127: Medical Management of Nonmalignant Pleural Effusions

Pleural effusions can occur as the consequence of a localized disease (exudative), or they can be a manifestation of systemic disease (transudative). They are fairly common, and chest physicians are often asked to diagnose and manage them. This chapter reviews the criteria for exudative and transudative pleural effusions, as well as the diagnostic techniques and medical management of several types of nonmalignant pleural effusions, including parapneumonic, connective tissue disease-related effusions, hepatic hydrothorax, and chylothorax. Therapeutic methods, including ultrasound-guided thoracentesis and the indications for chest tube drainage and pleuroscopy are discussed, as well as the use of thrombolytic therapy.

Four types of fluid can occupy the pleural space: serous fluid (hydrothorax), blood (hemothorax), lipid (chylothorax), and pus (empyema). Once the presence of a pleural effusion is established, it is important to determine whether it is a transudate or an exudate. A transudative pleural effusion indicates the presence of a systemic process, implicating organ systems other than the lung. This transudative pleural effusion is caused by medical conditions that lead to volume overload, such as renal failure, heart failure, and hypoalbuminemia (Table 127-1). In contrast, exudative pleural effusions indicate a local pleural process and necessitate a different treatment approach (Table 127-2). In 1972, Light defined the classic criteria for distinguishing between exudative and transudative pleural effusions.¹ To qualify as an exudate, the pleural effusion must meet one of the following criteria: pleural fluid lactate dehydrogenase (LDH) greater than 200 IU/L, ratio of pleural fluid LDH to serum LDH greater then 0.6, or a ratio of pleural fluid protein to serum protein greater than 0.5 (Table 127-3). These criteria have a high sensitivity and low specificity.

Chest Radiography

The chest radiograph is usually the first diagnostic tool used for assessing a pleural effusion. An effusion that causes blunting of the costophrenic angle in the posteroanterior view usually has a fluid volume of approximately 300 mL. In many cases, decubitus films are also obtained to assess whether the effusion is free flowing or is loculated. It is equally important to look for signs of mediastinal shift. An effusion usually shifts the mediastinum to the contralateral side. When the mediastinum is shifted to the ipsilateral side, other causes are implicated, including atelectasis of the underlying lung secondary to an endobronchial lesion, fixation of the mediastinum by fibrosis, or encasement of the lung by a peel.²

Other Imaging Modalities

CT scanning further enhances the abnormalities imaged by chest radiography. Most important, CT scanning differentiates between pulmonary parenchymal and pleural abnormalities. The importance and role of MRI in evaluating pleural effusions are yet to be elucidated.

Ultrasound

Ultrasound has a variety of therapeutic and diagnostic uses, including the ability to image the pleural space at the bedside. It is helpful for determining the presence, size, extent, and location of the pleural effusion. It also can suggest the presence of a complicated and loculated effusion. In complicated effusions, thin echogenic bands appear in the fluid. Ultrasound also can reveal pleural-based masses, which suggest a malignant cause. Therapeutically, ultrasound is used to direct pleural fluid aspiration under visual guidance. Ultrasound guidance decreases the incidence of pneumothorax in nonventilated and ventilated patients.

Thoracentesis

Diagnostic pleural aspiration is essential to the workup. Pleural effusions in patients with congestive heart failure are not usually aspirated; however, the presence of fever or an elevated white blood cell count justifies pleural fluid sampling by means of thoracentesis. The appearance of the thoracentesis sample suggests the etiology of the effusion. The sample is often bloody in patients with trauma, cancer, pulmonary embolism, or tuberculosis. It is milky white in patients with chylothorax and empyema. A yellow-green color suggests rheumatoid pleurisy, and food particles in the pleural fluid suggest esophageal rupture. Once obtained, the pleural fluid is sent for Gram stain and culture. In addition, cell count with differential, amylase, glucose, protein, LDH, pH, and albumin determinations should to be obtained. Despite all these tests, cultures of infected pleural fluid are still negative in 40% of cases. The presence of pus, organisms, or both on pleural fluid Gram stain indicates empyema and requires drainage of the pleural space. Pleural fluid pH less than 7.2 in the setting of infection also suggests a complicated effusion that should be drained.³ Reduced glucose (<35 mg/dL) and elevated LDH (>1000 IU/L) levels similarly support the diagnosis of a complicated effusion.

Before being considered for an elective thoracentesis, the patient must have an international normalization ratio of less than or equal to 1.5 and a platelet count of greater than or equal to 50,000 per microliter. The volume of fluid that can be aspirated safely at thoracentesis is still unknown. It is important to monitor pleural pressures as the fluid is being withdrawn and to stop drainage when the pleural pressure reaches –25 cm H₂O or if the patient complains of chest pain and discomfort because both are signs of lung entrapment. Whenever a thoracentesis is performed, however, it is important to withdraw as much fluid volume as is safely possible to avoid the necessity of a repeat procedure.

