AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Pleural effusion is defined as the collection of at least 10-20 mL of fluid in the pleural space. Pleural effusion develops because of excessive filtration or defective absorption of accumulated fluid. Pleural effusion may be a primary manifestation or a secondary complication of many disorders.

Pathophysiology

The inner surface of the chest wall and the surface of the lungs are covered by the parietal and visceral pleural, respectively, with a potential space of 10-24 µm between the 2 pleural surfaces. This space is normally filled with a small amount of fluid. However, large amounts of fluid can accumulate in the pleural space under pathologic conditions. The parietal pleura have sensory innervation and small apertures that aid in the absorption of particles and fluid.

Systemic arterial vessels supply both pleural surfaces. Lymphatic vessels from the parietal pleura drain to lymph nodes along the anterior and posterior chest wall, whereas lymphatics from the visceral surface drain to the mediastinal lymph nodes. The pleural space normally contains 0.1-0.2 mL/kg of a colorless alkaline fluid, which has less than 1.5 g/dL of protein. The venous side drains approximately 90% of accumulated fluid in the pleural space, whereas lymphatics absorb the other 10%.

A delicate balance between the oncotic and hydrostatic pressures of the pleural space and the capillary intravascular compartments regulates filtration and drainage of pleural fluid. Hydrostatic and oncotic pressures are many times higher in the plasma than in the pleural space, but the net absorption of pleural fluid is slightly higher than the net filtration forces. In addition, lymphatic drainage from the parietal pleura can surpass the rate of fluid filtration in the pleural space by several fold.

Chest-wall and diaphragmatic movements enhance absorption of pleural fluid by the vascular and lymphatic vessels. Excessive filtration of fluid can overwhelm these efficient absorptive mechanisms and lead to the formation of pleural effusion.

Pleural effusions are usually classified as transudates and exudates. Diseases that affect the filtration of pleural fluid result in transudate formation, such as in congestive heart failure and nephrosis. Transudates usually occur bilaterally because of the systemic nature of the causative disorders. Inflammation or injury increases pleural membrane permeability to proteins and various types of cells and leads to the formation of exudative effusion.

Infectious effusions are usually unilateral. However, a recent large Turkish study revealed bilateral effusion in 5% of 515 children.

Frequency

United States

American and international frequencies are similar. The prevalence of pleural infections appears to be increasing in some developed countries; this could partly be due to increased referral of patients with these conditions to tertiary-care pediatric hospitals.

Byington and colleagues reported a significant increase in the incidence of empyema in children in Utah, from 1 case per 100,000 children to 14 cases per 100,000 children between 1993 and 2003.^{1, 2} 

International

Nonbacterial infectious agents, such as viruses and Mycoplasma pneumoniae, cause more pleural effusion in children than bacterial organisms. Although bacteria are more likely than viruses to cause effusion, viral infections in children occur more frequently than bacterial infections, explaining the observation above. As many as 20% of the viral infections can cause small and transient effusions that resolve spontaneously.

Several decades ago, pleural effusion was a complication in 70% of all cases of Staphylococcus aureus pneumonia, with positive cultures in 80% of pleural fluid specimens. In the late 1970s, pleural effusion occurred in 75% of cases of pneumonia secondary to Haemophilus influenzae type b.³ In a report by Murphy et al, empyema complicated the course of pneumonia in 9 of 21 patients with Streptococcus pneumoniae pneumonia.⁴ Chartrand and McCracken indicated that empyema complicated the course of pneumonia in 57 of 79 patients with S aureus infections.⁵

Pleural effusion occurs in 6-12% of all cases of pulmonary tuberculosis (TB) in children. Of 175 Spanish children with pulmonary TB, 39 (22.1%) had pleural effusion.⁶

Congenital effusions, including chylothorax, occur in 1 per 10,000-15,000 live births annually. In a review of 74 patients with intrathoracic lymphomas, Chaignaud et al found pleural effusions in 10 of 14 children (71%) with lymphoblastic lymphoma and in 7 of 60 children (12%) with non-Hodgkin lymphoma.

Mortality/Morbidity

• Most effusions caused by viral and mycoplasmal infections spontaneously resolve.
• Empyema has a complicated course if not treated early, especially in children younger than 2 years. Thirty years ago, the mortality rate from empyema was close to 100%. At present, the mortality rate from empyema is 6-12% in infants younger than 1 year.
• In a series of 74 children with pneumococcal empyema, 5% died, 5.5% had hemolytic uremic syndrome, 38% had bacteremia, and 51% were admitted to intensive care.⁷    
• Malignant effusion worsens the patient's prognosis depending on the underlying tumor.

Sex

Pleural effusions may be more common in boys than in girls.

CLINICAL

Section 3 of 11  

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History

The clinical picture and presenting symptoms depend on the underlying disease and the size of the effusion.

