668 Medicine Update

Exudative Pleural Effusion:

114 Approach to Management

AJIT VENNIYOOR, ALOK BANERJEE

INTRODUCTION pleural space. Therapeutic centesis hence has a role in

CCF by reducing systemic fluid overload and thus
The normal pleural space contains approximately 1 contributing to a decrease in pulmonary capillary
ml of fluid. Pleural fluid is filtered in the parietal pleural pressures.
compartment from the systemic capillaries down a small
In several pathological states leading to increased
pressure gradient into the pleural space. Pleural fluid
formation or reduced drainage (Table 1), pleural fluid
secretion is greatest at the apex while absorption is
can accumulate, producing symptoms, and becomes a
maximum towards the diaphragm and mediastinum,
where the parietal lymphatics are concentrated. The management issue. If correctly worked up, it also holds
the key to correct diagnosis.
fluid is drained out predominantly through the stomata
of the parietal lymphatics lying between the parietal Pleural effusion can be transudative or exudative;
mesothelial cells. These stomata merge into small this review will deal exclusively with the latter.
lymphatic channels which, in turn, form larger vessels
ultimately drain into the mediastinal lymph nodes. The Table 1: Pathological basis of pleural effusion
parietal stomata possess valve-like structures to Condition Example
guarantee a unidirectional flow of fluid out of the pleural
1. Increased hydrostatic pressure Congestive cardiac failure
space1. The lymphatic drainage system can cope with
up to several hundred milliliters of additional fluid per 2. Reduced oncotic pressure Hypoalbuminemia
day without the development of an effusion. Therefore 3. Lymphatic block Malignancy
any pleural effusion represents a severe imbalance of 4. Increased permeability Pneumonia
pleural fluid formation and/or drainage capacity. In case 5. Decreased intra-pleural pressure Atelectasis
of congestive heart failure, even a small pleural effusion 6. Diaphragmatic defects Hepatic hydrothorax
signals a severe pulmonary fluid overload. 7. Rupture of thoracic duct Chylothorax
The visceral pleura does not play a significant role
in pleural fluid turnover.
Definition
One implication of pleural fluid dynamics is that,
despite statements to the contrary, effusions in CCF do A pleural fluid protein level of > 35 gm/L is normally
not indicate right heart failure. It is actually a function considered an exudate while a level of < 25 gm/L is
of elevated pulmonary capillary wedge pressures rather suggestive of a transudate. However, a more precise
than to pulmonary artery or right heart pressures2. This diagnosis is made by using Lights criteria3 (Table 2).
is due to left ventricular dysfunction with pathological Lights criteria needs measurement of both pleural and
flow of interstitial pulmonary fluid into the pleural space serum protein analysis. Criteria have also been
across the visceral side. In animal models of cardiogenic suggested to diagnose exudative effusion based on
pulmonary edema, it has been shown that up to 25% of pleural fluid analysis alone (Table 3). However, for all
the edema fluid flows via the visceral pleura into the practical purposes, Lights criteria are most specific and
 Exudative Pleural Effusion: Approach to Management 669

