Malignant Pleural Effusion

Single center experience on talc poudrage morbidity: focus on high talc dosage

Pleural Anatomy, Physiology, and Diagnostic Procedures

The pleural space is real, approximately 10 to 20 µm in width and situated between the mesothelium of the parietal and visceral pleurae. The parietal and visceral pleurae are continuous at the hilum, where they are penetrated by the pulmonary and bronchial vessels and the two main bronchi with their accompanying nerves and lymphatic vessels. The areas of the two pleural surfaces are approximately equal (2000 cm2 in a person weighing 70 kg) if the interlobar fissures of the visceral pleura and the costophrenic recesses of the parietal pleura are included. Both the visceral and parietal pleurae consist of a single layer of pleomorphic mesothelial cells, a basement membrane, and layers of collagen and elastic tissue in addition to the microvessels and lymphatics. The mesothelial cells vary in shape from flattened with an elongated nucleus and minimally discernible cytoplasm to cuboidal or columnar with a round nucleus and an indistinct luminal surface. Despite differences in morphology, mesothelial cells remain a single layer at all sites. Mesothelial cells vary in thickness from 1 to 4 µm and in surface diameter from 16 to 40 µm. Mesothelial cells contain surface microvilli that are approximately 0.1 µm in diameter and up to 3 µm in length. The density of microvilli is higher on the visceral than on the parietal mesothelial cells, possibly to trap hyaluronic acid-rich glycoprotein, particularly in the lower portion of the thorax, to decrease friction between the lung and chest wall. Openings between mesothelial cells, called stomata, range in size from 2 to 12 µm and are found only on the parietal pleural surface by scanning electron microscopy. These stomata communicate directly with lymphatic lacunae, the roofs of which contain bundles of collagen. Stomata are the usual exit point for pleural liquid, protein, and cells that are removed from the pleural space. In humans, the visceral pleura is supplied by branches of the bronchial circulation. The venous return from the subpleural capillaries drains largely into the pulmonary veins. The human parietal pleura is supplied by branches of the arteries that flow to the adjacent chest wall. The costal pleura is supplied by branches of the intercostal and internal mammary arteries; the mediastinal parietal pleura by branches of the bronchial and upper diaphragmatic, internal mammary, and mediastinal arteries; and the apical pleura by branches of the subclavian artery. The venous system of the parietal pleura drains into the bronchial veins. The diaphragmatic pleura is supplied by branches of the internal mammary artery, thoracic and abdominal aorta, and celiac arteries; drainage is into the inferior vena cava and brachiocephalic trunk. The lymph drainage of the pleural space has a major impact on the accumulation of pleural fluid in normal and disease states. Lymphatic drainage of the pleural space begins at the stomata that are located mainly in the mediastinum caudally and on the intercostal and diaphragmatic pleurae. The stomata connect with lymphatic lacunae situated immediately below the mesothelial layer and appear to be closed at their end by the endothelium of lymphatics to form valves. The lymphatic lacunae drain into larger lymphatic channels that course along the intercostal space and drain into the mediastinum. The origin of lymphatic vessels in the parietal pleura determines the node into which the fluid drains. The pleura of the anterior thoracic wall and anterior portion of the diaphragm drains to the sternal lymph nodes; the middle portion of the diaphragmatic pleura drains to the middle mediastinal lymph nodes; the anterior portion of the diaphragmatic and mediastinal pleura drains into the anterior mediastinal lymph nodes; the posterior portion of the diaphragmatic pleura drains to the posterior mediastinal lymph nodes; and the costal parietal pleura drains to the intercostal lymph nodes. The majority of the visceral pleura drains to the middle mediastinal lymph nodes, whereas the visceral pleural drainage of the lower lobes flows into the posterior mediastinal lymph nodes. Most of what is known about normal pleural fluid turnover is derived from noninvasive studies of pleural fluid formation in the sheep, an animal with a pleural anatomy similar to that of humans. The assumption is made that in the steady-state condition, pleural fluid absorption is equivalent to pleural fluid formation. The normal pleural fluid-to-plasma protein ratio is approximately 0.15, and the pleural fluid volume is about 0.1 to 0.2 mL/kg. Studies from sheep show that pleural fluid is formed at an hourly rate of 0.01 mL/kg, the equivalent of 0.6 mL/h in a 60-kg person. Pleural fluid is essentially an ultrafiltrate of the systemic pleural microvessels. Because the parietal pleural microvessels are closer to the pleural space than are the visceral pleural microvessels, the interstitial fluid in the parietal pleura moves between mesothelial cells into the pleural space along a pressure gradient; most or all of the interstitial liquid that moves out of the visceral pleural microvessels is removed by lung lymphatics because the fluid would have to travel a greater distance to enter the pleural space. Therefore, in normal humans, the parietal pleura is responsible for most or all pleural fluid formation. Pleural fluid exits the pleural space via the lymphatic stomata of the parietal pleura. Most pleural fluid exits the pleural space by bulk flow, not by diffusion. In addition to the pleural liquid being removed through the stomata, cells and protein exit by this route. The lymphatic flow from the pleural space is influenced by both the contractility of the lymph vessels and respiratory movements. The circulation of fluid in the pleural space enabling liquid to move into stomata may be driven by respiratory movements. The lymphatic drainage of the pleural space appears to