Relative contraindications to thoracentesis include a bleeding diathesis, anticoagulation, and a small pleural effusion that is difficult to tap. The most significant complication associated with the procedure is pneumothorax. Chest pain is common, occurring in up to 30% of patients, and may be a sign of an intrathoracic “vacuum” resulting from lung entrapment. Cough owing to lung expansion, hypoxemia owing to an increase in the ventilation/perfusion mismatch, vasovagal reactions, bleeding secondary to intercostal artery laceration, infection, and reexpansion pulmonary edema all have been reported as side effects and complications. A chest radiograph is not necessarily needed after a thoracentesis unless the patient is symptomatic but is essential if documentation of lung expansion is required.

Parapneumonic Effusions and Empyema

Definition/Natural History

Pneumonia accounts for up to 60% of pleural effusions. Most of these effusions are sterile, clear exudates that generally resolve with antibiotic treatment and rarely require tube drainage. Some (5%), however, are complicated with loculations and fibrin deposits. The fluid may be infected, as suggested by a low glucose, an elevated LDH, and a low pH. This stage of pneumonia is not thought to resolve with antibiotics alone and predisposes the patient to complications such as continued pleural sepsis and empyema.

Empyema progresses through three stages: exudative, fibrinopurulent, and organizing. In the exudative stage, the pleural fluid is nonviscous and freely flowing, with minimally inflamed pleural membranes, and the patient is likely to respond to antibiotics. The early fibrinopurulent stage is characterized by increasing viscosity of the fluid, thickening of the pleural membranes, and formations of intrapleural loculations. Patients may respond to antibiotic therapy alone but often require emptying of the pleural space. In the organized stage, more aggressive intervention is indicated, and on many occasions, the patient will require management for the pleural peel that has formed.

All patients with pleural infections should be treated with antibiotics. Depending on the clinical picture, anaerobic coverage is also included. Published guidelines are followed if the culture comes back negative.⁴ In designing a specific treatment plan, it is important to recognize that antibiotics penetrate the pleural space to varying degrees. As a rule, aminoglycosides usually are avoided because of their poor pleural space penetration and weak action in an acidic environment.

Drainage Methods

In 2000, a consensus statement was published by the American College of Chest Physicians.⁵ The statement proposed the following recommendations for drainage in the management of parapneumonic effusions:

1. Patients with category 1 and 2 effusions are at low risk for poor outcome and do not require drainage.

2. Drainage is recommended for the management of patients with category 3 and 4 parapneumonic effusions because of the increased risk for mortality and need for a second intervention.

3. Therapeutic thoracentesis or tube thoracostomy alone is insufficient for the management of patients with category 3 and 4 parapneumonic effusions.

4. Fibrinolysis and video-assisted thoracic surgery are acceptable approaches for these patients based on mortality and need for a second intervention.

Recurrent Nonmalignant Pleural Effusions

Data that would guide the use of pleurodesis in nonmalignant pleural effusions are scarce. There are no controlled trials comparing various agents and methods of pleurodesis in nonmalignant effusions. In two cohorts,^6,7 the authors studied the outcome of talc poudrage in patients with nonmalignant pleural effusions. Their success rate was 97% during a follow-up period of 1 to 84 months. Side effects included prolonged drainage (50%), reexpansion pulmonary edema (2%), and empyema (2%). Acute respiratory distress syndrome did not develop in any patient. From these limited data, it would appear that the success of pleurodesis in the management of nonmalignant pleural effusions is higher than one would expect. We do not recommend pleurodesis as a first-line treatment, but only after treatment of the causative disease has been fully maximized, if the patient is still experiencing symptoms attributable to the pleural effusion.

Immunologic and Connective Tissue Disorders

The effectiveness of steroid therapy in treating a variety of immunologic and connective tissue disease entities is well established. However, the data used to define the role of steroids in the management of connective tissue disease-related pleural effusions are limited to case reports and small series.

Rheumatoid Pleurisy

Pleural involvement in patients with rheumatoid arthritis is clinically evident in up to 5% of patients. These effusions are characterized by low glucose levels that develop within 5 years of articular manifestations. Once steroid treatment is instituted, the pleural effusion usually resolves within 3 to 4 months. Treatment can be systemic or intrapleural, and the response to therapy is independent of the articular inflammation. Half of these patients, unfortunately, will have a protracted course.

Lupus Pleuritis

Among the connective tissue disorders, systemic lupus erythematosis is the most common cause of pleuritis. Pleuritis in systemic lupus erythematosis presents more often in women than in men, with pleural effusions occurring in up to 30% of patients. The pleural symptoms may antedate other disease manifestations and can be bilateral, unilateral, or alternate from one side to the other. A 60- to 80-mg dose of prednisone daily produces positive results in patients with lupus-related pleural effusions.

Sarcoidosis

Pleural effusion is a rare complication of sarcoidosis. The natural history of sarcoidosis-related pleural effusions is variable; some resolve spontaneously, whereas others resolve with treatment within the same time frame. The approach to a sarcoidosis-related pleural effusion is individualized, and treatment is reserved for symptomatic patients. The dose of prednisone used is variable, ranging between 20 and 40 mg/day with a taper over 3 to 4 weeks.