Table 2: Lights criteria Investigations

1. Pleural fluid serum protein ratio more than 0.5.
Investigations are of three types 7 . Initial
2. Pleural fluid serum LDH ratio more than 0.6. investigations are biochemical and imaging. However,
3. Pleural fluid LDH levels more than two thirds normal serum value the gold standard is a tissue diagnosis based on pleural
fluid cytology or pleural biopsy.
Table 3: Defining exudate based on pleural biochemistry alone
1. Pleural fluid LDH level more than 0.45 of upper limit of normal
Pleural Aspiration
serum value.
2. Pleural fluid cholesterol more than 45 mg% A diagnostic pleural fluid sample should be gathered
3. Pleural fluid protein level more than 2.9 gm%. with a fine bore (21G) needle and a 50 ml syringe. The
sample should be placed in both sterile vials and blood
sensitive. In a meta-analysis of 8 studies with 1448 cases, culture bottles and analysed for protein, lactate
Lights criteria had the best discriminative value4. dehydrogenase (LDH, to clarify borderline protein
Caveat: In 20% of cases of transudates in persons values), pH, Gram stain, ZN stain, cytology, and
exposed to diuretic therapy, such as in congestive cardiac microbiological culture.
failure, a chronic transudative can resemble an exudate Pleural aspiration should not be done if a transudate
by Light criteria. If the serum minus pleural protein is suspected, which can be done easily based on the
concentration is greater than 3.1 gm%, the effusion is clinical picture.
transudative. A serum to effusion albumin gradient The appearance and odour of the fluid can be
greater than 1.2 gm% also indicates that the pleural diagnostic some conditions:
effusion is most likely a true transudative effusion5. Purulent fluid indicates an empyema.
Recently, serum and pleural fluid NT-proBNP Bile stained-chylothorax biliary fistula
concentrations of 4,000 ng/L was found to have Anchovy sauce-ruptured amoebic liver abscess
sensitivities and specificities of 90 and 93%, respectively, Milky, opalescent fluid-chylothoraxsecondary to
for the diagnosis of heart failure and thus can be useful lymphatic obstruction by malignancy or thoracic
in a situation as described above6. duct injury by trauma or surgery.
Bloody fluid with hematocrit level of more than 50%
Differential Diagnosis of the peripheral hematocrit level is a hemothorax
An exhaustive list of conditions giving rise to an due to malignancy, embolism and trauma (Hct < 1%
exudative effusion is given in Table 4. For all practical is not significant)
purposes, most of them are rare and the diagnosis is Putrid odor suggests an anaerobic empyema.
obvious. The first five are the commonest causes of Uriniferous smell suggests urinothorax (in ipsilateral
pleural effusion in India. obstructive uropathy). Pleural fluid creatinine is
more than serum creatinine.
Table 4: Causes of exudative pleural effusion
Turbidity persisting after centrifugation is suggestive
1. Parapneumonic of a chylothorax or a pseudo-chylothorax. Chylo-
2. Tuberculous
thorax has triglyceride level of > 110 mg%, while
3. Malignancy
pseudo-chylothorax has cholesterol level of > 200
4. Pulmonary embolism
mg%.
5. Collagen-vascular (rheumatoid arthritis, lupus)
6. Postcardiac injury syndrome
7. Pancreatitis Biochemical Investigations
8. Trauma
9. Sarcoidosis Pleural fluid and serum protein and LDH are
10. Esophageal perforation essential for diagnosing an exudative effusion.
11. Radiation pleuritis Sometimes, a cholesterol value is also useful.
12. Drug-induced (Amiodarone, nitrofurantoin)
13. Asbestos-related (Benign Asbestos Pleural Effusion, BAPE) Glucose and pH
14. Parasitic (Echinococcus, filarial, paragonimiasis)
15. Chylothorax The next set of investigations is a pH value and
16. Meigs syndrome glucose levels, which are interlinked and is reduced in
17. Yellow nail syndrome most conditions. Pleural fluid pH does not change
670 Medicine Update