have a large reserve, so that when an abnormal amount of pleural fluid accumulates in disease states, it must represent increased formation, decreased absorption, or both. Most probably both mechanisms contribute to pleural fluid formation. An increase in pleural fluid formation is unlikely to cause a pleural effusion clinically, as the pleural lymphatics have an extensive reserve to handle excess fluid formation. Furthermore, a decrease in pleural fluid absorption is unlikely to cause a pleural effusion clinically because the normal entry rate is slow. Mechanisms of increased formation of pleural fluid include the following: (1) an increase in microvascular pressure (as occurs in congestive heart failure); (2) a decrease in pleural pressure (as in atelectasis), which decreases the pressure surrounding the nearby microvessels and increases the gradient of pressures driving fluid across the microvascular barrier; and (3) a decrease in plasma oncotic pressure (as in hypoalbuminemia), which increases the forces for filtration until the balance is restored. When the lymphatic system is involved by disease at any point from the stomata of the parietal pleura to the mediastinal lymph nodes, a decrease in absorption rate can occur. Factors that may affect lymphatic flow include the following: (1) inhibition of lymphatic contractility during infiltration by malignancy or anatomic abnormalities (as in yellow nail syndrome); (2) limitation of respiratory movement (as in lung collapse); (3) blockage of lymphatic stoma by malignancy or fibrin; (4) acute increases in systemic venous pressure; and (5) decreased fluid availability to the stoma after pneumothorax. Pleural fluid can form when fluid moves across the diaphragm from the peritoneal cavity, either because of congenital diaphragmatic defects or by convection across the two mesothelial layers. Inflammation may also be a factor, as in acute pancreatitis and increased pleural capillary filtration. There is no evidence for the existence of direct lymphatic channels connecting the peritoneal and pleural spaces across the diaphragm. Lastly, mediastinal inflammation, as seen in esophageal sclerotherapy and esophageal perforation, can lead to a pleural effusion. When fluid from a pancreatic pseudocyst or rupture of the thoracic duct (chyle) collects in the mediastinum, a pleural effusion can form when the mediastinal pleura ruptures. The discovery of a pleural effusion provides an opportunity for the clinician to verify the disease, procedure, or drug that has caused the effusion. With a simple bedside procedure, thoracentesis, the fluid can be rapidly sampled and observed, its constituents observed microscopically, and its contents quantified. A comprehensive and systematic approach to analysis of pleural fluid in conjunction with the clinical presentation should allow the clinician to diagnose the cause of a pleural effusion in 75% of cases. A definitive diagnosis, such as the finding of malignant cells or specific organisms in pleural fluid, can be established in only one of four patients; however, a presumptive diagnosis, based on a clinical impression before thoracentesis, can be substantiated by pleural fluid analysis in an additional 50% of patients. Even with a nondiagnostic thoracentesis, pleural fluid analysis can be useful in excluding other possible causes of a pleural effusion, such as infection. Therefore, in three of four patients the cause of an effusion can be “diagnosed,” and in >90% of patients information relevant to clinical decision making can be gained by pleural fluid analysis. When a pleural effusion is suspected on physical examination and confirmed radiographically, a diagnostic thoracentesis should be performed in an attempt to establish the cause of the effusion. If the clinical diagnosis (e.g., uncomplicated congestive heart failure) is secure, it is reasonable to observe the patient's response to therapy and proceed with thoracentesis only when the clinical response is not appropriate. There are no absolute contraindications to diagnostic thoracentesis. Relative contraindications include a bleeding diathesis, anticoagulation, a small volume of pleural fluid, and mechanical ventilation. The needle should never be passed through an area of active skin infection. The patient on mechanical ventilation is not at increased risk for pneumothorax when undergoing thoracentesis, but tension pneumothorax is more likely to develop if the lung is punctured. Diagnostic thoracentesis should be a simple and rapid procedure for the operator and impose minimal discomfort on the patient. Patient anxiety can be minimized greatly if the procedure is explained completely at the time informed consent is obtained. It is rarely necessary to administer atropine, narcotics, or sedative drugs for a diagnostic thoracentesis. The selection of the site for thoracentesis is critical to a successful outcome. A chest radiograph should be available in the procedure room for review before site selection. The physical examination should dictate the precise placement of needle insertion. The site should be one to two interspaces below the level where the percussion note becomes flat and tactile fremitus decreases. With a free-flowing effusion, an area midway between the spine and the posterior axillary line should be selected, as the ribs are easily palpated in this location. When the interspace is selected, the needle should be passed over the superior surface of the rib to avoid possible laceration of the neurovascular bundle, which courses near the inferior rib margin. This is especially applicable in elderly patients, who tend to have tortuous intercostal arteries that may impinge on the intercostal space, so that the risk for laceration is increased. If the fluid is loculated or small, as demonstrated by decubitus radiographs, thoracentesis should be done under ultrasonic guidance. Thoracentesis should be performed with the patient positioned exactly as during ultrasonography. Good technique minimizes complications. The operator