http://www.interna.fk.ui.ac.id/ami-online/ami3302/Review_article2.

htm

Thoracic Empyema
Alfian Nurbi, Asril Bahar Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia

Abstract
There have been many developments in the management of thoracic empyema that complicates pneumonia. Delayed management disturbs and prolongs the healing process. Several controlled studies suspect that early intervention is associated with more successful management compared to more conservative treatment methods.

Introduction
Despite the availability of many potent antibiotics, bacterial pneumonia still has a high mortality and morbidity rates in the United States. The incidence of bacterial pneumonia reaches 4 million every year, and 20% of that number is estimated to require hospitalization. Twenty to forty percent of hospitalized pneumonia patients suffer from pleural effusion as a complication.1,2 The mortality and morbidity rate of pneumonia complicated by pleural effusion is higher than that for uncomplicated pneumonia.1 Without adequate antibiotics, pleural effusion could advance into complicated effusions. When pus ensues, the condition is then called empyema. 2 Effusion due to pneumonia usually improves without special treatment, and only 10% require surgical intervention.1,2 The best diagnostic approach and treatment is still controversial due to prospective researches. 8 This article will try to depict the etiology, microorganism pattern, diagnostic approach, and several management approaches that are currently being developed.

History
Empyema has been acknowledged as a serious problem for centuries. Approximately 500 year B.C., Hippocrates introduced the open drainage method for empyema management. Until the 19th century, the principle for empyema management had remained the same. Then, Bowditch from the United States and Trousseau from France popularized the use of thoracocenthesis. In 1876, Hewitt introduced the closed drainage method, and was the first person to use the water-sealed drain (WSD). 1 In the year 1890, two articles suggested thoracoplasty and decortication for the management of empyema. In the year 1923, Egger reported a study on 99 patients treated with decortication, demonstrating improvement in two thirds of the patients. During World War I, open drainage was the treatment of choice. 1

Definition
Parapneumonial effusion is pleural effusion associated with bacterial pneumonia, lung abscess, or bronchiectasis. Empyema is defined as the presence of pus in the pleural cavity. Vianna defined empyema as pleural effusion with positive bacterial culture or a leukocyte count of over 15,000/mm3 and a protein level of more than 3.0 g/dl. Empyema sometimes occurs without being preceded by pneumonia (see Table 1). Parapneumonial effusion is classified into uncomplicated effusion, where the fluid in the pleural cavity could be treated solely by the use of antibiotics, and complicated effusion, which requires drainage. 1

Pathophysiology
The process of parapneumonial effusion could be classified into 3 stages. The first stage is the exudative stage, where there is an increase in sterile pleural fluid, probably caused by increased visceral pleural capillaries due to increased permeability. There is serous liquid, leukocytes, LDH, low glucose level and normal pH. With the use of the right antibiotics, we could inhibit the progression of pleural effusion, and a WSD should not be needed. 1,2 This brief exudative phase may only last 48 hours.3 With inadequate use of antibiotics, bacteria could enter the pleural fluid from the pneumonia. The process would advance to the second of stage II, so called the fibrinopurulent stage, marked by a more cloudy and viscous pleural fluid containing more polymorphonuclear leukocytes, bacteria, and cellular debris. The collection of the three would produce fibrin on the surface of the visceral and parietal pleura, which in turn causes the pleura to lose its elasticity.1,2 During this stage, loci are often created. The loci inhibit empyema, but they also make future draining of the pleural fluid difficult. During this stage, the pH and glucose level of the pleural fluid is reduced, while the LDH

level is increased.1 This stage takes several days to several weeks. Therapy using antibiotics and WSD is usually inadequate, and sometimes decortication is called for.3 Stage III of the disease, so called the organizational stage, is marked by the presence of fibroblasts. Fibroblasts develop from the visceral and parietal pleural surface, which makes the membranes lose their elasticity. This process is called the pleural peel. Reduced elasticity would disturb lung filling, even if drainage were successful. 1 During this stage, the exudates become purulent; and if it remains untreated, the pus could spread to the chest wall or to the lungs, creating a bronchopleural fistula.1,2 This organizational phase lasts for 7 days to several weeks after the onset of pneumonia, depending on the virulence of the bacteria, and the severity of the pneumonia. 2