• Patients with parapneumonic effusion or empyema often have a history of a recent upper respiratory tract infection, bronchitis, or pneumonia.
• With antibiotics, most cases initially improve, then fever and chest pain recur.
• Pleurisy causes chest pain, tightness, and shortness of breath. Pain can be referred to the shoulder.
• Subpulmonic fluid collection can be associated with vomiting, abdominal pain, or abdominal distension caused by partial paralytic ileus.
• Patients with parapneumonic effusion and empyema usually present with chills, fever, anorexia, tachypnea, and sweating.
• An accumulation of a small amount of fluid may be asymptomatic.
• A large collection of fluid leads to dyspnea, respiratory distress, dull pain, and coughing. These symptoms may vary with an alteration in body position.
• Malignancy-related effusion often occurs after the diagnosis is established and can be associated with clinically significant and rapid weight loss.
• Although effusion occurs in association with systemic lupus erythematosus, it is rarely the initial manifestation. Inquire about any exposure to TB, recent trauma, surgery, and central-line placement.

Physical

• The patient may look dyspneic and anxious because of pain, discomfort, or hypoxemia.
• A pleural rub may be the only initial manifestation during the early stage of pleurisy. The rub disappears as fluid accumulates between the pleural surfaces.
• Dullness to percussion, decreased air entry, decreased tactile and vocal fremitus, and voice egophony over the effusion may be present but difficult to detect in younger children.
• A large fluid collection causes fullness of the intercostal spaces and diminished chest excursion on the affected side.
• Excessive unilateral fluid accumulation shifts the mediastinum and displaces the trachea and cardiac apex to the contralateral side.

Causes

In children, infection is the most common cause of pleural effusion. Congenital heart disease (CHD) constitutes the second most common etiology, followed by malignancy.

• In 1968, Wolfe reported 60 cases of empyema in 98 children with pleural effusion.⁸ Of the remaining 38 children, 34% had nonempyemic parapneumonic effusion, 26% had malignant effusion, and 16% had effusion caused by TB.
• In a Canadian study of 127 children with pleural effusion, Alkrinawi and Chernick reported the frequency of several types of effusions.⁹ About 50% of effusions were parapneumonic, 17% were caused by CHD, 10% by malignancy, 9% by renal disease, 7% by trauma, and 6% were associated with other causes.
• In another North American report of 210 children admitted with pleural effusion, Hardie et al showed that 68% of the effusions were parapneumonic (50 of 143 associated with empyema), 11% were caused by CHD, 5% were caused by malignancy, and 3% were associated with other causes.¹⁰
• The types of bacteria causing pleural effusions and their sensitivities to different antibiotics have changed over the years.
• • In the 1984 review by Freij et al of 227 cases of pediatric parapneumonic effusion and empyema, 76% had positive cultures.¹¹ S aureus accounted for 29% of cases, S pneumoniae accounted for 22% of cases, and Haemophilus species accounted for 18% of cases. Most of the cases due to H influenzae were due to type B.
  • In Brook's 1990 series of 72 patients with gross pus and positive cultures from empyema, careful anaerobic cultures were included.¹² A total of 93 organisms were isolated: 60 aerobic and 33 anaerobic. H influenzae, S pneumoniae, and S aureus were the predominant aerobic organisms found in association with pneumonia. Anaerobes, including Bacteroides and Fusobacterium species, were frequently found, particularly in empyema associated with aspiration pneumonia. Anaerobes were also found in empyema associated with intraoral and subdiaphragmatic abscesses.
  • In a series of 64 children with complicated parapneumonic effusions, 26 had positive cultures, 88% of which were due to S pneumoniae.¹³ About 26% of the S pneumoniae organisms were penicillin resistant. The decrease in complicated parapneumonic effusion caused by H influenzae is attributed to immunization. The authors speculate that the availability of broad-spectrum antibiotics effective against S aureus may account for the decrease in complicated parapneumonic effusion caused by this organism.
  • S pneumoniae is the most common organism that causes empyema in the developed countries such as the United States and the United Kingdom. S aureus is becoming a major infectious agent, especially during humid and hot seasons. Schultz et al reported a decrease in the prevalence of S pneumoniae since the use of pneumococcal conjugate vaccine and reported a predominance of S aureus, especially methicillin-resistant S aureus (MRSA), as the cause of empyema in a large children's hospital in the United States.¹⁴
  • Staphylococcus pyogenes can cause secondary pleural effusion and empyema in children with varicella infections.  
• Pleural effusion occurs in 8-22% of all cases of pulmonary TB in children. TB pleural effusion is usually unilateral and is associated with an underlying parenchymal disease in almost 60% of cases. According to Chiu, TB pleural effusion usually presents as an acute illness.¹⁵ The exudative effusion usually has a normal leukocyte count with a lymphocytic predominance. Sputum acid-fast bacillus (AFB) stain and culture seem more effective and sensitive, especially in children pulmonary involvement.
• Malignancy-related effusion is more often associated with lymphoblastic lymphoma than with Hodgkin disease.
• Congenital effusions, including chylothorax, occur in 1 per 10,000-15,000 births (see Media file 9).
• Congenital effusion can be associated with Down syndrome, diaphragmatic hernia, hydrops fetalis, polyhydramnios, and/or pulmonary hypoplasia.
• Chylothorax may be congenital or acquired.
• • Acquired chylothorax usually occurs after surgical trauma to the thoracic duct.
  • Obstruction, thrombosis, or high pressure in the superior vena cava caused by cardiac malformation or Fontan repair of various cardiac anomalies can also cause chylothorax.
• Unusual intrapleural fluid collections include fluids given by means of a central venous catheter that was inadvertently placed or that migrated to an intrathoracic location, as well as inadequate absorption of cerebrospinal fluid from a ventriculopleural shunt.
• Other rare causes of pediatric pleural effusion include rupture of a pulmonary hydatid cyst into the pleural space in association with Lemierre syndrome (postpharyngitis anaerobic sepsis with thrombophlebitis of the internal jugular vein).
• Hemothorax can occur as a result of trauma, malignancy, pulmonary infarction, and postpericardiotomy syndrome. Hemothorax has been reported from puncture of the pleura by a costal exostosis. Hemothorax should be suspected if pleural fluid hematocrit is more than 50% of peripheral blood hematocrit.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Chest mass
Pneumonia with pleurisy
Pleural thickening

