, it decreases the cost of the treatment because there are
no hospitalization costs.
There have been several recent articles in which attempts were made to induce pleurodesis in patients
with malignant pleural effusions on an outpatient basis (107,108,213,214). The method that uses the
PleurX catheter is discussed in detail early in this chapter in the section on Indwelling Pleural Catheter
(PleurX). The alternative system is that developed by Patz (213). With this system, a small-bore
(10.3–14 F) all-purpose drainage catheter is placed with imaging guidance. Then, up to 1,000 mL of
pleural fluid is drained and then the catheter is connected to a 600-mL bag (Tru-Close; UreSil LP;
Skokie, IL, USA) for gravity drainage. After a baseline chest radiograph is obtained, the patient is sent
home and asked to return if he or she experiences increasing pain, shortness of breath, or fever. When
the drainage is less than 100 mL/day, the patient returns for outpatient sclerotherapy. The following day,
the patient returns for tube removal. Patz (213) treated 19 patients with 60 units of bleomycin. At 30
days, 79% of the patients had either a total (53%) or partial (26%) pleurodesis response. In a second
study, talc was used as the pleurodesing agent rather than bleomycin (214). Studies are under way in
which sclerosing agents are injected through the PleurX catheter.
When the PleurX catheter is compared with the gravity drainage system of Patz, the PleurX appears to
have several advantages. It appears to be safer. If the gravity system of Patz becomes disconnected, there
is a greater likelihood of pneumothorax or pleural infection. The gravity system is less acceptable to the
patient because they are saddled with the drainage bag. The primary disadvantage of the PleurX catheter
is that it is more expensive.
For the reasons mentioned earlier, pleural sclerosis should be performed on an outpatient basis whenever
feasible. When pleural sclerosis is performed on an outpatient basis, there is no hurry to perform the
injection because there are no daily hospital costs. Therefore, the pleural effusion is drained for 7 to 10
days and then a radiograph is obtained to confirm that there is not a significant amount of fluid in the
pleural space.

Fibrothorax
When pleural inflammation is intense, its resolution may be associated with the deposition of a thick
layer of dense fibrous tissue on the visceral pleura. The patient is then said to have a fibrothorax. As a
result of the marked pleural thickening, the hemithorax becomes contracted, and its mobility is reduced
(81). As the fibrothorax progresses, the intercostal spaces may narrow, the size of the involved
hemithorax may diminish, and the mediastinum may be displaced ipsilaterally. Radiologically, a peel of
uniform thickness surrounds the lung. Calcification occurs frequently on the inner aspect of the peel
(Fig. 27.5) and provides an indicator by which the thickness of the peel may be accurately measured
(81). The three main causes of fibrothorax are hemothorax, tuberculosis, and bacterial lung infection
(81); but pancreatitis (82), collagen vascular disease (83), and uremia (84) can also lead to fibrothorax.
In a few instances, no etiology is ever discovered (85).
Clinical Manifestations
Pulmonary function is severely compromised in fibrothorax. The degree of functional abnormality is
much greater than one would expect from the degree of pleural disease (86). Pleural thickening in the
costophrenic angle can cause profound alterations in the ventilation of and blood flow to the entire lung.
Routine pulmonary function testing reveals mild-to-severe restrictive ventilatory dysfunction.
Surprisingly, the blood flow is reduced more than the ventilation of the affected side (87). In a study of
127 patients (87), the mean oxygen uptake on the affected side was 19% of the total, whereas the mean
ventilation was 33% of the total. This finding is in contrast to parenchymal diseases, in which the
oxygen uptake and ventilation are reduced to the same degree (87). In severe disease, there is no
ventilation or perfusion to the affected side (87).
Treatment
The only treatment available for fibrothorax is decortication, which involves removing the fibrous peel from the visceral
pleura. The functional improvement following decortication has been variable (81,86,87). The most important clinical factor
is the extent of the disease in the underlying lung (86,87). The vital capacity may improve more than 50% following
decortication if no underlying parenchymal disease is present, but the vital capacity may even decrease following
decortication in patients with extensive parenchymal disease. Even in patients with long-standing fibrothorax, decortication
can still lead to functional improvement. One case report noted a marked subjective improvement in a patient who had had a
fibrothorax for 44 years (86).
Which patients should have decortication? Patients with recent hemothorax (see Chapter 25), recent empyema in which
the infection is controlled (see Chapter 12), or recent tuberculous pleuritis (see Chapter 13) should not have a decortication
because the pleural thickening frequently resolves by itself over several months. Therefore, decortication should be
considered only if the pleural thickening has been stable or progressive over at least a 6-month period. If the pleural
thickening has been present for several months and if the patient's way of life is compromised by exertional dyspnea,
decortication should probably be performed unless previous chest radiographs demonstrated extensive parenchymal disease.
Decortication is a major surgical procedure and should not be performed on patients debilitated by other diseases. In one
series of 141 patients, the mortality rate with decortication was 3.5% (66).