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Dr. Mitrouska is Consultant in Pulmonary Medicine, University Hospital, and Dr. Bouros is Professor of Pneumonology, Medical School University of Crete, and University Hospital, Department of Pneumonology.
Correspondence to: Demosthenes Bouros, MD, FCCP, Professor of Pneumonology, University Hospital, Department of Pneumonology, Heraklion 71110, Crete, Greece;
At the end of 19th century, Starling and Tubby,1
in a landmark study, interpreted microvascular fluid and solute exchange as resulting from the balance between hydrostatic and colloidosmotic pressures, according to the following formula:
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D, P, and pi are filtration coefficient, surface area of the pleura, reflection coefficient for protein movement across the pleura (PL), hydrostatic pressure of the pulmonary capillary bed (CAP), and oncotic pressure of pleural space, respectively. Thirty years later, Neergard,2 using the Starling equation, offered an explanation for the pleural fluid turnover. He proposed a hypothesis claiming that pleural fluid filters at parietal pleura and is reabsorbed trough the visceral pleura. This hypothesis was further explored by Agostoni and Setnikar,3 who found that the difference between hydrostatic and colloidosmotic pressure in the pulmonary capillaries was large enough to account for the subatmospheric pressure of the pleural liquid. Based on the present state of knowledge, this old hypothesis is no longer valid. According to more recent data, the lung interstitium and the pleural space under physiologic conditions behave as functionally independent compartments due to the low water and solute permeability of the visceral pleura. Pleural fluid is produced at parietal pleural level, mainly in the less dependent region of the cavity. Reabsorption is accomplished by parietal pleural lymphatics in the most dependent part of the cavity, on the diaphragmatic surface and in the mediastinal regions.4
Although most pulmonary and cardiology textbooks claim that either right-sided or biventricular heart failure is necessary for the development of transudative pleural effusion, data suggest that pleural effusions in heart failure are more closely related to left than to right ventricular dysfunction and are mainly due to interstitial pulmonary edema.5 6 Pleural effusion secondary to congestive heart failure (CHF) may be bilateral (60 to 88%) or unilateral (right-sided effusions twice as common as left-sided effusions [8 to 28% vs 4 to 15%, respectively]), free flowing and, using Light’s criteria,7 usually transudative.8 9 10 There is a strong correlation between heart failure and pleural effusion; for this reason, the diagnostic thoracocentesis usually is not recommended. Indeed, in the presence of CHF, a thoracocentesis is recommended only if there is one of the following conditions: (1) the effusion is unilateral or is bilateral but not comparably sized, and (2) the patient has pleuritic chest pain or is febrile.11
Although it is a general belief that heart failure produces transudative pleural effusion based on Light’s criteria, recent data suggest that almost half of patients with heart failure, who underwent thoracocentesis for clinical indications, have exudate rather than transudate.12 13 The patient’s approach is different. If the fluid is transudate, therapy will be directed to the underlying CHF (or cirrhosis or nephrosis), but if the effusion is exudate further investigation is indicated.
