editorials VOLUME 102 I NUMBER 3 I SEPTEMBER, 1992
The Tip of the Thromboembolism Iceberg he article by Monreal et al in this issue (see page T 677) reminds us how much we have learned about
venous thromboembolism, as well as ho\v much we have yet to discover. Despite a serious effort to study 500 patients with thromboembolic disease using clinical information as well as both venography and ventilation-perfusion lung scan results, the study is a demonstration of how our understanding of this spectrum of elusive and dangerous conditions remains limited and how, even today, our clinical decisions have to be made in a setting of considerable uncertainty. This uncertainty stems from three major obstacles to the study of thromboembolism. First, deep venous thrombosis (DVf) is difficult to diagnose. It has been shown repeatedly that history and physical examination findings alone are inaccurate for DVT diagnosis. Contrast venography, the gold standard for OVT diagnosis, is accurate enough, but its routine use is restricted by its technical difficulty, potential for complications, and cost. Noninvasive alternatives to venography, primarily duplex ultrasound and impedance plethysmography, are widely available and are often performed before clinicians resort to venography. However, these tests are not useful in calf disease and, in the case of ultrasound, not effective for clot limited to the iliac vein. We have recently learned that the accuracy of these tests varies with the clinical situation. For example, in groups of hospitalized patients, the sensitivities of both ultrasound 1•2 and impedance plethysmographyt are lower than they are for outpatients with symptomatic OVT. Second, pulmonary embolism (PE), like DVT, is very difficult to diagnose clinically. Pulmonary arteriography, the gold standard for PE, has limitations similar to those of venography. Thanks to recent studies,4.5 we now have good information about ventilation-perfusion lung scans, the usual first step taken
by clinicians to diagnose PE. These results have confirmed the limitations of lung scans. For example, 31 percent' and 14 percent!) of patients with "lowprobability" lung scan interpretations had a PE according to pulmonary angiography, and 14 percent' and 13 percent!) of those with "high-probability" scans had normal angiograms. These findings mean that when we interPret research such as the study by Monreal et al we cannot assume that all patients with
lo\v-probability scans have not had PE and that all those \vith high-probability scans have had PE. Because the lung scan alone does not perform well enough to make the diagnosis of PE, clinicians must take into account clinical estimates of PE risk (prior probabilities) in interpreting scan results. 6 Third, it is difficult to assemble a thromboembolic disease "inception cohort." An inception cohort has been defined as "patients identified at an early and uniform point ('inception') in the course of their disease."; The study by Monreal et al documents well the importance of this problem. Almost half of the DVT patients with diagnostic lung scans had highprobability results; approximately half of those with high-probability scans had had no symptoms suggestive of PE. Thus, although this cohort was studied soon after hospital admission for symptomatic DVT (a . clinical inception cohort), Monreal et al have demonstrated that at presentation symptomatic DVT patients are already at many different stages in the natural history of thromboembolic disease. Recent thromboembolism research, rather than reassuring us that we are close to understanding the disease, instead has shown us that we have exposed only the tip of the thromboembolism iceberg. There is much more to learn about current and new diagnostic tests and strategies for DVf, H especially those that are noninvasive, cost-effective, and applicable to calf, chronic, and recurrent DVT. There is much to learn about PE diagnostic strategies, in particular for situations in which the clinical suspicion of PE is not congruent with the lung scan result. Additional studies about the natural history and treatment of thromboembolism should take into account that the usual methods of assembling patients find them at many different points in the course of the disease. As we gain greater understanding of how to overcome the obstacles to the study of this disorder, we will be better equipped to learn what lies beneath the surface of the water. John L Philbrick, M.D.; and Daniel M. Becker; M.D. CharloHesville, \tlrginia Department of Medicine, University ofVirginia School of Medicine.