Postcardiac Injury Syndrome

Postcardiac injury syndrome is an immunologic entity associated with a wide array of manifestations, including pericarditis, fever, leukocytosis, elevated sedimentation rate, pulmonary infiltrates, and pleural effusion. The syndrome can occur days, weeks, and even months after myocardial infarction, cardiac surgery, pacemaker placement, and angioplasty. It is seen more commonly after cardiac surgery, occurring in up to 30% of patients.⁸ The effusion is usually treated with antiinflammatory medication and exhibits a variable time course for adequate response. Nonresponders require steroids tapered over 3 to 4 weeks.

Hepatic Hydrothorax

Hepatic hydrothorax is the term for a pleural effusion arising in a patient with cirrhosis. It is usually the result of fluid transfer from the abdomen to the pleural space via defects in the diaphragm. Most often it is right-sided, and ascitic fluid can be absent in many patients. The first-line treatment is the administration of diuretics and sodium restriction. This treatment is given to counteract ascites caused by sodium retention in the kidney. An inappropriate increase in the dose of diuretics can precipitate hepatic encephalopathy in some of these patients, a severe and life-threatening complication. Common diuretics used include spironolactone and furosemide. If these treatment regimens fail, patients may benefit from a transjugular intrahepatic portosystemic shunt procedure. Thoracentesis is reserved for symptomatic patients and patients with fever, to rule out a spontaneous bacterial empyema. Tube thoracostomy with talc pleurodesis attempts have largely been unsuccessful. This therapy can result in prolonged chest tube drainage, excessive protein loss, renal failure, infection, and severe leak at the chest tube site. Treatment failures using this approach are probably secondary to the rapid formation of fluid in the pleural space, which prevents the formation of adhesions between the visceral and parietal pleura. Pleurodesis generally is not recommended for the medical management of hepatic hydrothorax. We have used indwelling drainage catheters in patients with needs for multiple thoracenteses with an overall good success rate. Patients with hepatic hydrothorax nonresponsive to diuretic treatment constitute a difficult population, and the treatment approach must be individualized.

Hemothorax

A hemothorax is defined as bleeding in the pleural space sufficient to raise the pleural space hematocrit to 50%. Independent of cause, large-tube drainage is the primary therapy because large volumes of blood in the pleural space rapidly form intrapleural loculations and increase the risk for empyema and fibrothorax. In some patients with retained intrapleural blood, fibrinolytic agents are instilled with good results.⁹ If performed early in the course of the injury, before pleural adhesions form, thoracoscopy can play an important role in the management of patients who sustain traumatic hemothorax complicated by major intrathoracic vessel injury and air leaks.

Chylothorax

Chylothorax, defined as the appearance of lymph and emulsified fat in the pleural effusion, is a rare cause of pleural effusion and is mostly owing to malignancy, thoracic surgical procedures, and chest trauma. A number of cases are associated with diseases such as lymphangioleiomyomatosis and lymphangiectasis. After the underlying cause is determined, specific treatment may be effective for managing the resulting chylothorax. The cornerstone of treatment involves nutritional intervention to prevent protein, vitamin, and lymphocyte loss. Success with a medium-chain triglyceride diet has been variable. Conservative management in a symptomatic patient involves drainage of the chylous effusion by thoracentesis or chest tube placement. Somatostatin has been used successfully in a few cases of chylous effusions refractory to chest tube drainage. Pleurodesis can be successful in the management of chylothoraces, especially if the rate of chyle flow is not high. In refractory cases, embolization and surgical interventions such as ligation, pleuroperitoneal shunting, and fibrin glue application are used.

Knowledge concerning vascular endothelial growth factor (VEGF) and its role in pleural effusions is accumulating rapidly. Evidence gleaned in vitro and in vivo supports the role of VEGF as a potent mediator in pleural fluid accumulation. VEGF is present in large quantities in human pleural effusions^10,11 and consistently higher in exudative than in transudative effusions. VEGF receptors are expressed in pleural tissues in both normal and diseased states.¹² In animal studies,¹³ pulmonary edema is induced successfully in mice by delivering VEGF DNA to the respiratory epithelium using an adenovirus vector. In parallel, these effects are abolished by pretreatment with an adenovirus vector expressing the truncated soluble form of the Flt-1 VEGF receptor. Current clinical trials using VEGF tyrosine kinase inhibitor are being conducted to evaluate its ability to prevent pleural effusion and ascites formation. Although all the in vivo studies evaluating the role of VEGF in effusion inhibition are currently being performed on patients with malignant disease, some in vitro evidence suggests that anti-VEGF antibodies decrease Staphylococcus aureus-induced mesothelial permeability. These findings are likely to be relevant to the future medical management of pleural effusions.

For the thoracic surgeon, a patient with bilateral pleural effusions has a medical problem – such as cardiac, renal, or hepatic dysfunction – until proved otherwise. Occasionally, patients with mediastinal lymphatic obstruction or pericardial restriction will develop bilateral pleural effusions and will benefit from an invasive procedure; but these unusual cases require careful assessment of heart, kidney, and liver function prior to any surgical intervention.