significantly over several hours if collected in a invasive procedure to establish the diagnosis of
heparinized syringe. malignancy and in itself, should not be used to establish
Pleural fluid pH less than 7.2 indicates the need for the diagnosis10.
urgent drainage of the empyema.
Markers for Connective Tissue Disorders
Pleural fluid pH more than 7.3 suggests that the
effusion may be managed with systemic antibiotics Measurement of C4 complement in pleural fluid may
alone. be of help, with levels below 0.04 g/l in all cases of
Pleural glucose concentration of <30 mg % indicates rheumatoid pleural disease. Rheumatoid factor can be
rheumatoid pleuritis or empyema. measured on the pleural fluid and often has a titer of
Levels of 30-60 mg% suggest malignant, tuberculous >1:320. However, it can be present in effusions of other
or lupus effusion, or esophageal rupture. etiology and often mirrors the serum value. The presence
of LE cells in pleural fluid is diagnostic of SLE. However,
Adenine Deaminase (ADA) ANA values are of no usealthough they are elevated
in most lupus effusions, they usually mirror serum
ADA is produced by most cells and catalyzes the values, and false positives are common, especially in
conversion of adenosine to inosine8. There are several malignancies11.
isoforms of ADA, but the prominent ones are ADA1 and
ADA2, which are coded by different gene loci. ADA1 Amylase
isoenzyme is found in all cells, with the highest
concentration found in lymphocytes and monocytes, Elevated levels (higher than the upper limits of
whereas ADA2 isoenzyme appears to be found only in normal for serum, or the pleural fluid/serum ratio is
monocytes. ADA2 is the predominant isoform in the >1.0) occurs in acute pancreatitis, pancreatic pseudocyst,
tuberculous pleural effusion, accounting for 88% of total esophageal rupture, ruptured ectopic pregnancy, or
ADA activity. In clinical practice, the difference in the pleural malignancy (especially adenocarcinoma).
use of total ADA and isoform ADA2 is not significant Approximately 10% of malignant effusions have raised
and total ADA value is taken to represent ADA2. pleural amylase levels. Pleural amylase due to
False-positive results can occur in less than 3% cases; esophageal rupture is of salivary origin while that due
this occurs with lymphoma, rheumatoid arthritis, SLE, pancreatitis is of pancreatic origin, and this can be
and rarely adenocarcinoma. A different isoenzyme distinguished by isoenzyme analysis. This is useful test
(ADA-1) is elevated in the presence of empyema, as occasional effusions are due to occult pancreatic
accounting for 70% of ADA activity. This cause for origin.
elevated total ADA activity can be distinguished by
doing isoenzyme studies but as this test is expensive, it Imaging
best avoided by not ordering, or ignoring ADA when
Chest X-ray
cytology is suggestive of empyema.
Elevated pleural fluid ADA level (> 40 U/L) in a Costophrenic angle is blunted in PA view if > 200
lymphocyte predominant exudate predicts tuberculous ml fluid is present.
pleural effusion with a sensitivity of 90 to 100% and a
Posterior CPA in a lateral film is blunted with as little
specificity of 89 to 100%.
as 50 ml fluid.
Tumor Markers Lateral decubitus film is useful to distinguish
between pleural thickening and free fluid. Thickness of
A panel of 4 tumor markers (carcinoembryonic free fluid of 10 mm or more predicts tappable fluid.
antigen (CEA), carbohydrate antigen 125 (CA 125),
carbohydrate antigen 15-3 (CA 15.3), and cytokeratin In a supine film (as in a critically ill patient), evidence
19 fragments) was used to differentiate malignant from of pleural effusion include haziness of hemithorax with
benign effusionsat least one was elevated in 54% of preserved vascular shadows, loss of silhouette of the
cancer cases while none was in benign cases. However, hemidiaphragm and thickening of minor fissure.
due to low sensitivity and specificity, it is suggested that Subpulmonic effusion can be missed on erect PA
presence of elevated levels of tumor markers in the view and can be demonstrated on decubitus films or by
pleural fluid should only serve as a pointer for a more ultrasound scan.
 Exudative Pleural Effusion: Approach to Management 671

Ultrasound Scan PET Scan

Thoracic ultrasound is useful in: Positron emission tomography (PET) scans are useful
Estimating the amount of pleural fluid (more for differentiating between benign and malignant
accurate than CXR PA) pleural diseases (sensitivity 97% and specificity 88.5%
in one study). It has been reported as helpful in
Guided tap when fluid is minimal or loculated and evaluating the extent of disease in mesothelioma.
when a blind tap fails12
Distinguishing transudates from exudates: those Tissue Diagnosis
with septated and homogenously echogenic patterns
are always exudates, whereas hypoechoeic effusions Cytology
may be either. Cytology can give a clue about the etiology based on
the predominant cell (Table 5). Cytology is of importance
CT Scan to establish the diagnosis of malignancy in a lymphocyte
predominant effusion where ADA levels are normal. In
Contrast enhanced helical CT scan diagnose
four major series totaling 1370 patients, malignant cells
pulmonary embolism better than a VQ scan; it also can
were detected only in 60% (range 40-87%); however,
detect the site of the origin of the thrombus13. success rates increased with:
Contrast enhanced CT scan performed after full Repeat samples (first sample 65% positive, second
drainage of pleural effusion can differentiate between additional 27% and third, further 5%).
benign and malignant pleural disease. CT scan features
suggestive of malignant disease include (Leungs Combining with pleural biopsy (+ 7%)
criteria14: Preparing both cell blocks and smears.
Nodular pleural thickening,
Table 5: Differential diagnosis of cytology report
Mediastinal pleural thickening,
Neutrophil predominant (> 50%):
Parietal pleural thickening greater than 1 cm
With parenchymal opacities:
Circumferential pleural thickening. Parapneumonic effusion
Infiltration of chest wall or diaphragm is also Pulmonary embolism
characteristic of malignancy. Bronchogenic carcinoma
Without parenchymal opacity:
CT scan also differentiates parenchymal lung abscess
Pulmonary embolism
from empyemacommonly displays the split pleura
Viral infection
sign, with lenticular opacification of the infected fluid.
Acute tuberculosis (10%)
Benign asbestos pleural effusion (BAPE)
Perfusion Scan
Eosinophilic effusion (> 10% eosinophils)
This was useful in diagnosing pulmonary throm- Parapneumonic effusion
boembolism, but this role is being gradually supplanted Tuberculosis
by helical CT scans. Drug induced (nitrofurantoin, bromocryptine, dantrolene)
Pulmonary embolism
MRI Churg Strauss syndrome
Parasitic disease (paragonimiasis)
A comparative study of CT versus MRI15 showed that BAPE
high signal intensity in relation to intercostal muscles Malignancy (rare)
on T2-weighted and/or contrast-enhanced T1-weighted Air or blood in pleural cavity
images in MRI were significantly suggestive for a
Lymphocyte Predominant (> 50%):
malignant disease. Using morphologic features in
combination with the signal intensity features, MRI had Tuberculosis
a sensitivity of 100% and a specificity of 93% in the Malignancy
detection of pleural malignancy. The authors concluded Sarcoidosis
that MRI is superior to CT in differentiation of malignant Chylothorax
from benign pleural disease. Rheumatoid disease
672 Medicine Update