What is the recommended diagnostic investigation if the patient has the clinical presentation of CHF but with exudative pleural effusion unilaterally or bilaterally? The clue for the answer is the medication that the patient is receiving and the number of thoracocenteses. Diuresis and to a smaller degree digitalis and/or afterload reduction can change the rules. In patients with CHF, diuretics move water through diffusion from the extravascular and the pleural space into the blood, leading to an increase in the protein and lactate dehydrogenase (LDH) concentration of the pleural fluid. However, the serum protein concentration increases but not as much as for pleuritic fluid, since the intravascular liquid is replaced from the extravascular space. Multiple thoracocentesis may also increase the pleural fluid LDH due to cell injury. Pleural fluid/plasma LDH ratio may be further increased because the improved liver function, as a result of improvement of cardiac function, decreases the LDH hepatic production.14 15
Are there criteria other than Light’s criteria separating with greater accuracy the transudates from exudates? Studies16 17 comparing the accuracy of Light’s criteria with cholesterol measurements, the bilirubin level, and the serum-effusion albumin gradient have shown a very high sensitivity of Light’s criteria (98%), a lower specificity (77% and 83%, respectively), and an overall accuracy almost 95%. The second best test was the serum-effusion albumin gradient, with a sensitivity of 87%, a specificity of 92%, and an overall accuracy of 89%.16 17 In a meta-analysis of eight primary studies, Heffner et al18 tried to find in 1,448 patients which of the above-mentioned tests has the better diagnostic accuracy. They found that all tests, except for bilirubin ratio, had similar diagnostic accuracies. Paired- and triplet-test combinations had higher diagnostic accuracy compared with individual tests.18 Cytokines, complement, and acute phase proteins have also been evaluated in distinguishing exudates from trans-udates in pleural effusions. Although of less diagnostic value than the classic criteria, they help to understand the pathogenesis of pleural effusions19 20 21 22
Recently, Romero-Candeira at al13 studied in 21 patients with CHF the influence of diuretics on the concentration of proteins and other components of pleural transudates. They found that furosemide, 40 to 80 mg/d, increased significantly the pleural concentration of most components from the initial to the final specimen. There was also an increase in the pleural fluid/serum ratio of albumin and LDH to the area of exudate. The authors concluded that calculation of the serum-pleural fluid gradients for protein and albumin may be the most useful way to distinguish transudates from exudates in patients with CHF who have undergone diuresis.
In this issue of the CHEST (see page 1518) Eid et al studied retrospectively the prevalence of exudative pleural effusion in patients with CHF. Their data are in accordance with previous studies demonstrating that almost half of the patients with CHF and pleural effusion have exudates. However, several points in this study should be taken into account: (1) From a total of 770 patients with CHF and pleural effusion, only 33% were included in the study. The remaining 77% had no thoracocentesis done, and for this reason there is no answer for the quality of the pleural fluid in the majority of patients with CHF. (2) With a more careful investigation, the vast majority of these patients (47%) had other causes explaining the exudative pleural effusion. (3) It seems that pleural fluid contamination by RBCs, due to lysis during thoracocentesis, plays an important role in the transformation of pleural fluid from transudate to exudate. (4) Patients with exudate who did or did not have cardiovascular surgery (coronary artery bypass graft surgery, etc) were treated with a dose of diuretics twice as often as patients with transudate.
Finally, facing a patient with exudate pleural effusion of unexplained cause on a background of typical clinical (increasing dyspnea on exertion, orthopnea, peripheral edema, distended neck veins, hepatojugular reflux, rales, and left-sided S3 gallop) and radiographic features of CHF or echocardiographic evidence of depressed left ventricular function, the physician has to decide if the exudate is attributed to diuretics or other causes should be considered. An exudate pleural effusion may be attributed to CHF if the following caveats are taken under consideration: (1) the patient is receiving diuretics; (2) the increase in the protein and LDH concentrations and their ratios is small and always with a decrease in the size of the pleural effusion; (3) when the exudate is based only on the increased LDH, the contamination of the pleural fluid by RBCs should be taken into account; a corrected LDH according to the proposal of Eid et al (corrected LDH = measured LDH - 0.0012 x RBC count/µL) is a useful tool; and (4) as a rule, when we calculate the pleural fluid components of a patient undergoing diuretic therapy, the calculation should include not only the Light’s criteria but the serum-pleural fluid albumin gradient as well; with a serum-pleural fluid gradient < 1.2 g/dL causes of pleural effusion other than CHF should be considered.
References
in the differentiation of exudates and transudates in pleural effusions. Anticancer Res 1999;19,3607-3612[ISI][Medline]
-2-macroglobulin, -1-acid glycoprotein, and C- reactive protein in pleural effusion differentiation. Respiration 2000;67,30-35[CrossRef][ISI][Medline]
, interleukin-6, and tumor necrosis factor in pleural effusions. Chest 2002;121,815-820
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