Pleural Effusion

Pleural effusion results in ventilatory compromise by preventing pulmonary expansion in response to diaphragmatic and thoracic movements. With large amounts of effusion, diaphragmatic and thoracic movement may be severely limited. The etiology of the effusion, volume, and rate of accumulation determine clinical signs and severity of the ventilatory compromise. The impairment of pulmonary expansion results in decreased vital capacity and maximum tidal volume, inspiratory reserve volume, and functional residual capacity, or pulmonary volume at the end of exhalation [1]. Atelectasis results, which may further exacerbate ventilation and perfusion abnormalities. Supportive treatment for cases of pleural effusion often includes thoracocentesis, fluid therapy, nutritional support, and other treatments depending on the type and etiology of the effusion. Repeated drainage of pleural fluid may result in significant loss of fluid, protein, electrolytes, and perhaps lipid, vitamins, and white blood cells, which underscores the need for supportive and specific therapeutic measures.

An understanding of the etiologies and pathophysiologies of pleural effusion is therefore vital to the management of clinical cases. In this chapter we provide insight into the diagnosis and pathophysiology of the different types and causes of pleural effusion.

Normal Anatomy

The normal pleural space is lined by a single layer of mesothelial cells with an adjacent layer of elastic connective tissue containing vascular and lymphatic channels. The parietal pleura lines the thoracic wall, diaphragm, and mediastinum, and the visceral pleura lines the pulmonary surfaces including the interlobar fissures. The normal pleural space is occupied by a small amount (2-3 ml) of fluid that is low in both cell numbers (< 500 cells/ml) and protein (< 1.5 g/dl) [2]. The pleural fluid lubricates the surfaces of the lungs and surrounding structures as they move throughout the ventilatory cycle. The parietal pleura is supplied by the systemic circulation (intercostal, diaphragmatic, and pericardial arteries), and venous drainage is via the azygous and internal mammary veins. The visceral pleura is supplied by the lower pressure pulmonary circulation (pulmonary and bronchial arteries) and drains via the bronchial veins. Stomas between mesothelial cells of the parietal pleura increase in numbers ventrally along the thoracic wall and diaphragm, increasing the drainage of lymph from the parietal pleura [3]. The parietal pleural lymphatic drainage proceeds into the intercostal lymphatics and eventually into the thoracic duct [4].

The visceral pleural lymphatic drainage enters the peribronchial and interlobar lymphatics and into the thoracic and right lymphatic duct, which receives lymph from the lungs, heart, abdomen, mediastinum, and diaphragm. The diaphragmatic lymphatics allow some communication between the peritoneal and pleural cavities. The thoracic duct is the continuation of the cisterna chyli, located ventral to the first through fourth lumbar vertebrae, and carries lymph from the abdominal viscera and caudal half of the body. The duct travels dorsolaterally to the aorta on the right in the dog and on the left in the cat. The duct crosses to the left in the dog at the fifth or sixth thoracic vertebra and terminates in the left external jugular or jugulosubclavian angle in most members of both species.

Normal Physiology

Fluid production in the pleural space is based on Starling's law, primarily on hydrostatic and colloid osmotic pressure differences between the capillary and lymphatic beds of the parietal and visceral pleura. The following equation provides the determinants of pleural fluid dynamics, including vascular permeability [1]:

Movement of fluid =
K x ([HPc parietal – HPc visceral) – HPif] – [COPc – COPif])
Adjust the equation – there are an unequal number of open- and closed-parentheses
K = filtration coefficient (ml/sec/cm2/cm H20)
HP = hydrostatic pressure (cm H20)
c = capillary
if = interstitial fluid
COP = colloid osmotic pressure (cm H20)