Microorganism Pattern
The microorganism pattern of the cause of parapneumonial effusion has changed since the era of antibiotics. Previously, the bacteria that colonized an empyema were either the Streptococcus pneumoniae, or S. hemolyticus. Between the years 1955 and 1965, Staphylococcus aureus was commonly found. In the early 1970s, anaerobic bacteria were commonly found. From 1980 to 1990, aerobic microorganism once again became more commonly found. Brook and Frazier (1993) studied the pattern of the microorganisms found in the pleural fluid of 197 patients with a positive pleural fluid bacterial culture. They found 64% cases that only contained aerobic bacteria, 13% that contained only anaerobic bacteria, and 23% that contained a combination of the two.1 Alfageme et al (1994) reported similar findings, where from 82 patients with empyema, 62% had only aerobic bacteria in their pleural fluid, 12% contained only anaerobic bacteria, and 16% contained a combination of both aerobic and anaerobic bacteria.5 Abdul Mukti et al (1978) from Surabaya reported that from 74 cases of empyema, 30 cases were caused by tuberculosis. 7 Suryatenggara et al (1980) from Jakarta reported that out of 23 empyema cases, 13 patients suffered from lung tuberculosis, while other bacteria that were found included Pseudomonas, Staphylococcus, Streptococcus, and E. coli.6 In the last three decades (1974, 1981, 1993), the bacterial pattern of 342 patients demonstrated aerobic bacteria in 181 patients (53%), anaerobic bacteria in 76 patients (22%), and a combination of both aerobic and anaerobic bacteria in 85 patients (25%). Thus, we can conclude that: 1. Aerobic bacteria are more commonly found than anaerobic bacteria. 2. S. aureus and S. pneumoniae is found in 70% of all gram positive bacteria. 3. If only one kind of gram-positive bacteria is found, it is usually S. aureus, S. pneumoniae, or S. pyogenes. 4. Gram positive aerobic bacteria are twice more likely to be found than gram-negative bacteria. 5. Even though E. coli is the most commonly found gram-negative bacteria, it is rarely the sole cause of empyema. 6. Klebsiella, Pseudomonas, and Haemophilus influenza are three gram-negative that are most commonly found after E. coli. Almost 75% of all gram-negative empyema are caused by a single type of bacteria. 7. Bacteroides and Peptostreptococcus are two anaerobic bacteria that are commonly found. 8. A single kind of anaerobic bacteria rarely causes empyema on its own, but instead together with other kinds (polymicrobial). 2 Barlett et al (1998) found a reduced incidence of Streptococcus pneumoniae of less than 10%, and an increase of gram-negative bacteria, anaerobic bacteria, and combined infections of over 25%, 20%, and 25% respectively.16 A. Gram-positive bacteria S. pneumoniae is still the main cause of pneumonia, many complicated by pleural effusion. Taryle et al (1978) studied 53 patients with pneumococcal pneumonia and found 57% complicated by effusion. Light RW (1980) found 40% out of 153 patients with pneumococcal pneumonia with pleural effusion.1 Le Mense et al (1995) reported Staphylococcus aureus as the most frequently identified bacteria.3 Pneumonia due to S. pyogenes is rarely found, but is almost always found with effusion. Basiliere et al (1968) reported 57% out of 95 patients with Streptococcus pneumonia who suffered from effusion. Positive bacterial culture is only found in 30-40% of pleural fluids. 1 Other literature stated that the cause of 57% of empyema cases could not be identified due to previous administration of antibiotics. 2 B. Gram-negative bacteria Pneumonia caused by E. coli is the main cause of complicated effusions. However, E. coli by itself never causes effusion. Pneumonia due to Pseudomonas is also often complicated by pleural effusion. A research demonstrated that 50% of pneumonia due to Pseudomonas developed pleural effusion. Even though K. pneumonia is a common cause of pneumonia, it is rarely complicated by effusion. H. influenzae and Proteus also rarely cause effusion.1 C. Other pathogenous bacteria Bacillus anthracis could cause effusion hematogenously. Effusion could also occur in 30-50% of pneumonia due to legionella. Pleural effusion is usually slight and insignificant, but there have been reports of multiloculated effusion due to legionella.1