Immunohistochemistry (IHC) studies are useful to Thoracoscopy

distinguish mesotheliomas from adenocarcinoma, and
amongst the latter, to identity primary site if unclear > 20% of patients with pleural effusion undergoing
(e.g., breast versus lung). Flowcytometry is useful to pleural fluid analysis and closed-needle pleural biopsy
subtype lymphomas. remain undiagnosed, and in up to 22% of cases, a
malignancy is detected later. Thoracoscopy is helpful in
Cytology can be negative if: such cases and is of two types: medical and surgical
the effusion is due to another etiology (e.g. embolism (Video assisted thoracoscopic surgery or VATS). Medical
associated with cancer) thoracoscopy is generally characterized as thoracoscopy
Some cancers like squamous cell cancer, sarcomas performed under local anesthesia in the endoscopy suite
and Hodgkins lymphoma. with the use of nondisposable instruments, and is
generally for diagnostic purposes. In contrast, VATS is
Pleural Biopsy a keyhole surgical procedure in the operating room,
under general anesthesia with one-lung ventilation
Pleural biopsy can be blind (Abrams or Copes using disposable instruments, generally for therapeutic
needle), or image guided (cutting needle) biopsy. purposes17.
Blind pleural biopsy using an Abrams needle is a Thoracoscopy can detect malignancy (if present) in
safe procedure in experienced hands, with a high > 90% of cases; however, more than 50% cases of
positivity for tuberculous and malignant effusion. The idiopathic effusion referred for thoracoscopy will be
diagnostic yield is similar to that of Copes needle but negative. In one series of 620 patients18, non-invasive
the sample size is bigger16. At least 4 samples should be workup established the diagnosis in all except 48 cases
taken and from the same sitechanging the site does (8%). Thoracoscopy established the diagnosis of
not increase diagnostic yield. malignancy in another 24 cases (50%), and benign
conditions in 16 (33%); which still left 8 cases
With tuberculous effusion, the initial needle biopsy
undiagnosed (17%).
is positive for granulomas in 5080% of patients; a
second biopsy will be positive 1040% of the time. A Ferrer19 has put forward four criteria that were
strongly predictive of malignancy:
specimen of the pleural biopsy should also be cultured
for mycobacteria as the combination of microscopy and CT scan suggestive of cancer
culture of the pleural biopsy makes a positive diagnosis Symptomatic period of greater than 1 month
in more than 80% of patients. Sero-sanguinous effusion
Needle biopsies are less reliable in malignancies (45% Absence of fever.
positivity), whereas fluid cytology is likely to be more Malignancy was detected by thoracoscopy in all
positive. This is due to the late involvement of parietal patients who fulfilled the four criteria and in 74% of
pleural, which also tends to be patchy in nature. those with three criteria. It is suggested that a conser-
However, the combination of cytology and biopsy vative approach may be adopted and thoracoscopy not
should establish the diagnosis in > 80% cases. performed in the subgroup of patients with one or none
Complications of Abrams pleural biopsy include site of the described criteria. This approach seems to be more
pain (115%), pneumothorax (315%), vasovagal logical than the use of tumor markers.
reaction (15%), hemothorax (<2%), site hematoma Common adverse events include subcutaneous
(<1%), transient fever (<1%) and, very rarely, death emphysema (6.9%), cardiac arrhythmia (0.35%), air
secondary to hemorrhage. If a pneumothorax occurs, embolism (rare); no deaths have been reported.
only 1% requires chest drainage.
Fibreoptic Bronchoscopy (FOB)
Pleural malignant deposits tend to occur near
midline and near diaphragm, where image guided FOB has a limited role in pleural effusion. In patients
biopsies are safer. A diagnostic accuracy of 90% is with an isolated pleural effusion, with no hemoptysis
possible. In a direct comparison of blind vs CT guided or pulmonary abnormality on the chest radiograph, the
biopsy, the latter had a far higher sensitivity (87% versus yield from bronchoscopy is low (16%) whereas pleural
47%) with a specificity of 100%. Repeat biopsy is avoided investigation yielded a positive diagnosis in 61%. If
in 40% of patients (with fewer passes) if CT-guided bronchoscopy is deemed necessary, it should be
biopsy is used as the preliminary investigation. performed after pleural drainage in order to perform
 Exudative Pleural Effusion: Approach to Management 673