General pressure gradients for fluid production and absorption are shown in Fig. 57-1. Because the systemic and pulmonary capillary hydrostatic pressures are greater than that of the pleural space, hydrostatic pressure favors fluid production. The gradient between the systemic circulation, or parietal pleura, and the pleural space is greater than that formed on the pulmonary side, or from the visceral pleura. Osmotic pressure of both the systemic and pulmonary vascular beds is greater than that of the fluid in the pleural space, favoring absorption of fluid across the parietal and visceral pleura. When the net hydrostatic and osmotic pressure gradients are added together, fluid tends to enter the pleural space from the parietal pleura and be absorbed by the visceral pleural lymphatics and capillaries. However, the parietal pleura contains many stomas, and parietal lymphatics may absorb fluid [5]. Absorption via parietal lymphatics is encouraged by the movement of the intercostal and diaphragmatic musculature and the lungs. Parietal lymphatics may play an important role in cases of pleural effusion in which pulmonary capillary absorption decreases or cannot maintain absorption in the face of high-volume effusion.

Figure 57.1. Forces and resultant gradients responsible for pleural fluid production and absorption. (Adapted from Pathophysiology in Small Animal Surgery, MJ Bojrab, Ed. Philadelphia: Lea & Febiger, 1981).

Pathophysiology

Abnormal fluid accumulation occurs upon alterations in hydrostatic pressure, osmotic pressure, vascular permeability, or with lymphatic dysfunction. Increased systemic hydrostatic pressure, as with right-sided congestive heart failure, may lead to increased fluid production. Decreased osmotic pressure, as in hypoalbuminemia, will affect fluid reabsorption in that the osmotic pressure of the vascular system is decreased, which decreases the gradient favoring fluid resorption by the parietal and visceral pleura. Inflammatory conditions of the pleural space lead to increased vascular permeability, increasing pleural fluid production. Concurrent vascular or lymphatic obstruction may alter hydrostatic pressures and lymphatic reabsorption of fluid. Lymphatic obstruction owing to reduction of flow or obstruction at the lymphaticovenous junction also decreases pleural fluid resorption and may lead to the leakage of fluid from the thoracic duct(s).

Other factors, such as trauma, neoplasia, or focal conditions may cause fluid accumulation by different forces. Generalized increases in hydrostatic pressure are not present, for example, in cases of lung lobe torsion, but a localized severe increase in hydrostatic pressure will cause fluid accumulation. Trauma to blood vessels or hemorrhage from abnormal blood vessels (e.g., neoplasia) leads to the accumulation of blood within the pleural space. Alterations in coagulation may also result in hemothorax from minimal trauma.

Types of Pleural Effusion

Pleural fluid is generally classified into three categories based on the protein concentration, cell count, and potentially the types of cells present and specific gravity of the fluid. Classification of the fluid is usually the first step in developing the definitive diagnosis of the condition. When the signalment, history, physical findings, and fluid type are combined with the laboratory classification of the fluid, the differential list is narrowed dramatically, and the etiology becomes apparent.

Laboratory classification of fluid includes transudate, modified transudate, and exudate. The protein content and cell count increase along the classification scheme. Some variation exists in the literature, but general divisions in protein content and cell numbers are listed in Table 57-1. The etiology of fluid accumulation is not included in this classification scheme. Further diagnostic testing may elucidate the cause of effusion and ultimately its diagnosis. Clinically useful classification of pleural fluid includes pure transudate, serosanguineous, sanguineous (or hemorrhagic), inflammatory, chylous, and neoplastic. Differentials for each type of effusion are listed in Table 57-2.

Pure Transudate

Pure transudates most often develop secondary to hypoproteinemia. Lack of serum protein, mainly albumin, results in decreased oncotic pressure of the vascular system. Lack of oncotic pressure results in increased fluid leakage (increased production) and decreased reabsorption, which causes fluid accumulation in the pleural space. Decreased protein production may be due to hepatic dysfunction, starvation, or severe nutritional deficiency. Significant protein loss may occur with conditions such as protein-losing enteropathy or nephropathy. Congestive heart failure may also result in production of a pure pleural transudate via increased hydrostatic pressure, but more often heart failure is associated with a modified transudate. Any chronic pure transudate may become modified over time; therefore, transudative etiologies must be considered in the diagnostic plan for a modified transudate.