One thousand cases of tuberculosis pleural effusion are reported in the United States every year. That is 4% of all newly reported cases. In Indonesia, tuberculosis is still the main cause of pleural effusion. 6,7 Pleuropneumonial infection by clostridium is rarely found. From the year 1970, only 17 cases were found, nearly all of them with pleural effusion.1 Effusion has also been reported as a complication of pneumonia due to Haemophilus parainfluenzae, Bacillus cereus, Citraobacter diversus, Listeria monocytogenes, and Francisella tularensis.1

Clinical manifestations
Clinical manifestations of parapneumonial effusion and empyema depend on the dominant microorganism. A. Pneumonia due to aerobic bacteria The clinical manifestations of pneumonia and parapneumonial effusion are very much alike. They are both marked by acute fever, chest pain, productive sputum, and leukocytosis. A research stated 59% out of 113 patients without effusion, and 64% out of 90 patients with effusion, suffered from pleuritic chest pain. Leukocytosis averages to about 17,000 in patients without effusion, and 17,800 in patients with effusion. Effusion must always be suspected in patients with fever of more than 48 hours or those that do not respond to treatment using antibiotics. 1,16 Not all patients with pneumonia complicated by effusion suffer from acute symptoms. Sahn et al (1973) reported 3 cases of aerobic empyema without any symptoms of fever, and with only minimal complaints. These three cases had been under steroids. Absence of fever or chest pain should not cross out the possibility of parapneumonial effusion, since in the last couple of years, there is a high incidence of pleural effusion in patients receiving steroid therapy. 1 B. Pneumonia due to anaerobic bacteria Opposite to pneumonia caused by aerobic bacteria, anaerobic infections of the pleura usually have subacute manifestations. Anaerobic infection often occurs in patients with alcoholism, episodes of a loss of consciousness, or other predisposing factors for aspiration.1,2 Bad oral hygiene is a source of infection, and so is chronic productive cough.1,2 Leukocytosis usually averages to 23,500/mm3, with slight anemia.1

Diagnosis
Parapneumonial effusion must always be suspected at the initial evaluation of a patient with pneumonia, since delayed drainage of the pleural fluid would increase morbidity. The presence of fluid in the pleural cavity can be demonstrated by an anterior-posterior and lateral chest-X-ray. If the two diaphragms are seen and the two posterior costophrenic corners are pointed, we could assume that there is no pleural fluid. If one or both posterior costrophrenic agles are blunt, or if the diaphragm is blurred by infiltrate, a lateral decubitus chest X-ray should be taken.1 If the pleural fluid is more than 10 mm thick in a lateral decubitus chest X-ray, a diagnostic thoracentesis should immediately be performed. Examine color, consistency, and odor, then send it to the lab to examine the glucose level, LDH, amylase, protein, pH, and leukocyte count. The sample should also be sent for aerobic and anaerobic bacterial culture, gram stain, cytology, as well as TB and fungi culture.1 Not all patients with acute symptoms, infiltrate in the parenchyma, and pleural effusion suffer from bacterial pneumonia. Lung emboli, acute pancreatitis, tuberculosis, and other diseases may have the same manifestations. The possibility for lung emboli should always be considered, and a lung scan should be performed if the patients sputum is not purulent or his or her leukocyte count is not over 15,000/mm3. Normal levels of amylase cross out the possibility of pancreatitis, and many patients with acute tuberculous pleuritis are commonly found without infiltrate in their chest X-ray.1 Parapneumonial pleural effusion fluid varies from clear and yellowish exudates to mucous, odorous pus. Polymorphonuclear cells dominate the leukocyte count. Dominance of lymphocytes marks the possibility of tuberculosis or malignancy.16 A feculent odor is common for anaerobic infections. A study shows only 60% of anaerobic empyema is malodorous.1 Pleural effusions are often loculated at initial examinations. It is often difficult to identify loci with infiltrate at the peripheries of the lungs from a chest X-ray. Therefore, an ultrasound examination is needed, since it is effective in identifying 5 cc loculated pleural fluid. If a loculated empyema is suspected, an ultrasound or CT scan should also be performed.1 Loculated empyemas should be suspected in all patients with pneumonia irresponsive to adequate antibiotics after 48 hours. If the ultrasound examination turns out loculated, the examination should be performed over the entire pleural cavity, since it could be multiloculated. Loculated empyema demonstrates a strong inflammatory response of the pleural cavity.1,2 A CT scan should intensify the presence of loculated empyema, and should be able to differenciate loculated hydropneumothorax accompanied by bronchopleural fistulas from lung abscess. This is important since loculated hydropneumothorax with bronchopleural fistulas require immediate installation of WSD to prevent the spread of the

