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contains a small amount of fluid for lubrication. The Nahid P and Broaddus VC (2003) Liquid and protein exchange.
volume of the pleural fluid can increase dramatically In: Light RW and Lee YCG (eds.) Textbook of Pleural Diseases,
with various pleural diseases. The respiratory me- pp. 3544. London: Arnold.
Noppen M (2001) Normal volume and cellular contents of pleural
chanics are altered to accommodate the extra volume fluid. Current Opinion in Pulmonary Medicine 7: 180182.
of fluid, resulting in dyspnea. Categorizing the effu- Noppen M (2004) Pleural lavage as a diagnostic and research tool.
sion into transudates and exudates using Lights Lung Biology in Health and Disease 186: 175182.
criteria may provide insight on the etiology and Noppen M, DeWaele M, Li R, et al. (2000) Volume and cellular
pathogenesis of the effusion. Congestive cardiac fail- content of normal pleural fluid in humans examined by pleural
lavage. American Journal of Respiratory and Critical Care
ure, hepatic cirrhosis, and renal failure are the most Medicine 162: 10231026.
common causes of transudative effusions, whereas Wiener-Kronish JP, Broaddus VC, Albertine KH, et al. (1988) Re-
infective (including tuberculosis) and malignant pleu- lationship of pleural effusions to increased permeability pulmo-
ral diseases account for a majority of exudative pleu- nary edema in anesthetized sheep. Journal of Clinical
ral effusions. Research on the immunologic basis Investigation 82: 14221429.
of pleural vascular hyperpermeability may provide
novel strategies for future management of recurrent
exudative effusions.
Pleural Fluid Analysis,
See also: Mesothelial Cells. Pleural Effusions: Over-
view; Pleural Fluid Analysis, Thoracentesis, Biopsy, and
Thoracentesis, Biopsy, and
Chest Tube; Parapneumonic Effusion and Empyema; Chest Tube
Malignant Pleural Effusions; Pleural Fibrosis; Chylotho- J E Heffner, Medical University of South Carolina,
rax, Psuedochylothorax, LAM, and Yellow Nail Syndrome; Charleston, SC, USA
Hemothorax. Pleural Space. Signs of Respiratory
Disease: Lung Sounds. Vascular Endothelial Growth & 2006 Elsevier Ltd. All rights reserved.
Factor.
Abstract
Further Reading Analysis of pleural fluid assists the diagnosis of intrathoracic
and systemic disorders that cause pleural effusions. Nearly 75%
Broaddus VC and Araya M (1992) Liquid and protein dynamics of patients with pleural effusions gain either a definitive or pre-
using a new minimally invasive pleural catheter in rabbits. Jour- sumptive diagnosis after a systematic analysis of pleural fluid.
nal of Applied Physiology 72: 851857. The need for further diagnostic studies depends on whether
Broaddus VC, Wiener-Kronish JP, and Staub NC (1990) Clearance pleural fluid is classified by pleural fluid analysis as exudative or
of lung edema into the pleural space of volume-loaded anest- transudative in nature. A Bayesian approach to discriminating
hetized sheep. Journal of Applied Physiology 68: 26232630. between exudative and transudative effusions increases diag-
Ferrara N (2000) VEGF: an update on biological and therapeutic nostic accuracy. Patients with exudative effusions may benefit
aspects. Current Opinion in Biotechnology 11: 617624. from pleural biopsy if the diagnosis remains uncertain after
Gourgoulianis KI (2004) Physiology of the pleura. Lung Biology in thoracentesis. Infected pleural fluid or large, symptomatic effu-
Health and Disease 186: 4552. sions benefit from chest tube drainage. Biopsy can be performed
Grove CS and Lee YCG (2002) Vascular endothelial growth fac- by closed needle, image-guided needle, open surgical, and
tor: the key mediator in pleural effusion formation. Current thoracoscopic techniques. The diagnostic yield of each of these
Opinion in Pulmonary Medicine 8: 294301. procedures varies in different clinical settings. Chest tubes rep-
Lee YCG (2003) Experimental models for pleural diseases. In: resent the primary technique for draining symptomatic effusions
Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp. and performing chemical pleurodesis. The type and caliber of
149166. London: Arnold. chest tube varies depending on the etiology and physical prop-
Lee YCG and Lane KB (2001) The many faces of transforming erties of the effusion.
growth factor beta in pleural diseases. Current Opinion in Pul-
monary Medicine 7: 173179.