Serosanguineous Effusion

Serosanguineous effusion most often is concurrently categorized as a modified transudate. Red blood cell numbers, and thus the hematocrit, of the fluid are far below that of the peripheral blood. Many conditions can result in serosanguineous effusion via different pathologic routes. Lung lobe torsion causes venous and lymphatic occlusion in the presence of intact arterial blood flow. This results in significant increased hydrostatic pressure and increased production of pleural fluid. Lymphatic absorption is concurrently decreased. The initial effusion associated with lung lobe torsion may be sanguineous; however, lung lobe torsion may be primary or secondary [5]. Suspension of pulmonary parenchyma in a pre-existing pleural effusion may predispose more mobile lung lobes, such as the right middle lobe or caudal lung lobes, to twist around their long axis [5]. Primary effusion, such as chylothorax, must be ruled out, as pneumolobectomy will not result in resolution of the effusion. Diaphragmatic hernia with hepatic entrapment may similarly cause venous and lymphatic obstruction. Fluid leaks from the congested hepatic parenchyma. Pericardial effusion resulting in cardiac tamponade and right-sided heart failure cause increased fluid production owing to increased vascular hydrostatic pressure. Neoplasia can result in a variety of effusions via lymphatic or vascular obstruction, decreasing serum protein concentrations, or by inciting inflammation. Diffuse neoplasia such as mesothelioma or carcinomatosis commonly results in serosanguineous effusion. Lastly, idiopathic pleuritis and pleural effusion has been diagnosed in both dogs and cats. It is most often associated with a modified transudate [6].

Sanguineous Effusion

Hemorrhage into the pleural space is commonly associated with trauma, which may be blunt, penetrating, or surgical. The packed cell volume of the blood in the effusion is similar to that of the periphery, but owing to rapid defibrination, it may not clot. The source of iatrogenic hemorrhage depends on the approach taken and the procedures performed. Intercostal, internal thoracic, pulmonary, pericardial, mediastinal, and cardiac vasculature are all possible sources. Intercostal vessels are at risk during lateral thoracotomy, which may also traumatize the internal thoracic vessels if extended ventrally on the thorax. The other vessels may be traumatized depending on the procedure done and the condition of the structures. Mediastinal vessels may be increased in size and number with inflammatory conditions of the thorax. Tumors within the chest can erode into vessels or adjacent tissue, leading to significant hemorrhage. Common tumors include chemodectoma, which may invade adjacent great vessels, and hemangiosarcoma of the right atrial appendage. Certain tumors (e.g., hemangiosarcoma) or diffuse neoplasia can be associated with disseminated intravascular coagulopathy and hemothorax.

Life-threatening hemorrhage of any etiology requires aggressive stabilization and potentially surgical intervention. Blood loss and atelectasis must both be considered prior to surgical intervention. Supportive care and stabilization are appropriate and may preclude surgery, allowing for reabsorption of blood from the pleural space. Autotransfusion may be considered as well, as contamination of the effusion with bacteria is rare. Neoplastic cells may be present in the transfusate, and the long-term prognosis should be considered in light of the need for autotransfusion. It is unlikely that the neoplastic cells in the transfusate will significantly decrease prognosis in a case of neoplasia-induced hemothorax [3].

Chylous Effusion

Chylothorax is usually grossly apparent, as the fluid is milky white or white with a pink hue. Chyle is classified as a modified transudate with protein values usually less than 4 g/dl, cell counts less than 7000/ml, and specific gravity less than 1.032 [2]. The cells may be predominantly lymphocytes, but with time non degenerate neutrophils may be more numerous. A definitive diagnosis is made by comparing serum triglyceride and cholesterol levels with those of the effusion. Triglyceride is higher and cholesterol lower in the fluid compared with serum levels. Pseudochylous effusion in which the cholesterol level is elevated compared with serum, triglyceride content is low, and chylomicrons are not present has been described in people but not in dogs or cats. Other diagnostic tests include staining chylomicrons in the fluid with Sudan black or performing an ether clearance test. Pleural fluid is placed into two tubes and both are alkalinized with potassium hydroxide. Ether is added to one tube and tap water to the other. The ether will cause clearance of the opacity, water will not.