infection to other parts of the lungs. On the other hand, only antibiotics are needed for lung abscess. So, when in doubt whether plural fluid is in the pleural cavity or in the parenchyma, an ultrasound or CT scan must be conducted.1,2 LeMense (1995) suggested the CT scan as an initial selection on all empyema patients to determine further intervention.3

Management
There are two important things in the initial management of pneumonial effusion. Firstly, we should administer the right antibiotics. Secondly, should a WSD be inserted? Antibiotics are a crucial part of pneumonia management since it reduces the possibility of pneumonial effusion and empyema. Antibiotics are usually administered according to empirical knowledge of which bacteria commonly causes empyema. The span of antibiotic treatment depends on the clinical condition of the patient, but it is usually administered for several weeks. 8,10 The type of antibiotics administered for pneumonial effusion depends on whether it is a community-acquired pneumonia (CAP) or a hospital-acquired pneumonia (HAP), and the patients clinical condition. Patients with CAP who are hospitalized and are moderately ill are usually given second or third generation cephalosporin or beta lactams, or beta-lactamase inhibitors. Patients hospitalized for severe CAP should receive macrolide plus third generationc cephalosporin with an anti-pseudomonas effect, such as ceftazidime or cepoperazone. HAPs are usually caused by gram-negative organisms, P. aeruginosa, or the gram-positive S. aureus, with or without anaerobic bacteria. If a gram-negative organism is suspected to be the cause, use third generation cephalosporin or beta lactams, or beta-lactamase inhibitors plus aminoglicocydes. Infections by S. aureus should be treated with nafcillin or vancomycin. Anaerobic infections should be treated using clindamycin or metronidazole. A positive gram stain of the pleural fluid may help us determine the antibiotics that should be used. The dosage of the antibiotics does not need to be adjusted, since the level of antibiotics in the pleural fluid equals that of the serum. The decision to insert a WSD should be based on pleural fluid examination. If the pleural puncture truly reveals thick pus, it should be sent to the lab for gram stain, glucose level test, pH testing, and LDH level measurement. If the pH of the pleural fluid is less than 7.0 or the glucose level is less than 40 mg/dl, a WSD should be inserted immediately, since pleural effusion of this kind is almost always complicated. The same goes for a positive result of the gram stain of the pleural fluid. Glucose and pH level of the pleural fluid could be used to determine WSD insertion only for cases of pneumonial effusion. Other kinds of pleural effusion, such as that secondary due to rheumatism, tumors, and tuberculosis, may also have low glucose and pH levels, but do not necessarily require a WSD.1 The reduction in the pH level of the pleural fluid precedes the drop in glucose level. Thus, pH level is a more sensitive indicator. The pH level is reduced because glucose metabolism by the leukocytes in the pleural fluid produces lactic acid and carbon dioxide. 1,9 Heffner et al (1995) concluded that pH level has the highest diagnostic value according to chemical meta-analysis of the pleural fluid for pneumonial effusion. 15 A. WSD (Chest tube) & Image direct catheter A WSD is expected to drain out as much pus as possible so that the lungs can inflate with the aid of the negative pressure of the WSD. If the WSD is successful, there should be clinical and radiologic improvements after 24 hours, due to the inflation of the lungs. If the lungs do not inflate, a cause should be sought out. Inspect the WSD system, and inspect for the possibility of a fistula, pleural peel, or an obstruction of the respiratory tract. Adequate antibiotics should be able to close the fistula and enable the lungs to inflate. Obstruction can be cleared using a bronchoscope. If there is pleural thickening that inhibit lung inflation, try continuous suction to inflate the lungs. If none of these efforts prevails, surgery cannot be avoided.1,7 In addition to that, could conduct a bacterial culture of the pleural fluid, a CT scan and ultrasound to see whether the effusion is loculated or to see the position of the WSD. If the WSD is misplaced, its position must be corrected. If the effusion turns out to be multiloculated, administration of an intrapleural thrombolytic agent may be required. 1 If insertion of a WSD produces a clinical and radiologic response, the question that follows is when should it be removed? A WSD should normally be removed if the volume of the pleural fluid is less than 50 cc/24 hours, or if the color of the fluid has turned to clear yellow.1 Management of complicated effusions using WSD is still highly unsuccessful. The success rate for WSD insertion for aerobic pleural infection is 60%, while for anaerobic pleural infection it only reaches 25%. The cause of failure is usually delayed insertion of the WSD, because it was misplaced or the effusion has already become loculated. 1 Even though the success rate for delayed insertion of WSD for empyema is low, it is still the first-line form of therapy.3 The success rate is higher for image-guided catheter drainage. Since its placement is aided by either ultrasound, CT scan or fluoroscope, the catheter is more correctly placed.3,8,16 La Mense et al (1995) suggested that optimal