WORKUP

Section 5 of 11  

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Lab Studies

• Initial studies
• • Initially obtain a CBC count, differential WBC count, and blood culture in a patient with a suspected pleural effusion.
  • Although nonspecific, the erythrocyte sedimentation rate (ESR) is often elevated in children with empyema and may be useful for comparison during follow-up.
  • However, these investigations, along with other acute-phase reactants such as ESR, C-reactive protein (CRP) levels, and procalcitonin levels, have not helped in differentiating bacterial from viral infections.
  • CRP levels tend to drop faster than the ESR and may be a good marker of adequate treatment. 
• Other studies: Studies helpful in interpreting results of pleural-fluid analysis (described below) include measurements of pH and/or serum glucose, lactate dehydrogenase (LDH), protein, triglycerides, and electrolyte levels.
• Serologic studies: These may be helpful if specific organisms, such as Mycoplasma species, Legionella species, or adenovirus, are suspected.
• Pleural-fluid analysis
• • Unless frank pus is obtained, fluid should be sent for Gram staining and culture; acid-fast staining and culture; cell counts; cytology; and determination of pH, protein, glucose, LDH, and triglyceride levels. Stains and cultures may be adequate studies if frank pus is collected.
  • Obtain pleural fluid hematocrit if hemothorax is suspected.
  • Counterimmunoelectrophoresis of urine and pleural fluid can help in identifying some common bacterial organisms when no pathogens are isolated.
  • Measurement of adenosine deaminase activity in the pleural fluid can be helpful if TB is suspected.
  • Pleural effusions are usually classified as transudates or exudates. Examination of the pleural fluid facilitates diagnosis, although criteria for distinguishing transudates and exudates, often called Light criteria, are based on studies in adults. Alkrinawi and Chernick have challenged the usefulness of these criteria, finding that 4-12 of 26 children with parapneumonic effusion had transudative instead of exudative biochemistries.¹⁶
  • • An exudate has one or more of the following characteristics: pleural protein–systemic protein ratio higher than 0.5, pleural LDH–systemic LDH ratio higher than 0.6, and pleural LDH higher than two thirds of the upper limit of the normal serum LDH value.
    • In general, exudates generally have protein concentration higher than 3 g/dL or a specific gravity of 1.020 on a refractometer.
    • In exudative effusion, the pleural glucose level is usually less than 60 mg/dL. A pleural glucose–serum glucose ratio less than 0.5 can be seen in several conditions, such as parapneumonic effusion, TB, malignancy, esophageal rupture, or rheumatoid effusions.
    • Arterial pH affects pleural pH. Simultaneous pH measurement may be needed to ensure that systemic acidosis is not the cause of low pleural pH. In measuring pleural pH, the fluid should be collected anaerobically in a heparinized syringe and transported on ice (which may keep the pH constant for 12 h if the temperature is kept at 0°C). Low fluid pH is usually associated with low glucose and high LDH levels, and any discrepancy in these measures may indicate laboratory error. Pleural fluid pH less than 7.2 is usually observed in exudative effusions, urinothorax, and systemic acidosis. A complicated parapneumonic effusion with a pH less than 7 is most likely to require chest-tube drainage, whereas an effusion with a pH of 7-7.2 may or may not need drainage. Production of ammonia by urea-splitting bacteria (eg, Proteus species) may increase and not decrease pleural fluid pH.
    • Exudates are caused by infection, pancreatitis (left-sided), systemic lupus erythematosus and other rheumatologic diseases, chylothorax, malignancy, or trauma. In chylothorax, the lipid level is typically 1-4 g/dL, but it may be lower in unfed patients, particularly newborns. Lymphocytes are the predominant cell.
    • Hemorrhagic effusion can be caused by malignancy, trauma, vascular erosion, or coagulopathy. In malignancy, cytologic studies may be diagnostic if results are positive, but negative cytology does not rule out malignancy. In a retrospective study, Chaignaud et al found that cytologic examination and immunotyping of the cells in the pleural fluid were diagnostic in 71% of children with lymphoblastic lymphoma, obviating general anesthesia and open biopsy of the mediastinal masses.¹⁷
    • A transudate has none of the chemical characteristics of an exudate. The protein concentration is usually less than 3 g/dL, pleural LDH is less than two thirds the upper level of normal serum LDH, and pleural protein and LDH concentrations and serum levels are less than 0.5 and less than 0.6, respectively. A pH of 7.45 or a pH higher than the patient's blood pH is consistent with transudative effusion.
    • Transudates are caused by congestive heart failure, hypoalbuminemia, nephrosis, hepatic cirrhosis, and iatrogenic causes (eg, misplaced central line, complication of ventriculopleural shunt).
• Pleural fluid cultures are usually negative because of the common practice of using antibiotics before fluid samples are cultured. For example, in a multicenter British study, only 17% of the cases had positive culture findings.
• New techniques, such as pneumococcal or broad-range 16S polymerase chain reaction (PCR), may be helpful in identifying possible infectious agents in culture-negative samples. In a study by Menezes-Martins et al (2005), PCR was compared with traditional bacterial fluid cultures in 37 children.¹⁸ PCR and bacterial cultures revealed a bacterial organism in 95.2% and 33.3% of the cases of complicated effusions, respectively. PCR revealed a bacterial agent in 31.3% of uncomplicated effusions. According to PCR results, most effusions were caused by MRSA and S pneumoniae.
• TB or malignancy may proportionally increase the number of lymphocytes in pleural fluid samples.