Lee YCG and Lane KB (2003) Cytokines in pleural diseases. In: Introduction
Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp.
6389. London: Arnold. Thoracentesis and pleural fluid analysis represent the
Lee YCG, Malkerneker D, Thompson PJ, Light RW, and Lane KB cornerstones of evaluating patients with undiagnosed
(2002) Transforming growth factor-b induces vascular end-
othelial growth factor elaboration from pleural mesothelial cells
pleural effusions. Pleural fluid analysis provides a
in vivo and in vitro. American Journal of Respiratory and Crit- definitive or presumptive diagnosis in 75% of pa-
ical Care Medicine 165: 8894. tients with pleural effusions who undergo thoracent-
Light RW (2001) Physiology of the pleural space. In: Light RW esis. Patients with exudative effusions who remain
(ed.) Pleural Diseases, 4th edn., pp. 820. Baltimore: Lippincott
undiagnosed after pleural fluid analysis can undergo
Williams & Wilkins.
Light RW (2003) Physiological effects of pleural air or fluid. In: pleural biopsy to establish a diagnosis. An accurate
Light RW and Lee YCG (eds.) Textbook of Pleural Diseases, pp. diagnosis guides decisions for selecting patients for
4555. London: Arnold. chest tube placement and pleural fluid drainage.
PLEURAL EFFUSIONS / Pleural Fluid Analysis, Thoracentesis, Biopsy, and Chest Tube 363
Table 3 Gross characteristics of pleural fluid Table 4 Common conditions associated with transudative or
exudative effusions
Appearance Suggested diagnosis
Transudates
Purulent Empyema Congestive heart failure
Anchovy paste Amoebic liver abscess Hepatic hydrothorax
Putrid smelling Anaerobic empyema Nephrotic syndrome
Ammonia smelling Urinothorax Peritoneal dialysis
Bloody Malignancy, chest trauma, Hypoalbuminemia
postcardiac injury, pulmonary Urinothorax
infarction, benign asbestos Atelectasis
pleurisy Constrictive pericarditis
Milky Chylous effusion, chyliform Trapped lung
effusion, extravascular Superior vena caval obstruction
migration of central venous Pulmonary embolism (may also be exudative)
catheter used for infusion of
lipid products Exudative effusions
Green Biliothorax Intrapleural infections
Yellow-green or fluorescent Rheumatoid pleurisy Drug induced
green Pulmonary embolism
Appearance of intravenous fluid Extravascular migration of Esophageal perforation
central venous catheter Malignancy
Pancreatitis
Collagen vascular disease
Benign asbestosis pleurisy
Chemical Tests Radiation pleurisy
Uremic pleurisy
The measurement of pleural fluid protein, lactate Sarcoidosis
dehydrogenase (LDH), glucose, pH, and amylase as- Postcardiac injury syndrome
Hemothorax
sist the initial evaluation of pleural effusions.
Chylothorax
Pseudochylous effusion
Protein, LDH, and exudative versus transudative Vasculitis
Hypothyroidism
effusions Pleural fluid and blood are sent for meas-
Ovarian hyperstimulation syndrome
urement of protein and LDH to allow classification of Yellow nail syndrome
the pleural fluid as an exudative or transudative ef- Lymphangiomyomatosis
fusion. Exudative pleural effusions most often de- Lymphangiectasia
velop as a consequence of malignant or inflammatory Subphrenic inflammatory or neoplastic process
alteration of the permeability of pleural and vascular
membranes or obstruction of pleural lymphatics that
drain the pleural space. These conditions promote pleural fluid LDH (4two-thirds the upper limits of
intrapleural accumulation of fluid that has a high normal for serum LDH), pleural fluid-to-serum LDH
concentration of high molecular weight compounds, ratio (40.6), and the pleural fluid-to-serum protein
such as protein and LDH. Exudative pleural fluid can ratio (40.5). Fulfillment of any one of the three cri-
also accumulate by the flow of protein-rich fluid from teria supports the exudative nature of the effusion.
