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STATE OF THE ART CLINICAL ARTICLE

Pleural EmpyemaRichardE Bryant and Christopher J Salmon

Pleural empyema is a serious complication infection adjacent to or within the chest that rarely resolves without appropriate medical therapy and drainage procedures [ 3]. Hostdefenses are seriously compromised by the anatomy and physiology an infected pleural space, and subtleties presentationmay delay recognition and appropriate management. Empyemais usually a complication pneumonia but may arise frominfections at other sites. Presentation and microbial etiology aremodified by local trauma or surgery or by underlying conditionssuch as malignancy, collagen vascular disease, immunodeficiency disorders, and adjacent infection involving the oropharynx, esophagus, mediastinum, or subdiaphragmatic tissues.Clinical features depend upon the primary organ or space infected, the microbial pathogen(s), and host defense defects.

Recent advances in imaging and instrumentation have facilitated the recognition and management bacterial empyema[4-9], and scholarly work in the field has improved our understanding its pathophysiology and clinical presentation [1,10-14]. Use the thrombolytic agent urokinase, in conjunction with precise and timely placement drainage cathetersunder imaging guidance, has made it possible to reduce therisk pleural fibrosis and lung entrapment while avoidingthoracotomy [15- 21]. Likewise, video-assisted thoracoscopictechniques also provide an effective, less invasive means assessing and managing the infected pleural space without fullthoracotomy [22, 23].

Historical PerspectiveIt is interesting that Aristotle recognized the clinical entity

empyema and described drainage pus with incision, cautery, and a metal tube [24]. He also described the risk oflethalpneumothorax when such interventions were undertaken beforeloculation pleural pus had occurred. Twenty-five centurieslater, appreciation that risk formed the basis for the recommendation Dr. Evarts A. Graham and the World War I

Received 19 December 1995; revised 19 January 1996.Reprints or correspondence: Dr. Richard E. Bryant, Director, InfectiousDiseases Division, Oregon Health Sciences University, 3181 SW Sam JacksonPark Road, L457, Portland, Oregon 97201.Clinical Infectious Diseases 1996;22:747-64 1996 by The Universi ty of Chicago. All rights reserved.1058-4838/96/2205-0016 02.00

From the ivisions Infectious iseases and Thoracic ImagingOregon Health Sciences University Portland Oregon

Empyema Commission that an empyema should not be treatedby open drainage in the acute pneumonic phase in order tolessen the risk of fatal pneumothorax [25]. Thereafter, simplebut ingenious closed drainage systems favorably modified therisks associated with the pleural evacuation, facilitating earlierand more efficacious drainage. Although closed chest tubedrainage empyema had been described by Hewitt in 1875,it came into widespread use only after Graham's report of 1918[26].

More recently, sophisticated imaging technologies havegreatly enhanced our ability to identify, sample, and drain collections of infected pleural fluid [4-10, 27]. Despite such rapidadvances in diagnosis and therapy, it is still possible for anempyema to remain undetected unless the risks this complication are appreciated and appropriate diagnostic measures areused. Although currently available antimicrobial agents cancontrol some the systemic manifestations of empyema, themorbidity and mortality caused by undrained pleural pus arestill high [28- 31]. Optimal treatment requires drainage. Thiswas recognized by Osler, who underwent a rib resection fortreatment of postpneumonic Haemophilus influenzaeempyema,which ultimately caused his death [20, 30]. Current technologyhas increased the speed and finesse with which pleural empyemas can be drained and has improved our understanding ofwhy it is necessary to drain them [1, 2, 4-13].

AnatomyThe pleura is derived embryologically from the primitive

coelomic cavity [14]. It consists two mesothelial layers withtheir associated vascular, lymphatic, and connective tissue portions. The visceral and parietal pleurae are continuous with oneanother at the root the lung, where the hilar airways andvessels enter the lung parenchyma, and are closely apposed tothe individual pulmonary lobes, the inner aspect the thoraciccage, and the lateral margin the mediastinum. The resultantpleural space contains scant fluid and is normally a potentialspace that becomes a true space only in disease states thatcause accumulation pleural fluid (liquid or air).

The visceral pleura is attached to the lung surface and iscontiguous with the subpleural pulmonary interstitium [32]. Itis u thick and apparently derives its blood supplyfrom both pulmonary and systemic arteries, draining to thepulmonary veins. The visceral pleura individually invests pul-