REFERENCES 1 Pedersen OM, Aslaksen A, Vik-Mo II, Bassoe AM. COJlUlression ultras()no~raphy in hospitalized patients with suspect~~eep venous thromhosis [abstnlct]. Arch Intern ~ted 1991; 151:2217-20 2 \Vhite RH, Daschhach MM, Moehrin~ liD, Matthe\\'s JG. The CHEST I 102 I 3 I SEPTEMBER, 1992
657
accuracy of duplex color Row ultrasound in asymptomatic deep vein thrombosis (DVf). Clin Res 1992; 4O:565A 3 Agnelli G, Cosmi B, Ranucci ~ Renga C, Mosca S, Lupatelli L, et aI. Impedance plethysmography in the dia~osis of asymptomatic deep vein thrombosis in hip surgery: a venographycontrolled study. Arch Intern Med 1991; 151:2167-71 4 Hull RD, Hirsh J, Carter CJ, Raskob GE, Gill SJ, Jay RM, et al. Diagnostic value ofventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest 1985; 88:819-28 5 PIOPED investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990; 263:2753-59 6 Becker OM, Philbrick JT, Schoonover FW: Teates CD. Suspected pulmonary embolism and lung scan interpretation: trial of a Bayesian reporting method. J Gen Intern Med 1990; 5:285-91 7 Department of Clinical Epidemiolo~ and Biostatistics, McMaster University Health Sciences Centre. How to read clinical journals: III. To learn the clinical course and proWlosis ofdisease. CMA J 1981; 124:869-72 8 Hillner BE, Philbrick JT, Becker OM. The optimal management of suspected lower extremity deep vein thrombosis: an evaluation with cost assessment of 24 management strategies. Arch Intern Med 1992; 152:165-75
What Is the Origin of Pleural Transudates and Exudates? he classic teaching has been that pleural effusions T arise from the pleural capillaries. Transudates
were thought to result from an imbalance of the hydrostatic and osmotic forces in the pleural capillaries, leading to an increased flow of low-protein liquid into the pleural space, and exudates were thought to result from increased permeability of the capillaries in the pleura, leading to the accumulation of highprotein liquid in the pleural space. We now believe that this theory needs to be modified to include another common source of the liquid, namely: the interstitial space of the lungs. In recent experimental and clinical studies involving hydrostatic pulmonary edema, transudates have been shown to arise from the interstitial space of the lung. When sheep were volume-loaded to cause lung edema, transudative liquid flowed across the visceral pleura of the isolated in situ lungs. 1 The pleural fluid contained the same protein concentration as did the lung lymph and the interstitial edema liquid in the lung. The volume of pleural fluid constituted about 25 percent of all edema liquid formed in the lung. In other experiments with high-pressure pulmonary edema in sheep, pleural fluid accumulated only after the development of pulmonary edema. 2 In patients with congestive heart failure, the presence of pleural effusions on ultrasound correlated more closely with the pulmonary venous pressure than with the systemic venous pressure; the likelihood of pleural effusions increased with the severity of pulmonary edema on 658
chest radiographs. 3 Transudates associated with congestive heart failure therefore probably represent pulmonary edema liquid, and the pleural space may serve as another important route by \vhich edema liquid clears the lung. Exudates found in association with increased-permeability pulmonary edema probably also originate from the lung interstitium. When increased-permeability edema was induced in sheep by the infusion of oleic acid, pleural fluid accumulated only after pulmonary edema developed. 4 By morphologic study, there was no detectable injury to the visceral pleura. When pulmonary edema was induced by xylazine5 or hyperoxia6 in rats or by ethchlorvynol in sheep, 7 the investigators concluded that the high-protein pleural effusions arose from the parenchymal interstitial spaces of the lungs. By extension, we believe that when the lung is injured (eg, by pneumonia, pulmonary emboli, or lung transplantation), associated exudative pleural effusions probably also arise from the lung interstitium. Should we still classify pleural effusions as transudates or exudates? To this we answer an unequivocal yes! The classification of the fluid as a transudate or an exudate will still indicate whether the fluid results from increased hydrostatic pressure or decreased osmotic pressure or from increased permeability. This will be a useful distinction whether the fluid arises from the pleura, the peritoneum, or, as is commonly the case, the lungs. \( Courtney Broaddus, M.D. San Francisco; and Richard W Light, M.D., F.C.C.P. Wng Beach, California Dr Broaddus is Director, Medical ICU, San Francis(.'O General Hospital, and Assistant Professor of Medicine, University of California, San Francisco. Dr Light is Associate Chief of Staff for Research and Development, Veterans Administration Medical Center, Lon~ Beach, and Professor of Medicine, University of California, Irvine.