adjacent body compartments, as occurs in patients Lights criteria have greater than 95% diagnostic ac-
with pancreatitis. Transudative effusions develop curacy when applied to large groups of patients. Two
when an intravascular increase in hydrostatic or de- of Lights criteria, pleural fluid LDH and pleural fluid-
crease in oncotic pressure promotes transudation of to-serum LDH ratio, correlate closely with each other
fluid from intrathoracic vessels into the pleural space. because they are mathematically coupled and share
Transudative effusions also develop with migration of an identical element (pleural fluid LDH). Therefore,
transudates from the mediastinum (extravascular mi- the diagnostic accuracy of Lights criteria is not di-
gration of central venous catheters), retroperitoneum minished significantly by excluding either the pleural
(urinothorax), peritoneum (ascites), or central sub- fluid LDH or the pleural fluid-to-serum LDH ratio
arachnoid space (cerebrospinal fluid). Transudative from consideration (abbreviated Lights criteria).
effusions have low concentrations of high molecular Other clinical rules perform as well as Lights cri-
weight compounds. Table 4 shows the differential teria and have some clinical advantages because they
diagnosis of exudative and transudative effusions. do not require serum blood tests. For instance, pa-
Lights criteria represent the classic approach for tients with any one of the following criteria are likely
discriminating between exudative and transudative to have an exudative effusion: pleural fluid protein
effusions. This clinical rule assesses three criteria: the 43.0 g dl 1, pleural fluid cholesterol 445 mg dl 1,
PLEURAL EFFUSIONS / Pleural Fluid Analysis, Thoracentesis, Biopsy, and Chest Tube 365
or pleural fluid LDH 4two-thirds the upper limits of pleural effusions. A high ratio can also rarely occur
normal for a serum LDH. Increasing any of these in patients with parapneumonic effusions, cirrhosis,
criteria into multiple-criteria rules, as is done with and ectopic pregnancies. Chronic pancreatic effu-
Lights criteria, increases the sensitivity for detecting sions typically have pleural fluid amylase concentra-
exudative effusions but decreases the specificity. tions 4100 000 IU l 1. A pleural fluid amylase is
As with all diagnostic rules that use a binary ap- obtained only when pancreatic or esophageal disor-
proach (i.e., exudative effusion is either present or ders are suspected because the frequency of an ele-
absent), the criteria discussed above perform less vated amylase in patients suspected with malignant
accurately when patients have test results near any of disease is insufficiently common to warrant its rou-
the criterias cut-off points. For instance, when any tine assay. Both malignant pleural effusions and ef-
one of the three Lights criteria has a result near its fusions due to a ruptured esophagus are rich in the
cut-off point, the diagnostic accuracy of the Lights salivary amylase isoform.
criteria decreases to 75%. Therefore, it has been
suggested that physicians use a Bayesian approach to
Lipid tests Clinical suspicion of a chylous or chyli-
categorize effusions as exudates or transudates
form effusion warrants assay of pleural fluid for tri-
wherein the pretest probability of an exudate is es-
glycerides and cholesterol. A triglyceride content
timated with calculation of the post-test probability
4110 mg dl 1 supports the diagnosis of a chylous
using likelihood ratios. Several reports have pub-
effusion and a content o50 mg dl 1 excludes the di-
lished multilevel likelihood ratios and formulas for
agnosis. Intermediate values require lipoprotein anal-
calculating continuous likelihood ratios for several
ysis of pleural fluid to detect chylomicrons, which
pleural conditions (see Further reading).
confirm the diagnosis. Extravasation of lipid-contain-
ing parenteral nutrition into the pleural space results
Glucose A pleural fluid glucose o60 mg dl 1 oc-
in a pleural fluid-to-serum glucose ratio 41. A pleural
curs most often in patients with rheumatoid pleurisy,
fluid cholesterol concentration 4200 mg dl 1 with
pleural infections, malignant effusions, tuberculous
a low triglyceride level supports the diagnosis of a
pleuritis, lupus pleuritis, or esophageal rupture. Some
chyliform effusion. A combined elevation in both
experts recommend the use of pleural fluid glucose to
cholesterol and triglyceride levels warrants measure-
guide the selection of patients with parapneumonic
ment of chylomicrons to discriminate between chy-
effusions for chest drainage because patients with
lous and chyliform effusions.