Chylous effusion can result from any condition that increases hydrostatic pressure in the cranial vena cava; obstruction or relative obstruction of the lymphaticovenous junction leads to dilation and leakage from the thoracic lymphatics. Pulmonary lymphatics may also be a source of chylous effusion [7]. Blunt or penetrating trauma can cause chylothorax, but the thoracic duct is expected to heal spontaneously [8]. Other conditions associated with chylothorax are listed in Table 57-1. Specific conditions include cardiomyopathy, mediastinal masses (e.g., lymphosarcoma and thymoma), dirofilariasis, blastomycosis, jugular venous thrombosis, diaphragmatic hernia, pericardial effusion, congenital anomalies (e.g., tetralogy of Fallot, tricuspid dysplasia, cor triatriatum dexter, or a thoracic duct anomaly), and heart-based tumors. Despite the numerous conditions associated with chylothorax, the most common cause is idiopathic and is associated with thoracic lymphangiectasia. Afghan hounds and Siamese cats may be affected more often than other breeds, and lung lobe torsion may be associated with long-standing chylous effusion.

The etiology of the effusion is determined by performing thoracic radiographs after removal of the effusion to rule out mass lesions. Failure of the lungs to expand after therapeutic thoracocentesis suggests fibrosing pleuritis. Fibrin deposition on the visceral pleura occurs secondary to chronic inflammation, which causes mesothelial cell changes. Cellular changes include altered permeability, increased desquamation, and coagulation cascade activation.9 Increased collagen production and subsequent fibrosis with decreased fibrinolysis leads to constriction of the pulmonary parenchyma [9]. Decreased fibrinolysis may be a dilutional effect of the pleural fluid on plasminogen activator or may be due to alterations in mesothelial cell function [9].

Ultrasound of the chest requires some fluid to obtain an acoustic window to evaluate structures in the mediastinum; the heart and its function should also be examined. Routine blood work may show lymphopenia and hypoproteinemia secondary to loss into the effusion. Diagnostic testing should be complete before backing into the most frequently diagnosed etiology - idiopathic chylothorax. Cases of idiopathic chylothorax usually also undergo further imaging with lymphangiography, which is traditionally performed by catheterizing an intestinal lymphatic vessel. Water-soluble contrast is injected at a dose of 1 ml/kg diluted 1:1 in sterile saline. Thoracic radiographs are taken to identify the number and location of thoracic duct branches to be ligated. Post-ligation lymphangiography is used to confirm complete occlusion of all duct branches [10].

Inflammatory Effusion

Inflammation of the pleural space may or may not be associated with infection. Nonseptic effusions are usually associated with a much lower nucleated cell count than is septic inflammation ( [Table 57-1].). Lymphocytes, macrophages, and neutrophils may be present; degenerative changes of the neutrophils occur with septic inflammation. Septic exudate filling the pleural space is referred to as "pyothorax" or "thoracic empyema". Fluid accumulation secondary to inflammation is a result of increased production owing to vasodilation and increased vascular permeability. Decreased fluid reabsorption may also occur owing to increased oncotic pressure of the pleural space and thickening of the pleura as the condition becomes more chronic.

Nonseptic inflammation may be caused by infectious diseases (e.g., feline infectious peritonitis), chronic chylous effusion, diaphragmatic herniation of abdominal organs, neoplasia, or abdominal conditions such as pancreatitis. The inflammatory effusion associated with pancreatitis may be a result of the localized inflammation associated with the diaphragm and release of pancreatic enzymes known to cause localized fat necrosis and inflammation [3]. The exudate associated with feline infectious peritonitis is high in protein (5-12 g/dl) and specific gravity (> 1.017); the nucleated cells are usually non degenerate neutrophils, but with chronicity, macrophages, plasma cells, and lymphocytes appear [1]. Chronic diaphragmatic hernia, chronic chylothorax, and chronic lung lobe torsion may also cause nonseptic inflammation. Fungal and bacterial cultures should be pursued in any case of pleural exudation to rule out the possibility of an infectious process, even if organisms are not apparent on cytologic examination. Idiopathic pleural effusion has also been associated with exudative effusion [6].