management requires initial examination using a CT scan, which would be the basis of further management to avoid a lengthy hospital stay.3 B. Intrapleural antibiotics Clagett (1963) was the first to use intrapleural antibiotics following a pneumomectomy. Afterward, several researchers have used intrapleural antibiotics on empyema, with positive outcomes. However, not a single one of those studies used a control group.1 The most recent study was reported by Storm et al (1992), who studied 94 patients with empyema using two different forms of treatment. The first 51 patients were treated using daily thoracentesis, NaCl rinsing, and systemic antibiotics, and 50% received intrapleural antibiotics. Next, 43 patients were treated with a WSD and systemic antibiotics. Out of the first 51 patients, only 3 (6%) required rib resection or decortication. On the other hand, 33 out of 43 patients (77%) of the second group needed rib resection or decortication. This study indicates the possibility of a role for intrapleural antibiotics in complicated effusions. Its benefit is still under study. 1 C. Intrapleural fibrinolytics The goal of administration of fibrinolytics is to prevent fibrinolysis, increase fluid drainage, and prevent possible surgical intervention,16 since it is usually difficult to drain complicated loculated effusions. Tillett et al (1951) was the first to suggest the administration of streptokinase or streptodornase for empyema to eliminate the loculation. Bergh et al (1970) reported that 10 out of 12 patients with empyema who received intrapleural injection of streptokinase demonstrated improvement.1,2 Temes et al (1996) reported that use of intrapleural fibrinolytics is safe and effective, and can prevent the possibility of thoracotomy up to 69%. 11 Sanchez (1996) reached a success rate of 92% in a prospective and multicenter study.12 Intrapleural thrombolytics are recommended for all patients with class 5 and 7. Streptokinase and urokinase are supposed to be equally effective. The dose for streptokinase is 250,000 U diluted in 100 cc of NaCl, while the dose for urokinase is 100,000 units diluted in 100 cc of NaCl. After administration of thrombolytics through a WSD, the tube should be sealed for 1 to 4 hours to give a chance for the thrombolytic to take action, while the patient is placed to his or her sides several times to ensure even distribution. Afterward, the seal should be opened and the fluid collected. The therapy is considered successful if the fluid in the pleural cavity increases, and if there is radiologic improvement. The WSD is removed after radiologic improvement and whence less than 100 cc of fluid is secreted in 24 hours. This thrombolytic agent could be administered daily for 14 days. A vial of urokinase contains 250,000 IU and costs US$258, while a vial of streptokinase contains 750,000 IU and costs US$156. D. Thoracoscopy Patients with loculated effusion irresponsive to intrapleural thrombolytics may be considered for thoracoscopy. Thoracoscopy would enable more optimal placement of the WSD, and it is a less invasive procedure compared to thoracotomy. The surface of the pleura could be more clearly seen to determine the need for further intervention, such as decortication. If during the thoracoscopy the pleura was found to be thick and full of debris, while the lungs trapped, a thoracoscopic incision could be performed followed by decortication. Thoracoscopy often does not improve donditions. In a study, 12 out of 18 patients (67%) require additional surgical procedures following thoracoscopy.1,2 Wait et al (1997) stated that Video Assisted Thoracic Surgery (VATS) is the best choice for patients with loculated empyema at the fibrinopurulent stage, viewed from the aspect of success rate, length of treatment, and cost. 13,14 However, the use of VATS for initial management still require further study.15 E. Decortication If the lungs cannot inflate due to thick fibrin covering the visceral pleura, decortication is the best choice of treatment. This procedure enables all fibrous tissue to be removed from the visceral pleura, and all pus to be removed from the pleural cavity. Decortication is a major operation that requires wide thoracic incision and is not conducted on patients with weak conditions. Decortication is a procedure of choice on patients who are candidates for surgery, those with empyema uncontrollable by WSD, intrapleural thrombolytics and/or thoracoscopy. Decortication would shorten the length of hospitalization compared to open drainage. 1 Le Mense (1995) produced a success rate of 95% , with a mortality rate of less than 5%.3 Lim and Chin (1999) studied two groups of patients with empyema. One group was conservatively treated using WSD and intrapleural fibrinolytics, and the other aggressively (with WSD, fibrinolytics, and surgery early on). They concluded that the hospitalization and mortality rate is lower in the more aggressively treated group. 16 They suggest a stepladder approach (Table 3). F. Open Drainage This method is best if closed drainage using WSD and fibrinolytics were successful. However, its high morbidity and lengthy hospitalization become a disadvantage. 3 This procedure is conducted on patients with a general