Imaging Studies

• Chest radiography
• • A chest radiograph may reveal underlying pneumonia before pleural fluid starts accumulating (see Media file 1). Most effusions are found on anteroposterior (AP) and lateral chest radiographs. On an upright image, and even on lateral decubitus images, the costophrenic angle is lost (see Media files 2-6).
  • As the size of the pleural effusion increases, the hemidiaphragm is obscured, and a mass effect with shift of the mediastinum away from the affected side is seen (see Media file 9). If an image is obtained with the patient supine, one may see only a nonspecific haze over the affected hemithorax, as the fluid layers in the posterior area.
  • To confirm that the fluid is free flowing, posteroanterior and lateral decubitus images obtained with the affected side down are often obtained (see Media files 7-8, 10-11). Conventional wisdom holds that, if a 10-mm layer of fluid is visible, sufficient fluid is present for thoracentesis to be successful. In large effusions, the affected side is opacified, and the decubitus image is not helpful (see Media file 9).
  • In adults, the minimum amount of fluid required before it is observed on an upright radiograph film is approximately 400 mL, whereas lateral decubitus images (obtained with the affected side down) may reveal as little as 50 mL of accumulated fluid.
  • A lateral decubitus image obtained with the affected side up may facilitate the evaluation of the underlying lung for atelectasis or infiltrates.
• Ultrasonography
• • Ultrasonography is effective for visualizing an effusion and determining if fluid is free flowing or loculated. It may also be used to guide thoracentesis (see Media files 12-13). Ultrasonography may also help in distinguishing a large solid chest mass from an effusion.
  • In a retrospective study, Ramnath et al suggested a beneficial role for early use of ultrasonography to identify effusions with evidence of organization.¹⁹ Patients with complicated effusions had significantly shortened hospital stays when aggressively treated with decortication rather than tube thoracostomy. Children who had no evidence of organization on chest ultrasonography and who were treated with intravenous (IV) antibiotics and thoracentesis or a chest tube had a hospitalization course similar to that of children who had comparable ultrasonography findings but who were treated aggressively with thoracoscopy or decortication.
  • In a series of 81 children with complicated parapneumonic effusion, Chiu et al used ultrasonography to monitor, classify, and guide the surgical intervention of these patients.¹⁵ The effusions were classified into 3 stages based on fibrin deposition and formation of fibrin septae. These fluid characteristics were used to guide the use of chest tube versus video-assisted thoracoscopic surgery (VATS). Early chest tube drainage of effusion with fibrin deposits eliminated the need for further surgical treatment, whereas initial use of VATS for effusion with fibrin septae lead to shortening of fever and hospital stay.  
• CT scanning
• • CT, especially contrast-enhanced CT, can provide additional information about the effusion and the pleural surfaces around it (see Media file 14).
  • In adults, parietal pleural thickening on a contrast-enhanced CT scan is a specific but nonsensitive indicator of an exudate.
  • Unless an underlying mass is a concern, chest CT scanning may not be necessary to diagnose a simple pleural effusion. However, it is useful in identifying purulent and loculated effusions.
  • Enhanced and nonenhanced chest CT scans are helpful in identifying underlying lung parenchymal conditions, necrotizing pneumonias, lung abscesses, and hilar lymphadenopathy (see Media file 14).
  • In addition, chest CT scanning (especially contrast-enhanced CT scanning) is valuable in making management decisions in cases of complicated effusions and in cases that do not respond to therapy.

Other Tests

• A purified protein derivative (PPD) test should be performed, particularly if risk factors for TB are present.
• Merino et al reported a sensitivity of 97.4% for TB pleural effusion in 39 children with a PPD induration of more than 5 mm.⁶

Procedures

• Thoracentesis
• • Thoracentesis is recommended for diagnosing most pleural effusions of sufficient size; however, prospective studies in children are lacking.
  • Thoracentesis is often not performed if the diagnosis is thought to be certain, and the likelihood of empyema or malignancy is low. Such circumstances include small bilateral infiltrates in congestive heart failure or nephrosis or a small parapneumonic effusion in an afebrile child recovering from pneumonia.
  • Thoracentesis should be performed when pleural effusion compromises the patient's respiratory status, in patients with empyema or malignancy, or in newborns.
• Pleural biopsy: This may be needed in cases of unexplained inflammatory effusion, suspected TB, or malignancy.