Septic inflammation is primarily traumatic in origin. The route of bacterial access to the pleural space may be extension from any of the following: penetrating thoracic wall trauma, esophageal trauma or foreign body, tracheal trauma, foreign body inhalation and migration through the small airways or lung, caudal cervical trauma or infection leading to mediastinitis, repeated thoracocentesis, or cervical or thoracic surgery. Extension from a systemic infection, pneumonia, or rupture of a pulmonary abscess less commonly results in a septic pleural exudate. Both aerobic and anaerobic cultures should be performed on any pleural exudate. Exudates are most often polymicrobial, and anaerobes are common in polymicrobial pleural infection [11]. Special care should be taken to evaluate and culture for Actinomyces and Nocardia, which are frequently present in chronic septic exudates [12].

Neoplastic Effusion

Obstruction of vessels and lymphatics, inflammation, decreased serum albumin, and increased oncotic pressure within the pleural space may all contribute to fluid accumulation associated with a neoplastic condition within the pleural space. Specific tumor types erode vessels (e.g., hemangiosarcoma) to cause hemorrhagic effusion or may obstruct or erode into the thoracic duct (e.g., mediastinal neoplasia) to cause chylous effusion. Diffuse neoplasia may be primary, as with mesothelioma, or secondary, as in cases of carcinomatosis. Diffuse neoplasia usually results in the accumulation of a modified transudate; however, neoplastic cells are rarely identified within the fluid. Cytologic evaluation rarely provides the diagnosis of neoplasia, because reactive mesothelial cells display many characteristics of neoplasia, making the two cell types difficult to differentiate. The diagnosis may require more invasive techniques with tissue sampling for histopathologic examination.

Clinical Signs

Pleural fluid accumulation usually results in tachypnea owing to the lack of pulmonary expansion. The ventilatory pattern is referred to as "restrictive" and is characterized by rapid and shallow ventilation in an effort to maintain minute ventilation. The duration and rapidity of fluid accumulation will determine the severity of clinical signs. Animals with a small amount of effusion may be asymptomatic. Likewise, a slow accumulation of fluid allows the animal to compensate and adapt to the change in residual capacity until stressed by activity, increased ambient temperature, or anxiety. The rapid accumulation of a large volume of pleural fluid results in more severe signs such as an acute onset of tachypnea, dyspnea, and/or collapse. Cyanosis, orthopnea, and a distended thoracic cage may also occur with large volumes of pleural fluid. Other clinical signs accompanying pleural effusion include exercise intolerance, cough, lethargy, inappetance, reluctance to lie down, and weight loss. Additional clinical signs may depend on the etiology of the effusion.

Physical examination findings consistent with pleural effusion include a restrictive ventilatory pattern and diminished heart and lung sounds, especially ventrally. Bronchovesicular sounds may be increased dorsally. The chest may sound dull on percussion, or percussion may demonstrate a fluid line. Cats may exhibit apparent "breath holding" in which inspiration seems forced and exhalation is somewhat delayed. Fever may accompany exudative effusions, a heart murmur, jugular venous distention, hepatomegaly, ascites, or lymphadenopathy may be present depending on the primary disease process.

Conclusion

Noncardiogenic pleural effusions should be approached based on their type (transudate, modified transudate, etc.) and etiology. The forces resulting in the accumulation of fluid include decreased oncotic pressure, increased hydrostatic pressure, increased vascular permeability, abnormal lymphatic function or permeability, and relative lymphatic volume overload. These forces should be understood, as they are vital in the diagnosis of pleural effusion. Sampling of the pleural fluid provides the type of effusion, prompts further specific testing, and narrows the list of possible causes. Definitive diagnosis then allows for the development of therapeutic options and provides a prognosis for the patient.