condition that prohibits decortication. 1 It could be conducted with a simple procedure of rib resection, followed by insertion of a large tube into the empyema cavity and daily irrigation. A more complex procedure would be creating a muscle flap.

Complications
Empyema could create a complication to the chest wall, or to the lung parenchyma through the bronchopleural fistula. A bronchopleural fistula should be suspected if there is a lot of sputum when the patient lies to one side. Anterior-posterior chest x-ray would demonstrate air-fluid level. CT scan is needed if it is unclear whether the airfluid level resides in the lung parenchyma or in the pleural cavity. A bronchopleural fistula requires immediate and adequate insertion of a WSD, since the microorganism could spread into the lung parenchyma.

Conclusion
1. All pneumonia should be suspected for the complication of pleural effusion if the patient remains feverish after 48 hours of adequate administration of antibiotics. 2. Not all parapneumonial effusions have acute clinical manifestations. 3. Pleural fluid more than 10 mm in thickness is an indication for pleural puncture to determine the presence of complicated effusions. 4. The presence of pus, a positive finding on gram stain or bacterial culture, or a pH level of less than 7 and a glucose level of more than 40 mg/dl is an indication for WSD. 5. Aerobic microorganisms are the cause of 50-60% of all cases of empyema, anaerobic organisms in 15-20%, and a combination in 20-25%. 6. Studies in Indonesia show that tuberculosis is the cause of 40-50% of empyema cases. 7. A dominance of lymphocytes in the pleural fluid could indicate a tuberculosis infection. 8. The antibiotic of choice depends on whether it is CAP or HAP. 9. Extremely malodorous pus might indicate anaerobic infection, which should be combatted with clindamycin or metronidazole. 10. General management is based on the patients clinical condition, classification, and available resources. 11. A classification scheme (Light, 1995) and a stepladder approach is the standard procedure in the management of empyema. 12. Lemense suggested a CT scan as the initial step in determining consequent action. 13. Insertion of a WSD would be more optimal if aided with an ultrasound or fluoroscope. 14. Intrapleural antibiotics are still under study, since many antibiotics become inactive in acidic conditions. 15. Intrapleural fibrinolytics are still too expensive to be administered in Indonesia. 16. Thoracoscopy is an alternative to avoid thoracotomy. It could also be used to identify loculated empyema and optimize WSD insertion. 17. Decortication is the best choice of treatment for advanced stages that demonstrate no improvements with previous management. 18. Open drainage is the choice of treatment for empyema with a general condition which prohibit decortication.