REFERENCES
1 Broaddus VC, Wiener-Kronish J~ Staub NC. Clearance of lung edema into the pleural space of volume-loaded anesthetized sheep. J Appl Physiol 1990; 68:2623-30 2 Allen S, Gabel J, Drake R. Left atrial hypertension causes pleural effusion formation in unanesthetized sheep. Am J Physiol 1989; 257(2 pt 2):H690-92 3 Wiener-Kronish J~ Matthay MA, Callen P\~ et al. Relationship of pleural effusions to pulmonary hemodynamics in patients with congestive heart failure. Am Rev Respir Dis 1985; 132:1253-56 4 Wiener-Kronish J~ Broaddus VC, Albertine KI-I, Gropper MA, Matthay MA, Staub NC. Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep. J Clin Invest 1988; 82:1422-29 5 Amouzadeh HR, Sangiah S, Qualls CW Jr, Cowell RL, Mauromoustakos A. Xylazine-induced pulmonary edema in rats. lbxicol Appl Pharma(.'()11991; 108:417-27 6 Bernaudin JF, Theven D, Pinchon MC, Brun-Pascaud M, Bellon Editorials
The Tip of the Thromboembolism Iceberg he article by Monreal et al in this issue (see page T 677) reminds us how much we have learned about
venous thromboembolism, as well as ho\v much we have yet to discover. Despite a serious effort to study 500 patients with thromboembolic disease using clinical information as well as both venography and ventilation-perfusion lung scan results, the study is a demonstration of how our understanding of this spectrum of elusive and dangerous conditions remains limited and how, even today, our clinical decisions have to be made in a setting of considerable uncertainty. This uncertainty stems from three major obstacles to the study of thromboembolism. First, deep venous thrombosis (DVf) is difficult to diagnose. It has been shown repeatedly that history and physical examination findings alone are inaccurate for DVT diagnosis. Contrast venography, the gold standard for OVT diagnosis, is accurate enough, but its routine use is restricted by its technical difficulty, potential for complications, and cost. Noninvasive alternatives to venography, primarily duplex ultrasound and impedance plethysmography, are widely available and are often performed before clinicians resort to venography. However, these tests are not useful in calf disease and, in the case of ultrasound, not effective for clot limited to the iliac vein. We have recently learned that the accuracy of these tests varies with the clinical situation. For example, in groups of hospitalized patients, the sensitivities of both ultrasound 1•2 and impedance plethysmographyt are lower than they are for outpatients with symptomatic OVT. Second, pulmonary embolism (PE), like DVT, is very difficult to diagnose clinically. Pulmonary arteriography, the gold standard for PE, has limitations similar to those of venography. Thanks to recent studies,4.5 we now have good information about ventilation-perfusion lung scans, the usual first step taken
by clinicians to diagnose PE. These results have confirmed the limitations of lung scans. For example, 31 percent' and 14 percent!) of patients with "lowprobability" lung scan interpretations had a PE according to pulmonary angiography, and 14 percent' and 13 percent!) of those with "high-probability" scans had normal angiograms. These findings mean that when we interPret research such as the study by Monreal et al we cannot assume that all patients with
lo\v-probability scans have not had PE and that all those \vith high-probability scans have had PE. Because the lung scan alone does not perform well enough to make the diagnosis of PE, clinicians must take into account clinical estimates of PE risk (prior probabilities) in interpreting scan results. 6 Third, it is difficult to assemble a thromboembolic disease "inception cohort." An inception cohort has been defined as "patients identified at an early and uniform point ('inception') in the course of their disease."; The study by Monreal et al documents well the importance of this problem. Almost half of the DVT patients with diagnostic lung scans had highprobability results; approximately half of those with high-probability scans had had no symptoms suggestive of PE. Thus, although this cohort was studied soon after hospital admission for symptomatic DVT (a . clinical inception cohort), Monreal et al have demonstrated that at presentation symptomatic DVT patients are already at many different stages in the natural history of thromboembolic disease. Recent thromboembolism research, rather than reassuring us that we are close to understanding the disease, instead has shown us that we have exposed only the tip of the thromboembolism iceberg. There is much more to learn about current and new diagnostic tests and strategies for DVf, H especially those that are noninvasive, cost-effective, and applicable to calf, chronic, and recurrent DVT. There is much to learn about PE diagnostic strategies, in particular for situations in which the clinical suspicion of PE is not congruent with the lung scan result. Additional studies about the natural history and treatment of thromboembolism should take into account that the usual methods of assembling patients find them at many different points in the course of the disease. As we gain greater understanding of how to overcome the obstacles to the study of this disorder, we will be better equipped to learn what lies beneath the surface of the water. John L Philbrick, M.D.; and Daniel M. Becker; M.D. CharloHesville, \tlrginia Department of Medicine, University ofVirginia School of Medicine.