should maintain appropriate sterile technique and clean a wide area around the site selected for needle puncture. A 10% povidone-iodine solution decreases the usual cutaneous bacterial population by 85% for about 1 hour. The quaternary ammonium compounds, such as benzalkonium chloride, have a rapid onset of action, but their activity is antagonized by soaps and tissue constituents, and when these compounds are applied to the skin, they tend to form a film under which bacteria may remain viable. Furthermore, these compounds do not kill spores and require more than 5 minutes to decrease the bacterial population by 50%. The normal pleural space appears to have effective mechanisms for clearing bacteria; however, patients with severe pleural injury or immunosuppression probably are at increased risk for iatrogenic empyema if careful aseptic technique is not maintained. If the skin, periosteum of the rib, and parietal pleura are properly injected with lidocaine, the patient should have minimal pain, similar to the discomfort associated with venipuncture. When pleural fluid is obtained by aspirating with the syringe containing lidocaine, the syringe and needle should be withdrawn and a 22-gauge needle, 1 1/2 inches long and attached to a 50-mL syringe, should be used along the same tract to obtain fluid for diagnostic evaluation. One milliliter of heparin (1:1000) should be added to prevent clotting of the fluid. Occasionally the thoracentesis will be “dry.” This may result from the absence of pleural fluid, incorrect needle placement, or a needle of inappropriate length. If air is obtained in the syringe, the lung has been punctured because the needle was placed superiorly to the effusion. If no air, or possibly blood, is obtained, the needle may have been inserted too inferiorly or been too short for an obese patient. If there are no adverse consequences of this misadventure, then appropriate adjustment of the technique usually results in a successful procedure. A longer needle should be used in a patient who is markedly obese. Fifty milliliters of fluid is all that is necessary for complete pleural fluid analysis. The tests requested should be based on the clinical presentation. It is not clinically efficacious or cost-effective to request an entire battery of pleural fluid tests. It is probably cost-effective and clinically efficacious to order the following tests for all patients who undergo a diagnostic thoracentesis: total protein, lactate dehydrogenase (LDH), nucleated cell count and differential, and either a glucose or pH determination. Concomitant serum protein, LDH, and glucose levels should be measured; arterial pH should be measured if the pleural fluid pH is below 7.30 and acidemia is suspected. The aforementioned tests provide information that allows characterization of the fluid as a transudate or an exudate, narrows the differential diagnosis of an exudate, and indicates the degree of pleural inflammation and the acuteness of pleural injury. Gram, acid-fast bacilli (AFB), and potassium hydroxide (KOH) stains should be performed and pleural fluid cultured when infection is suspected. Pleural fluid cytology should be requested when malignancy is suspected or if an exudate is undiagnosed; lipid studies should be ordered when the fluid is milky, and immunologic studies should be performed if rheumatoid or lupus pleuritis is suspected. Amylase concentration should be measured when pancreatitis, pancreatic pseudocyst, esophageal rupture, or malignancy is considered. Complications of diagnostic thoracentesis include pain at the needle insertion site, bleeding (local, intrapleural, or intra-abdominal), pneumothorax, empyema, and spleen or liver puncture. Pneumothorax is the most common clinically important complication of diagnostic thoracentesis and has been reported to occur in up to 10% of patients. The rate of pneumothorax correlates indirectly with operator experience. However, the pneumothorax usually is small and often can be treated expectantly. Liver or spleen puncture tends to occur when the patient is not sitting absolutely upright, because movement toward a recumbent position causes cephalad migration of the abdominal viscera. However, even if the liver or spleen is punctured with a small-bore needle, generally the outcome is favorable if the patient is not receiving anticoagulants and does not have a bleeding diathesis. There are only a select number of diagnoses or causes of the effusion that can be established definitively by thoracentesis. These include malignancy, empyema, tuberculous pleurisy, fungal infection of the pleural space, lupus pleuritis, chylothorax, urinothorax, esophageal rupture, hemothorax, peritoneal dialysis, and extravascular migration of a central venous catheter (Table 1). Confirming the diagnosis of chylothorax does not establish the cause but provides evidence that the thoracic duct has been violated; lymphoma is the cause in >50% of cases. Esophageal rupture is the single entity associated with a pleural fluid having a high amylase concentration and a pH of <7.00. A pancreatic pleural effusion is associated with a high amylase concentration but the pH is virtually always >7.30. Some malignant pleural effusions have high amylase concentrations and the pH is >7.30 in two thirds of these patients; when the pH is low in malignant effusions, it rarely is <7.05. Empyema, tuberculous pleurisy, rheumatoid disease, and lupus pleuritis can all be associated with a low pleural fluid pH (<7.30), but the pleural fluid amylase concentration is less than the concomitant serum value. With extravascular migration of a central venous catheter, the resultant pleural effusion can be similar to the infusate and may be hemorrhagic and neutrophil-predominant because of trauma and inflammation. The pleural fluid-to-serum glucose ratio is >1.0; however, the pleural fluid glucose level is usually lower than that of the infusate, as glucose is transported rapidly from the pleural space.

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