adequate bronchoscopy without extrinsic airway reported sensitivities range from 10 to 47% for pleural
compression by pleural fluid. fluid culture, 39 to 84% for pleural biopsy histology and
56 to 82% for pleural biopsy culture. However, the last
APPROACH TO DIAGNOSIS facility does not exist in many centers, and is invasive
and time consuming. 10 to 20% of patients will not have
Three questions arise when confronted with a pleural positive culture results or granulomas on biopsy
effusion20: specimen.
1. Should a thoracocentesis be performed? Five tests are available to help the clinician. They are
2. Is it a transudate or an exudate? polymerase chain reaction (PCR), lysozyme levels,
3. If it is an exudate, what is the etiology? interferon gamma and interleukin 16 levels, and adenine
deaminase levels. Polymerase chain reaction has a
While most patients with pleural effusion need a
relatively low sensitivity in pleural fluid (0.42 to 0.81)
diagnostic or a therapeutic tap, in two situations, this
and is fairly expensive. The sensitivity of an elevated
should be deferred; one, if it is too small and two, if there
interferon level appears better (0.89 to 0.99) but this test
is congestive cardiac failure. In a lateral decubitus film,
is not freely available. Recently, interleukin 16 (IL-16)
if the thickness of fluid is < 10 mm, a tap is not
has been found to be significantly elevated in
recommended as the chance of obtaining fluid is less
tuberculous effusion and has been found useful for
than the chance of puncturing the lung. However, an
differentiating this from malignant effusions. Lysozyme
ultrasound guided tap can be done if the thickness is
pleural fluid to serum ratio improves the sensitivity of
10-15 mm.
the pleural fluid ADA.
The second step is to confirm the presence of an
ADA level of > 40 U/L in a lymphocyte predominant
exudate by Lights criteria. A lymphocyte predominant
exudate is highly specific and sensitive for tuberculous
exudate should undergo ADA analysis and a value of
effusion. However, it is often recommended that ADA
> 40 U/L establishes the diagnosis of TB. The excluded
should not be used as a diagnostic test or as an
group is a cause for worry as a high percentage of them
alternative to biopsy and culture9.
are likely to harbor a malignancy. They should undergo
an imaging procedure; CT scan/MRI/PET scan. CT scan Treatment of tuberculous effusion is as for
would establish a pulmonary embolism or suggest a parenchymal TB, with the standard EHRZ for 2 months
malignancy. The diagnosis of the latter can be then followed by HR for four months. The role of initial
confirmed by a blind pleural biopsy or one guided by steroids is controversial with some centers using a short
CT scan. Persons fulfilling Ferrers criteria above can course for 2 to 4 weeks; there is no evidence for or against
proceed to a thoracoscopy as the possibility of a this practice22. Intercostal tube drainage of tuberculous
malignancy is high. Those remaining undiagnosed and effusion has not been found to be useful23.
fulfilling the 6 criteria given below (see undiagnosed
effusions) can be observed safely. EMPYEMA