TREATMENT

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Medical Care

Treatment of the underlying disorder is generally all that is required for effusions caused by renal, cardiac, or rheumatologic diseases.

• Parapneumonic effusion usually progresses through 3 stages: exudative, fibrinopurulent, and organizational.²⁰
• • The exudative stage is associated with capillary leak during the first 3 days.
  • The fibrinopurulent stage is associated with bacterial invasion of the pleura at 3-7 days.
  • The organizational stage is characterized by fibroblast growth occurring at 2-3 weeks if the effusion is not treated properly.
• Parapneumonic effusion and empyema are initially treated with empiric antibiotics based on the patient's age and the organisms and sensitivities commonly present in the community. As stated above, the most common cause is S pneumoniae.
• • Antibiotics can be changed if a positive culture is obtained.
  • In a hospitalized patient with complicated parapneumonic effusion, antibiotics are administered IV while a thoracostomy tube is present until the patient is afebrile and clearly improving clinically. Oral (PO) antibiotics are frequently continued for weeks following these procedures.

Surgical Care

Prospective studies in pediatric parapneumonic effusion and empyema are lacking. Much of current practice is based on studies in adults and retrospective analysis of series of children. Technologic and pharmacologic advances have provided options and changes in approach. In the early exudative stage, thoracentesis and antibiotics may be effective.²¹

• Chest-tube placement is necessary to drain fluid causing respiratory distress.
• • Some clinicians believe that unorganized parapneumonic effusion or empyema can be treated with antibiotics alone, without chest-tube placement.
  • In the late 1960s, Walter et al reviewed their experience in treating 38 children with pleural effusion and 60 with empyema over 15 years. None of the patients with nonempyemic effusions required chest-tube drainage, and 13 of 60 patients with empyema needed only thoracentesis, without placement of a chest tube.
  • Murphy et al described 9 children with empyema secondary to S pneumoniae, and 3 of these patients had thoracentesis but did not require chest tubes.⁴
  • Redding et al treated 8 of 15 children with empyema without chest-tube drainage.²² The 7 patients who had chest-tube drainage had hospital stays and durations of parental antibiotic therapy longer than those of patients who did not have chest tubes.
  • Ginsburg et al reported that 49 of 65 children with H influenza pneumonia had pleural effusion.²³ Only 20 of the 49 children required chest-tube placement; 1 required open chest drainage, and the rest did not need chest-tube drainage.
  • Chan et al reviewed their experience of treating 47 children with empyema over 26 years in a Canadian institution.²⁴ The empyema was divided into acute, fibropurulent, and chronic effusions. Of the patients who had acute empyema, 3 out of 7 did well without chest-tube placement. Most of the 39 children with fibropurulent effusions were successfully treated with chest tubes, and only 7 required decortication for persistent loculation.
  • Criteria for chest-tube placement based on pleural fluid characteristics derive mainly from experience in adults and include the following:
  • • Frank pus on thoracentesis
    • Organisms seen on Gram stain
    • Pleural fluid pH less than 7 or glucose concentration less than 40 mg/dL.
  • As the effusion becomes fibrinopurulent and subsequently organizes, chest tubes often become ineffective because fibrinous strands and loculations divide the pleural space into compartments.
  • • Chest ultrasonography and CT scanning may demonstrate this process (see Media files 12-14).
    • To avoid or treat this condition, fibrinolytic agents have been instilled by means of the thoracostomy tube.
    • Streptokinase, urokinase, and alteplase have been safely used in children, with good results and without surgery in 90%.
    • Urokinase (10,000-100,000 units once or twice a day, based on the child's age) was used in 2 pediatric studies.²⁵
    • In a large double blind study in the UK, Maskell et al reported that use of intrapleural streptokinase did not improve mortality, the rate of surgery, or the length of the hospital stay.²⁶
    • Recombinant tissue plasminogen activator (tPA) may prove useful, but studies are lacking. Hawkins et al instilled tPA via chest tubes in 58 children with empyema.²⁷ Fifty four (93%) improved without further surgical intervention, 3 needed VATS, and one had open thoracotomy with decortication.
    • According to Ampofo, use of VATS in children with empyema in a tertiary pediatric care facility in Utah has decreased from 77% in the late 1990s to 20% in the early 2000s after implementing a protocol that combines early chest tube placement with tPA.⁷ 
    • Alteplase (0.1 mg/kg once a day) has been used.
    • Concerns about these agents (allergy [in the case of streptokinase], fever, bleeding, local discomfort, and possible transmission of viral agents from human neonatal kidney cells used to produce urokinase) have dampened enthusiasm for the use of these drugs.
• VATS allows visualization of the pleural space and is less invasive than open thoracotomy. VATS has made early surgical intervention more attractive than before.
• • In a retrospective analysis, early VATS in children decreased the number of procedures and hospital days compared with the previous practice of thoracentesis, fibrinolytic therapy, and failed thoracotomy or VATS.^{28, 29}
  • Several authors have reported that early VATS is safe and effective and that it shortens hospital stay in the management of empyema in children and adults.^{30, 31}
  • In a retrospective 10-year study, Padman et al reported their experience and clinical course of 109 children; 50 patients had VATS, and 59 did not.³² The use of VATS within 48 hours of admission lead to significant reduction of hospital stay by 4 days, compared with delayed use of VATS after 48 hours of admission.
• Gates et al reviewed the results of various therapeutic interventions for empyema, including chest-tube placement, fibrinolysis, VATS, and thoracotomy.³³ Early VATS or thoracotomy shortened hospital stay compared with other interventions. The use of antibiotics and duration of chest-tube placement was not correlated with any of the intervention methods.
• Open thoracotomy with lysis of adhesions should be reserved for late-manifesting or complicated cases of empyema, chronic empyema, and cases with severe pleural fibrous changes.
• Pleural biopsy may be needed in cases of unexplained inflammatory effusion, suspected TB, or malignancy.