References
1. Light RW. Parapneumonic efusions and empyema. In: Pleural disease. 3rd ed. Baltimore: A Waverly Company;1995. p.129-53. 2. Heffner JE. Pneumonia and empyema. In: Niederman MS, Sarosi GA, Classroth J editors. Texbook of respiratory infections. Philadelpia: WB Saunders Company; 1994. p.265-75. 3. LeMense GP, Strange C, Sahn SA. Empyema thoracis. Therapeutic management and outcome. Chest 1995,107:1532-07. 4. Mejias CS, Antinolo FG, Cortes LFL, Ruiz MC, Pachon J. Interleukin-b in pleural fluids of different etiologies. Its role as inflamatory mediator in empyema. Chest 1995;108:942-05. 5. Alfageme A, Munoz F, Pena N, Empyema of the thorax adults. Etiology, microbiologic findings, and management. Chest 1993;103:839-43. 6. Suryatenggara W, Kusnan B, Soekoesno J. Pengobatan empiema di rs persahabatan. Naskah lengkap konas II IDPI edisi 1978:729-36. 7. Mukti A, Hariadi S. Empiema di rs dr. soetomo surabaya: Tinjauan 74 kasus. Kumpulan naskah lengkap konggres I IDPI edisi II 1978:729-36. 8. Sahn SA. Management of complicated parapneumonic effusions. Am Rev Respir Dis 1993;148:813-7.

9. Heffner JE, Brown LK, Barbieri C, De Leo JM. Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med. 1995;151:1700-8. 10. Morgenroth A, Pfeuffer H. pylori, Seelmann R, Schweisfur th H. Pleural penetration of ciprofloxacin in patients with empyema thoracis. Chest 1991;100:406-09. 11. Temes RT, Follis F, Kessler RM, Pett SB. Intrapleural fibrinolitics in management of empyema thoracis. Chest 1996;110:102-6. 12. Sanchez CJ, Rivera AR, Elizalde JJ, Delgado R, Cicero C. Intrapleural fibrinolisis with streptokinase as an adjunctive treatment in hemothorax and empyema. A multicenter trial. Chest 1996;109:1514-09. 13. Wait MA, Sharma S, Hohn J, Nogare AD. A Randomized trial of empyema therapy. Chest 1997;111:1548-51. 14. Landreneau RJ, Keenan RJ, Hazelrigg SR, Mack MJ, Naunheimm KS. Thoracoscopy for empiema and hemothorax. Chest 1995;109:18-24. 15. Connors AF, Altose MD. Pleural inflamation and pleural efusion.In: Baum GL, Wolinsky E. Texbook of pulmonary disease.5th ed. Boston: Little Brown;1994. p.1853-8. 16. Lim TK. Menagement of pleural sepsis complicating community acquired pneumonia. Med Prog 1999;15-20. 17. Suryatenggara W. Penanganan empiema. Naskah simposium pleural disease 1997. Bagian pulmonologi FKUI RSUP Persahabatan.1997:1-7.