TUBERCULOUS PLEURAL EFFUSION Pneumonia is associated with an exudative pleural

effusion in up to 57% of cases. The majority resolves with
Tuberculous pleural effusion usually resolves antibiotic treatment, but some can progress through an
spontaneously, but in more than two-third cases, will exudative phase (simple parapneumonic effusion) to
relapse within 5 years with parenchymal disease. Hence, a fibrinopurulent stage (complicated parapneumonic
the necessity to diagnose and treat this condition. effusion), eventually organizing into fibrotic scar tissue
However, as the Mantoux test is negative in 30% and formation, or proceeding to a frankly purulent
pleural fluid culture is negative in 75% (as the fluid is empyema 24 (Table 6). Other causes of empyema
due to a delayed hypersensitivity reaction to rupture of included thoracic surgery (20%), trauma (5%),
a Ghons focus into the pleural cavity), specific diagnosis esophageal perforation (5%); rare causes include
of tuberculous effusion presents a problem21. thoracocentesis, pneumothorax and abdominal
Needle biopsy of the pleural for histology and culture infection. Empyema may also present as an indolent
significantly improves diagnosis in up to 86% of cases; illness with constitutional symptoms and be confused
this combined with pleural fluid and sputum cultures with malignancy. Complications of empyema include
increase the yield to 90%. Studies have reported variable bronchopleural fistula, lung abscess, and empyema
results for the diagnosis of tuberculous pleural effusion; necessitatis (spontaneous perforation through the chest
674 Medicine Update

Table 6: Parapneumonic effusions

Type of effusion Appearance Biochem/microbiol Treatment

Parapneumonic effusion-simple Clear fluid Exudate Drainage not needed

Parapneumonic effusion Fluid clear or turbid, pH < 7.2 Drainage needed
complicated although infected Glucose < 30 mg%
LDH > 1000 IU/L
Gm stain/culture maybe
positive
Empyema Purulent fluid Gm stain/culture may
be positive Drainage needed

wall). Early diagnosis is essential as the mortality of substance is diluted in 100 ml saline and instilled via
empyema is as high as 15% and up to 40% of these the chest tube. The tube is then clamped for 1 to 4 hours.
patients require surgery because medical treatment The instillation is usually repeated once daily, and is
fails25. continued for several days, sometimes for periods of up
A chest radiograph showing consolidation with to 2 weeks.
effusion should raise the possibility of empyema. The recently published MIST1 study26 was the first
Patients with pneumonia not responding to antibiotics large double-blind, randomized, controlled trial (454
should be assessed for the presence of pleural infection. patients) to address this issue. Results revealed that there
CT scanning can help differentiate empyema from was no improvement in outcomes with STK. There was
abscess and pleural thickening, with the former having an increase in adverse events with STK, especially chest
a typical encapsulated and biconvex configuration. All pain and allergic reactions. Also, there was an elevated
patients with suspected parapneumonic effusion should antibody response to STK which raised concerns about
undergo diagnostic pleural fluid sampling, ideally with receiving STK in any future thrombotic events. The
ultrasound localization. Recommendations include: authors concluded that intrapleural streptokinase should
1. the pleural fluid pH should be measured in all generally be avoided in pleural infections. A subsequent
parapneumonic effusions except for those that are meta-analysis27 also came to the same conclusion but
frankly purulent or have a positive Gram stain added that selected patients may still benefit by this
(immediate indication for tube drainage, regardless approach.
of the pH);
Recombinant deoxyribonuclease (dornase alpha) has
2. glucose measurements correlate well with pH and been used successfully in some cases 28 . Surgical
do not add relevant information and are not intervention is frequently necessary in patients who fail
essential, unless there is doubt about the quality of to improve with medical management alone; however,
the pH measurement; the optimal timing and nature of surgery is unknown.
3. pH values <7.0 should usually lead to tube Control of infection is the major indication for early
drainage, in all other cases the pH should not be surgery; even thick pleural peels resolve slowly and
the sole criterion to decide on the necessity of a chest surgery can be delayed.
tube;
4. effusions with pH 7.07.2 should be observed MALIGNANT PLEURAL EFFUSION
closely (repeat thoracocentesis);
5. effusions with pH >7.2 should be observed; those Lung cancer is the most common metastatic tumor
with pH values >7.3 are very unlikely to take a to the pleura in men and breast cancer in women.
complicated course. Together, both malignancies account for approximately
Small tubes are as effective as larger ones; double 50-65% of all malignant effusions. Lymphomas, tumors
lumen tubes can be used to irrigate the cavity with saline; of the gastrointestinal and genitourinary tract account
irrigation with antibiotics is not recommended. Anti- for a further 25%. Pleural effusions from an unknown
biotic regimens remain the same, but anaerobic cover is primary are responsible for 7-15% of all malignant
recommended as 15% are caused exclusively by pleural effusions (Table 7)29.
anaerobic bacteria. Massive pleural effusions are defined as those
Use of intrapleural fibrinolytics were previously effusions occupying the entire hemithorax. While only
recommended and included streptokinase (2.5 lakh 10% of patients have massive pleural effusions on
units) and urokinase (1.0 lakh units). The fibrinolytic presentation, malignancy is the most common cause of
 Exudative Pleural Effusion: Approach to Management 675