Consultations

• Pediatric surgeon
• Pediatric pulmonologist
• Pediatric infectious disease specialist

Diet

A dietician should be consulted early in patients with chylothorax and in those with complicated pleural effusion and empyema, for whom the course may be prolonged.

• Chylothorax may respond to a diet with fat supplied as medium-chain triglycerides (MCT) with a resolution of the chylous effusion at the end of 2 weeks. MCT oil is absorbed directly into the portal circulation and does not contribute to chylomicron formation. Its use may decrease lymph flow as much as 10-fold.
• If chylothorax persists, a trial of IV alimentation for 4-5 weeks may be considered.
• Children with complicated pleural effusion and empyema may have clinically significant anorexia and increased needs. High-calorie high-protein foods that appeal to the child should be provided early, and nasogastric feeds should be considered early, particularly in young children.

Activity

• Pain and chest-tube placement may limit the patient's motility.
• Analgesia can facilitate cough and clearance of the airway, especially in the presence of an underlying pneumonic process.

MEDICATION

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Antibiotics are administered for parapneumonic effusions caused by aerobic and anaerobic organisms. Specific agents should be based on the patient's age and the types of organisms and sensitivities common in the community. Therefore, the list of antibiotics below is only a guide. More than 1 agent may be used for synergy and for polymicrobial infections. Antibiotics may be changed if the organisms and their sensitivities are identified. Initially administer antibiotics IV while a thoracostomy tube is present and until some arbitrary time after the child is afebrile and improving clinically; then, the IV drugs can be switched to PO medications for 1-3 weeks.

Empyema usually requires prolonged antimicrobial therapy.

Anti-TB drugs for TB-associated effusion should be administered for 6-9 months. Chemotherapeutic agents are used for malignancy. Steroids are indicated for connective-tissue disorders and may be useful for TB effusion.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Oxacillin (Bactocill, Prostaphlin)
Description	Bactericidal antibiotic that inhibits cell-wall synthesis. Used to treat infections caused by penicillinase-producing staphylococci. May be used to start therapy when a staphylococcal infection is suspected.
Adult Dose	500-1000 mg PO q4-6h 4-12 g/d IV/IM divided q6h
Pediatric Dose	50-100 mg/kg/d PO divided q6h 150-200 mg/kg/d IV/IM divided q6h
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of contraceptives and tetracycline; may increase levels of disulfiram and probenecid when administered concomitantly; effect of anticoagulants increase when large IV doses given
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in hypersensitivity to cephalosporins and in severe renal impairment

Drug Name	Vancomycin (Lyphocin, Vancocin, Vancoled)
Description	Can be used for MRSA and S pneumoniae. Potent antibiotic against gram-positive organisms and active against Enterococcus species. Indicated for patients who cannot receive or whose conditions fail to respond to penicillins and cephalosporins or those with infections with resistant staphylococci. To avoid toxicity, current recommendation is to assay vancomycin trough levels 30 min before fourth dose. Use creatinine clearance (CrCl) to adjust dose in renal impairment.
Adult Dose	500 mg to 2 g/d IV divided tid/qid
Pediatric Dose	40-45 mg/kg/d IV in divided doses q6h
Contraindications	Documented hypersensitivity; patients with previous hearing loss
Interactions	Erythema, histaminelike flushing and anaphylactic reactions may occur when administered with anesthetics; with concurrent aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced, when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal failure, neutropenia; red man syndrome caused by too-rapid IV infusion (dose given over few min) but rare when given IV over 2 h or as PO or IP; red man syndrome not an allergic reaction

Drug Name	Penicillin G (Pfizerpen)
Description	Used to treat S pneumoniae infection or anaerobic bacteria. Interferes with synthesis of cell-wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	2-24 million U/d IV divided q4-6h
Pediatric Dose	250,000-400,000 U/d or 150-240 mg/kg/d IV divided q4-6h
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in impaired renal function; possible cross-allergy to cephalosporins