REFERENCES 1 Pedersen OM, Aslaksen A, Vik-Mo II, Bassoe AM. COJlUlression ultras()no~raphy in hospitalized patients with suspect~~eep venous thromhosis [abstnlct]. Arch Intern ~ted 1991; 151:2217-20 2 \Vhite RH, Daschhach MM, Moehrin~ liD, Matthe\\'s JG. The CHEST I 102 I 3 I SEPTEMBER, 1992
657
accuracy of duplex color Row ultrasound in asymptomatic deep vein thrombosis (DVf). Clin Res 1992; 4O:565A 3 Agnelli G, Cosmi B, Ranucci ~ Renga C, Mosca S, Lupatelli L, et aI. Impedance plethysmography in the dia~osis of asymptomatic deep vein thrombosis in hip surgery: a venographycontrolled study. Arch Intern Med 1991; 151:2167-71 4 Hull RD, Hirsh J, Carter CJ, Raskob GE, Gill SJ, Jay RM, et al. Diagnostic value ofventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest 1985; 88:819-28 5 PIOPED investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990; 263:2753-59 6 Becker OM, Philbrick JT, Schoonover FW: Teates CD. Suspected pulmonary embolism and lung scan interpretation: trial of a Bayesian reporting method. J Gen Intern Med 1990; 5:285-91 7 Department of Clinical Epidemiolo~ and Biostatistics, McMaster University Health Sciences Centre. How to read clinical journals: III. To learn the clinical course and proWlosis ofdisease. CMA J 1981; 124:869-72 8 Hillner BE, Philbrick JT, Becker OM. The optimal management of suspected lower extremity deep vein thrombosis: an evaluation with cost assessment of 24 management strategies. Arch Intern Med 1992; 152:165-75
What Is the Origin of Pleural Transudates and Exudates? he classic teaching has been that pleural effusions T arise from the pleural capillaries. Transudates
were thought to result from an imbalance of the hydrostatic and osmotic forces in the pleural capillaries, leading to an increased flow of low-protein liquid into the pleural space, and exudates were thought to result from increased permeability of the capillaries in the pleura, leading to the accumulation of highprotein liquid in the pleural space. We now believe that this theory needs to be modified to include another common source of the liquid, namely: the interstitial space of the lungs. In recent experimental and clinical studies involving hydrostatic pulmonary edema, transudates have been shown to arise from the interstitial space of the lung. When sheep were volume-loaded to cause lung edema, transudative liquid flowed across the visceral pleura of the isolated in situ lungs. 1 The pleural fluid contained the same protein concentration as did the lung lymph and the interstitial edema liquid in the lung. The volume of pleural fluid constituted about 25 percent of all edema liquid formed in the lung. In other experiments with high-pressure pulmonary edema in sheep, pleural fluid accumulated only after the development of pulmonary edema. 2 In patients with congestive heart failure, the presence of pleural effusions on ultrasound correlated more closely with the pulmonary venous pressure than with the systemic venous pressure; the likelihood of pleural effusions increased with the severity of pulmonary edema on 658
chest radiographs. 3 Transudates associated with congestive heart failure therefore probably represent pulmonary edema liquid, and the pleural space may serve as another important route by \vhich edema liquid clears the lung. Exudates found in association with increased-permeability pulmonary edema probably also originate from the lung interstitium. When increased-permeability edema was induced in sheep by the infusion of oleic acid, pleural fluid accumulated only after pulmonary edema developed. 4 By morphologic study, there was no detectable injury to the visceral pleura. When pulmonary edema was induced by xylazine5 or hyperoxia6 in rats or by ethchlorvynol in sheep, 7 the investigators concluded that the high-protein pleural effusions arose from the parenchymal interstitial spaces of the lungs. By extension, we believe that when the lung is injured (eg, by pneumonia, pulmonary emboli, or lung transplantation), associated exudative pleural effusions probably also arise from the lung interstitium. Should we still classify pleural effusions as transudates or exudates? To this we answer an unequivocal yes! The classification of the fluid as a transudate or an exudate will still indicate whether the fluid results from increased hydrostatic pressure or decreased osmotic pressure or from increased permeability. This will be a useful distinction whether the fluid arises from the pleura, the peritoneum, or, as is commonly the case, the lungs. \( Courtney Broaddus, M.D. San Francisco; and Richard W Light, M.D., F.C.C.P. Wng Beach, California Dr Broaddus is Director, Medical ICU, San Francis(.'O General Hospital, and Assistant Professor of Medicine, University of California, San Francisco. Dr Light is Associate Chief of Staff for Research and Development, Veterans Administration Medical Center, Lon~ Beach, and Professor of Medicine, University of California, Irvine.
REFERENCES
1 Broaddus VC, Wiener-Kronish J~ Staub NC. Clearance of lung edema into the pleural space of volume-loaded anesthetized sheep. J Appl Physiol 1990; 68:2623-30 2 Allen S, Gabel J, Drake R. Left atrial hypertension causes pleural effusion formation in unanesthetized sheep. Am J Physiol 1989; 257(2 pt 2):H690-92 3 Wiener-Kronish J~ Matthay MA, Callen P\~ et al. Relationship of pleural effusions to pulmonary hemodynamics in patients with congestive heart failure. Am Rev Respir Dis 1985; 132:1253-56 4 Wiener-Kronish J~ Broaddus VC, Albertine KI-I, Gropper MA, Matthay MA, Staub NC. Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep. J Clin Invest 1988; 82:1422-29 5 Amouzadeh HR, Sangiah S, Qualls CW Jr, Cowell RL, Mauromoustakos A. Xylazine-induced pulmonary edema in rats. lbxicol Appl Pharma(.'()11991; 108:417-27 6 Bernaudin JF, Theven D, Pinchon MC, Brun-Pascaud M, Bellon Editorials