massive pleural effusion. An absence of contralateral tumors, small cell lung cancer) can be ignored as most
mediastinal shift in these large effusions implies fixation will disappear with systemic chemotherapy.
of the mediastinum, mainstem bronchus occlusion by However, this still leaves a percentage of patients
tumor (usually squamous cell lung cancer), or extensive with metastatic disease but with relatively long life
pleural involvement (as seen with malignant span (> 6 months at least) who needs long-term relief
mesothelioma). About 15% of patients, however, will from large effusions (e.g., non-small cell lung cancer,
have pleural effusions < 500 ml in volume and will be breast cancer, colon cancer). These are best managed
relatively asymptomatic. Most present with dyspnea, with pleurodesis. Less commonly used options in this
cough or chest pain. group include indwelling catheters, pleuro-
Table 7: Primary malignancy in cases of malignant effusion*
peritoneal shunts, pleurectomy, or thoracoscopy with
talc poudrage.
Primary site Percentage The steps of chemical pleurodesis used in our center
Lung 37.5 are outlined below:
Breast 16.8 Pleural fluid is drained out using small bore (10-14
Lymphoma 11.5 Fr) intercostal tube.
GU tract 9.4 Lung re-expansion is confirmed by chest X-ray.
GI tract 6.9
Wait until pleural fluid drainage is less than 150 ml
Other 7.3
daily.
Unknown primary 10.7
Sclerosant is instilled after premedication and the
*Summary of 5 series with total of 2040 patients tube is removed.
Pleural effusions found with malignancy are not Patient is rotated to ensure even spread of the
always due to metastatic spread. For example, 5% of lung sclerosant.
cancers have effusions that are non-metastatic. The term Repeat chest X-ray is taken 24 hours later to re-
paramalignant effusions is reserved for those effusions confirm lung expansion.
that are not the direct result of neoplastic involvement Each of the above steps is not without controversies
of the pleura 30. Reasons include post-obstructive and is explained below. While it is traditional to insert
pneumonia with parapneumonic effusion; chylothorax; large bore tubes to avoid clogging, two small series
pulmonary embolism; and transudative effusions showed that small bore tubes are equally effective; rare
secondary to post-obstruction atelectasis and/or low instances of clogging can be cleared with guide wires.
plasma oncotic pressures secondary to cachexia; The effusion should be drained slowly initially (< 1.5 L
treatment related (radiation and drugs such as metho- at each setting to prevent re-expansion pulmonary
trexate, procarbazine, cyclophosphamide, bleomycin); edema); this can be repeated frequently (every 4-6 hours
and concurrent nonmalignant disease. Conversely, post- or so) in the first 24 hours until the fluid is completely
mortem studies have shown that more than 50% of cases drained. If pleural fluid pressure can be measured and
with pleural spread may not have effusion. does not decrease below - 20 cm H2O, much more fluid
Diagnosis is based on pleural fluid cytology, pleural can be removed safely. In patients with contralateral
biopsy, and in rare cases, by thoracoscopy. As little of mediastinal shift on chest radiograph, removal of several
10 ml of fluid is enough for diagnosis in some cases31; liters of pleural fluid is probably safe, so long as he
however, success increases with repeat sampling. tolerates thoracocentesis without chest tightness, cough,
Management depends on degree of symptoms (perfor- or dyspnea.
mance status), curability of the tumor, and the expected The presence of lung re-expansion as seen on X-ray
life span32-34. is more important indicator for pleurodesis than waiting
In a patient in poor condition with short life span for fluid drainage of < 150 ml/day. A randomized trial
(< 3 months), observation or repeated tapping has shown that success rate of 80% can be achieved with
(therapeutic thoracocentesis) is preferred, with the early pleurodesis as soon as lung expansion is achieved
likelihood that 100% of the effusions will recur within (usually within 24 hours); it is not necessary for fluid
the month. drain to be < 150 ml before pleurodesis. This also cuts
Pleural effusions in patients with extremely down on hospital stay and patient discomfort. However,
chemosensitive tumors (lymphomas, testicular our center prefers to wait till drainage is less than 150
ml per day.
676 Medicine Update