Drug Name	Cefotaxime (Claforan)
Description	Third-generation cephalosporin. Can be used for S pneumoniae or H influenzae infection. Arrests bacterial cell-wall synthesis, which inhibits bacterial growth.
Adult Dose	Moderate-to-severe infections: 1-2 g IV/IM q6-8h Life-threatening infections: 1-2 g IV/IM q4h
Pediatric Dose	Infants and children: 50-180 mg/kg/d IV/IM divided q4-6h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in history of renal impairment and colitis

Drug Name	Ceftriaxone (Rocephin)
Description	Third-generation cephalosporin; can be used for S pneumoniae or H influenzae. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Adult Dose	1-2 g IV q12-24h
Pediatric Dose	Neonates >7 days: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/d Infants and children: 50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; hyperbilirubinemic neonates, especially prematurely born neonates
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and in allergy to penicillin

Drug Name	Clindamycin (Cleocin)
Description	Can be used for S pneumoniae infection, anaerobes, and as alternative drug for MRSA. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer RNA (tRNA) from ribosomes causing RNA-dependent protein synthesis to arrest.
Adult Dose	150-450 mg/dose PO q6-8h; not to exceed 1.8 g/d 600-1200 mg/d IV/IM divided q6-8h, depending on degree of infection
Pediatric Dose	25-40 mg/kg/d IV divided q6-8h 8-20 mg/kg/d PO as hydrochloride or 8-25 mg/kg/d PO as palmitate divided tid/qid
Contraindications	Documented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade, induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Drug Category: Antituberculous Drugs

For treatment of drug-susceptible TB infection. Recent recommendations include 6-9 months of therapy. Six-month regimen includes 2 months of isoniazid (INH), rifampin, and pyrazinamide once per day followed by 4 months of INH and rifampin daily or 2 months of INH, rifampin, and pyrazinamide daily, followed by 4 months of INH and rifampin twice a week under directly observed therapy (DOT). For drug-resistant TB, initial treatment should include 4 drugs until susceptibility is determined. Therapy should last 12-18 months.

Drug Name	Rifampin (Rifadin, Rimactane)
Description	For use in combination with at least one other anti-TB drug. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Cross-resistance may occur. Treat 6-9 mo or until 6 mo have elapsed from conversion to negative sputum cultures.
Adult Dose	600 mg/d PO
Pediatric Dose	10-20 mg/kg/d PO; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin Blood pressure may increase with coadministration of enalapril; coadministration with INH may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if liver function test [LFT] results altered)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Orange discoloration of urine and other secretions; obtain CBC counts and baseline clinical chemistries before and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interrupted and high-dose intermittent therapy associated with thrombocytopenia (reversible if therapy discontinued as soon as purpura occurs); if treatment continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Pyrazinamide
Description	Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against Mycobacterium tuberculosis, depending on concentration of drug attained at site of infection; mechanism of action unknown. Administer for initial 2 mo of 6-mo or longer regimen for drug-susceptible cases. Treat drug-resistant cases with individualized regimens.
Adult Dose	15-30 mg/kg PO qd; not to exceed 2 g/d DOT: 50-70 mg/kg PO 2 times/wk; not to exceed 4 g/d or 50-70 mg/kg 3 times/wk; not to exceed 3 g/d
Pediatric Dose	20-40 mg/kg/d PO Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic damage, acute gout
Interactions	May decrease serum INH levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hepatotoxic effects and hyperuricemia; use only in combination with other effective anti-TB agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline determinations of serum uric acid levels; discontinue if signs of hyperuricemia with acute gouty arthritis; perform baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus

Drug Name	Streptomycin
Description	For treatment of susceptible mycobacterial infections. Use in combination with other anti-TB drugs (eg, INH, ethambutol, rifampin). The drug available in the US from X-Gen Pharmaceuticals 866-390-4411 via several wholesalers. For more information see the X-Gen Web site.
Adult Dose	2 times/wk dosing: 15 mg/kg/d IM; not to exceed 1 g/d 3 times/wk dosing: 25-30 mg/kg/d IM; not to exceed 1.5 g/d
Pediatric Dose	2 times/wk dosing: 20-40 mg/kg/d IM; not to exceed 1 g/d 3 times/wk dosing: Administer as in adults
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics; can potentiate neuromuscular blockade of succinylcholine
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Narrow therapeutic index; not intended for long-term therapy; caution in patients with renal failure not receiving dialysis; caution in myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Drug Category: Corticosteroids

These drugs may increase absorption of the pleural effusion.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Follow-up is required, especially in complicated cases, to assess for evidence or progression of pleural fibrosis.
• Children should be examined within 2-4 weeks after discharge, depending on the patient's clinical status, the severity of the effusion, and the use of outpatient IV antibiotics.

Further Outpatient Care

• Some experts recommend serial chest radiography to ensure clearing.
• Some perform CT scanning after the plain radiographs clear.

Deterrence/Prevention

• Tests may need to be ordered to rule out immune dysfunction or other underlying systemic or local pulmonary disorders that cause empyema.

Complications

• Complications are uncommon in properly treated parapneumonic effusions.
• Possible complications include respiratory failure caused by massive fluid accumulation, septicemia, bronchopleural fistula, pneumothorax, or pleural thickening.