glucose values o60 mg dl 1 are unlikely to respond
to antibiotic therapy alone. Existing data do not,
however, strongly support this recommendation. Adenosine deaminase Patients with tuberculous
pleuritis have an increased pleural fluid concentra-
pH Pleural fluid pH values range from 7.30 to 7.45 tion of adenosine deaminase (ADA) usually above
and 7.40 to 7.55 in exudative and transudative effu- 4560 U l 1. Assay of the isoenzyme ADA-2 further
sions, respectively. A pleural fluid pH below 7.30 increases diagnostic accuracy. Elevated pleural fluid
suggests the presence of rheumatoid pleurisy, pleural concentrations of ADA can also occur in patients
infections, malignant effusions, tuberculous pleuritis, with rheumatoid pleurisy, pleural infections, and
lupus pleuritis, or esophageal rupture. For patients pleural malignancies that include mesothelioma,
with parapneumonic effusions, a pH o7.20 increases pleural carcinomatosis, and intrapleural spread of
the probability that the fluid requires drainage, hematologic malignancies.
although the diagnostic accuracy of pH in this set-
ting is only weakly established. Some experts use Hematological Studies
pleural fluid pH to select patients with malignant
Red blood cells Grossly bloody effusions with pleu-
pleural effusion for pleurodesis because an indirect
ral fluid erythrocyte counts 4100 000 ml 1 suggest
association exists in populations of patients between
malignancy, trauma, benign asbestos pleural effusion,
pH and the probability of a successful pleurodesis
postcardiac injury syndrome, or pulmonary infarct-
and duration of patient survival after pleurodesis.
ion as the cause of the effusion. A hemothorax as
However, this association is not sufficiently strong to
defined by a pleural fluid-to-serum hematocrit ratio
allow its use for predicting the clinical courses of
40.50 occurs as a result of accidental or iatrogenic
individual patients.
chest trauma.
Amylase A pleural fluid-to-serum amylase 41.0 is
found most often in patients with acute or chronic White blood cells The number of white blood cells
pancreatitis, esophageal rupture, and malignant in pleural fluid is never diagnostic although acute
366 PLEURAL EFFUSIONS / Pleural Fluid Analysis, Thoracentesis, Biopsy, and Chest Tube
inflammatory conditions have higher white cell con- diagnostic value of these tests varies widely depend-
centrations usually above 10 000 ml 1. ing on the etiologic pathogen, the extent of pleural
infection, the presence of antimicrobial therapy, and
Nucleated cell differential Lymphocytosis 450% the timing of thoracentesis.
nucleated cells suggests the presence of lymphoma,
Immunologic Studies
chronic rheumatoid pleurisy, yellow nail syndrome,
chylothorax, tuberculous pleuritis, uremic pleurisy, Patients with lupus pleuritis tend to have increased
sarcoidosis, acute rejection of a transplanted lung, pleural fluid antinuclear antibody (ANA) titers
postcardiac surgery effusion (42 months after sur- (41:160320), pleural fluid-to-serum ANA ratios
gery), trapped lung, or malignant pleural effusion. 41, and decreased pleural fluid complement levels.
These conditions often have lymphocyte counts Patients with rheumatoid pleurisy often have pleu-
485% of nucleated cells except for malignant effu- ral fluid rheumatoid factor titers 41:320, pleural
sions, which are typically in the 5070% range. Most fluid-to-serum rheumatoid factor ratios 41, and de-
pleural lymphocytes are T-type cells; the presence of creased pleural fluid complement levels. However,
a predominance of B-type cells by flow cytometry limited data support the diagnostic value of pleural
suggests lymphoma or chronic lymphocytic leukemia fluid immunologic studies making their application
as the cause of the effusion. to individual patients uncertain.
Pleural fluid eosinophilia (410% nucleated cells)
suggests a benign condition characterized by blood
or air in the pleural space or a narrow differential of Pleural Biopsy
pulmonary infections. Neoplastic etiologies, how- Patients with undiagnosed lymphocytic-predomi-
ever, cannot be excluded by the presence of pleural nant, exudative pleural effusions or pleural-based
eosinophilia. The most common diagnoses include masses should undergo pleural biopsy to establish a
pneumothorax, hemothorax, Hodgkins disease, car- specific diagnosis. The available biopsy techniques
cinoma, benign asbestos pleurisy, parasitic disease, include closed needle biopsy, CT-guided needle bi-
pleural infections, or drug-induced effusions. opsy, thoracoscopy, and open pleural biopsy.