Choice of the sclerosant is limited by availability. As pleurodesis. In elephants, the pleural space seems to be
shown in Table 8, sterile talc is the most effective agent, congenitally obliterated. It has been hypothesized that
followed by tetracycline and doxycycline; however, it could function as a drip pan for pulmonary edema
these agents are not readily available in India. Our center fluid. However, there is no evidence of increased risk of
uses Inj Bleomycin at a dose of 1 unit/kg body weight pulmonary edema after pleurodesis, so even this role is
instilled in 100 ml of saline; patients are premedicated unlikely to be of clinical relevance. The only apparent
with antihistaminics and paracetamol as allergic advantage of the pleural cavity is to thoracic surgeons
reactions are common. Despite the figures in the table, many surgeries would not have been possible without
head to head trials have shown that bleomycin is this cavity!
superior to tetracycline. 45% of the dose is absorbed
systemically; however, this does not cause any UNDIAGNOSED EFFUSIONS
cytotoxicity.
Table 8: Sclerosants for pleurodesis
If after the initial evaluation the diagnosis is not clear
(as it happens in about 15% of patients) and the patients
Sclerosant Dose Success rate meet all the 6 criteria given below, further evaluation is
Sterile talc 2-5 gm 90% not necessary as the patient will have a benign, self-
Tetracycline 1-1.5 gm 75% limited illness:
Doxycycline 500 mg 65% Patients are clinically stable
Bleomycin 60 units 60% Patients do not have weight loss
The patient does not have a fever
Patient rotation is not essential studies with The effusion occupies less than 50% of the
radioactive tetracycline have shown that it spreads hemithorax
evenly within seconds of instillation. However, this is a The results of the Mantoux test are negative and the
reasonable maneuver to perform which may add to the pleural ADA value is less than 40 U/mL
efficacy. Most centers recommend clamping of the tube The pleural fluid differential cell count has less than
for an hour after instillation and then removing it within 95% lymphocytes.
12 to 72 hours later, provided the fluid drain is less than
250 ml. In our center, the tube is removed immediately 20% of patients remaining undiagnosed and not
after instillation as there is no purpose served in keeping meeting the above criteria will still have an underlying
the tube as this could remove the sclerosant also. disease (usually a malignancy) and can be worked up
with the knowledge that finding a curable disease is
40% of mesotheliomas tend to seed along the tube unlikely and invasive investigations have their own
tract, or even at sites of pleural tapping/biopsythese morbidity and mortality. These include surgical
areas should be marked with India ink for future procedures such as thoracoscopy and open thoracotomy,
radiotherapy. which have a more than 90% chance of success.
Failure of pleurodesis occurs in cases of partial re- Long-term (10 year) follow-up in a series of 40
expansion of the lung, or if the fluid could not be drained
patients35 showed that 80% recovered spontaneously
due to multiple loculations. Incomplete lung re-
within a mean of 5.6 months (range: 1 week to 48
expansion may be due to a thickened visceral peel
months). The diagnosis in the remaining 8 patients were
(trapped lung), pleural loculations, proximal large
asbestos related (3), adenocarcinoma (1), mesothelioma
airway obstruction, or a persistent air leak. Where
(1), CCF (1), cirrhosis (1), and rheumatoid arthritis (1).
complete lung re-expansion or pleural apposition is not
The recent isolation of Epstein Barr virus in some
achieved and the patient is unsuitable for surgical
effusions may explain some of these idiopathic
intervention, pleurodesis should still be attempted. In
effusions36.
the event of multi-loculated or septated malignant
effusions, intra-pleural streptokinase (2.5 lakh units) can
CONCLUSIONS
be safely instilled (without risk of allergic or hemorrhagic
reactions) and has been shown to be effective. In conclusions, pleural effusion is a sign which, if
A very interesting question is whether pleurodesis worked up and interpreted correctly, can lead to the
affects lung function, or rather, whether an intact pleural diagnosis of a systemic disorder in more than 95% cases.
space has any useful function. Surprisingly, there is no Common causes include infections (including TB) and
clear cut answer to this. There is no evidence to suggest malignancies; most of the other differential diagnoses
that lung function is significantly impaired post- are rare. Diagnosis can be established by relatively non-
 Exudative Pleural Effusion: Approach to Management 677

invasive methods but on occasion, invasive techniques 19. Ferrer J, Roldn J, Teixidor J, Pallisa E, Gich I, Morell F.
such as thoracoscopy can establish the diagnosis. Predictors of pleural malignancy in patients with pleural
effusion undergoing thoracoscopy. Chest 2005;127:1017-22.

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