Prognosis

• Most viral and mycoplasmal effusions spontaneously resolve.
• Empyema has a complicated course if not treated and drained early, especially in children younger than 2 years. Thirty years ago, the mortality rate from empyema was 100%. At present, the mortality rate from empyema is 6-12% in infants younger than 1 year.
• Most TB effusions completely resolve with the use of proper anti-TB agents.
• Malignant effusion worsens the prognosis, depending on the underlying tumor.
• Most patients recover well after parapneumonic effusion or empyema if appropriately treated.
• • Follow-up studies of children who have recovered from empyema are sparse but the data are encouraging.
  • Most children had complete clinical recovery with no residual radiologic or lung function changes.
  • Most children return to normal health by 4 weeks, and their chest radiographs return to normal by 3-6 months.
• McLaughlin et al evaluated the outcome of 16 children with pleural effusion over 11 years.³⁴
• • Fourteen patients had chest-tube drainage, and limited thoracotomy was performed in 5 of 16 patients.
  • Thirteen children were monitored for a mean of 66 months after their discharge from the hospital (range, 5-150 mo), and 3 children underwent chest radiography at 1, 2, and 3 months after discharge. Eight children had normal chest radiographs at follow-up visits, 7 had slight pleural thickening, and 1 had moderate pleural thickening 7 months after discharge.
  • No correlation between lung volumes and chest radiographic changes were observed in 5 patients who had a total lung capacity of less than 89% of the predicted value.
• Murphy et al reported the results of follow-up chest radiographs obtained 1 month to 7 years after discharge in 8 of 9 children with pneumococcal empyema.⁴ Radiologic improvement was usually not apparent for 1-2 weeks after the start of treatment. However, 6 patients had normal follow-up radiographs, and only 2 had minimal residual parenchymal or pleural thickening.
• The same article by Murphy et al reported follow-up pulmonary function results performed in 5 of 9 patients who had pneumococcal empyema. Four of the 5 patients had some increase in their residual volume with no other evidence of obstructive lung disease or impaired long-term performance.
• Redding et al described 15 children who underwent pulmonary function testing 2 years after developing empyema.²² No evidence of restriction was found, and only 7 children had mild obstruction. Most importantly, none reported reduced exercise tolerance. They observed no difference between children treated with and those treated without surgery.

Patient Education

• For excellent patient education resources, visit eMedicine's Lung and Airway Center. Also, see eMedicine's patient education article Pleurisy.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Lack of early diagnosis and drainage of empyema, especially in young children
• Failure to recognize pneumothorax after thoracentesis
• Development of constrictive pleural fibrosis in inadequately treated infectious or hemorrhagic effusions

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Upright chest radiograph in a 3-year-old child with dyspnea and fever obtained one day before the development of the pleural effusion reveals pneumonia on the left side.
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Media type:  Radiograph

Media file 2:  Upright chest radiograph in a 3-year-old child with dyspnea and fever (same patient as in Media file 1) reveals a large opacity on the left, with obliteration of the left costophrenic angle and a fluid stripe. These findings indicate a pleural effusion.
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Media type:  Radiograph

Media file 3:  Left lateral decubitus image in a 3-year-old child with dyspnea and fever (same patient as in Media files 1-2) reveals minimal layering of the fluid, which indicates a loculated effusion.
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Media type:  Radiograph

Media file 4:  Upright posterior anterior chest radiograph of a child with a right-sided pleural effusion.
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Media type:  Radiograph

Media file 5:  Lateral view in a child with right-sided pleural effusion (same patient as in Media file 4) reveals a pleural effusion and a fluid level.
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Media type:  Radiograph

Media file 6:  Right lateral decubitus radiograph in a child with a right-sided pleural effusion (same patient as in Media files 4-5). Image reveals partial layering of the fluid in the right side.
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Media type:  Radiograph

Media file 7:  Posteroanterior view in a patient with reaccumulated pleural effusion in the left side of the chest.
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Media type:  Radiograph

Media file 8:  Left lateral view in a patient with reaccumulated pleural effusion on the left side of the chest (same patient as in Media file 7) reveals layering of the effusion.
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Media type:  Radiograph

Media file 9:  Anteroposterior view of the chest reveals a large chylothorax on the right side of the chest in a neonate.
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Media type:  Radiograph

Media file 10:  Anteroposterior view in a neonate after birth (same infant as in Media file 9) reveals reaccumulation of the chylothorax in the right hemithorax after a chest tube was removed.
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Media type:  Radiograph

Media file 11:  Right lateral decubitus radiograph in a neonate (same patient as in Media files 9-10) reveals layering of the chylothorax effusion after a chest tube was removed.
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Media type:  Radiograph

Media file 12:  Ultrasonogram of the pleural effusion in a 3-year-old child with dyspnea and fever (same patient as in Media files 1-3) reveals many septa (arrowheads) and several large, loculated portions of fluid (arrows).
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Media type:  Ultrasound

Media file 13:  Ultrasonogram of the effusion in a 3-year-old child with dyspnea and fever (same patient as in Media files 1-3) reveals several fluid loculations (arrows) separated by septa (arrowheads). The lung is seen under the effusion.
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