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748 Bryant and Salmon m 1996;22 May

monary lobes. The interlobar fissures seen radiographically orby CT are due to the additive thickness of the visceral pleurallayers of the participating lobes. The normal pleural fluid volume is negligible and invisible by imaging. The major, oroblique, fissure separates the lower lobe from the upper lobeof the left lung or the lower lobe from the upper and middlelobes on the right side). The minor, or horizontal, fissure separates the right middle lobe from the upper lobe.The parietal pleura is composed of four layers but is slightly

thinner than the visceral pleura [32]. tis surrounded by a thinlayer of extrapleural or subcostal fat, which is surrounded bythe fibroelastic endothoracic fascia that constitutes the boundary of the thoracic cavity. The endothoracic fascia is attachedto the perichondrium of the costal cartilage, the ribs and intercostal muscles, and the prevertebral fascia surrounding the vertebral bodies and intervertebral disks. The extrapleural fat layeris normally ~ 2 5 j m thick but may become radiologicallydetectable in normal patients. tincreases diffusely in the presence of empyema, but not in obese patients. The parietal pleurais supplied and drained by systemic vessels. The lymph of thepleural space is drained by stoma in the parietal pleura, whichrepresents the predominant-ifnot exclusive-mechanism bywhich liquid is cleared from the pleural space [33, 34]. Theparietal pleura has abundant sensory innervation and should bewell anesthetized before it is manipulated or punctured [35].Although the quantity of pleural fluid is small, it efficiently

couples the lung to the diaphragm and chest wall during breathing and lubricates the movement of those structures. Nevertheless, little or no functional impairment results when the pleuralspace is obliterated either experimentally or because of clinicalnecessity [1].Anatomic anomalies of the pleura are rarely of clinical con

sequence but can cause confusing radiological patterns [36].Accessory fissures are very frequently encountered at surgeryor post mortem, but only two types are commonly encounteredin practice. The inferior accessory fissure separates the medialbasal segment of the right lower lobe or the medial subsegmentof the anteromedial basal segment of the left lower lobe) fromthe other basal segments of the lower lobe. Such fissures occurin ~ 4 0 5 0 of people, usually in incomplete forms invaginating the lower lobe at its diaphragmatic aspect. Superioraccessory fissures are present in ~ 30 of patients. These variant fissures are roughly horizontal and separate the superiorsegment of a lower lobe from the basal segments of that lobe.They may mimic a horizontal fissure on a chest radiograph.

thophysiologyThe diagnosis and treatment of bacterial empyema are best

understood in relation to the altered anatomy and pathologicalphysiology of the pleura and the associated host defense dysfunctions. Pleural effusions develop because of increased hydrostatic pressure or decreased oncotic pressure associated withcardiac, renal, hepatic, ormetabolic disease [I, 2]. Other factors

contributing to their development include alterations in pleuralpermeability due to noninfectious inflammatory diseases, infection, toxic injury, malignancy, or trauma [37-41]. The pleuralspace is normally sterile yet readily colonized once pleuralfluid has accumulated. Host factors predisposing patients toempyema include pneumonia and parapneumonic effusions aswell as contiguous infections of the esophagus, mediastinum,or subdiaphragmatic areas that may extend to the pleura. Bothtraumatic and iatrogenic injury to adjacent structures may leadto secondary infection and involvement of the pleura [3741]. Similarly, retropharyngeal, retroperitoneal, vertebral, orparavertebral infection can extend to the pleura.Pleural effusions arenutritionally rich culture media in which

WBC defenses are severely impaired. The classic studies ofWood and co-workers showed that effective phagocytosis ofbacteria by neutrophils requires a structure upon which WBCscan move and can ingest bacteria prior to development of specific antibodies [42]. Later in the course of infection, phagocytosis is enhanced by antibodies and opsonic factors. However,in a fluid-filled environment, bacteria can float away fromphagocytic cells and multiply relatively unimpeded [42]. Incurrent parlance this defect reflects the fact that whit cellscan t jump or swim) and thus cannot efficiently fulfill theirhost defense function in a liquid medium, whether in the infected pleura, pericardium, joint, or meninges.The formation of an empyema has been arbitrarily divided

into an exudative phase, during which pus accumulates; a fibropurulent phase, during which fibrin deposition and loculation of pleural exudate occurs; and an organization phase, duringwhich fibroblast proliferation and scar formation cause lungentrapment [43]. Prompt diagnosis and intervention should circumvent the second and third phases of empyema formation.To achieve this goal, physicians need to appreciate the subtleties of clinical expression of pleural empyema and the adverseeffects of the suppurative environment on antimicrobial efficacy and tissue injury in the pleural space.Bacteria in pleural fluid elicit a complex seriesof host defense

responses that are incompletelyunderstood despite significant recent advances in our knowledge of the role ofTNF, the cytokinecascade,andperturbationsof endothelialcell and leukocyte interactionsduring infection[44,45]. Whenthe inflammatoryresponseis too little or too late, bacteria may multiply until they reach astagnantgrowthphase, associatedwithconcentrationsof ~ 8 g l obacteria per mL [46]. Empyema fluid is relatively deficient inopsoninsandcomplementandbecomesprogressivelymoreacidic,hypoxic, and depleted of glucose as infectionproceeds [46,47].Gram-negativeaerobicbacilli may release endotoxins, and streptococci or staphylococcimay release enzymes that lyse granulocytes in pleural fluid.During the inflammatory process, leukocytes release intra

cellular constituents such as bactericidal permeabilityincreasing protein, defensins, lysozyme, cationic proteins, lactoferrin, and zinc-binding proteins [48]. The latter two components may contribute to suppression of bacterial growth by



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Table 1. onditions associatedwithnontuberculous bacterial empyema [31, 38-41, 60].

Microbial PathogensIn approximately one-halfof patients, empyema develops as

a complication of pneumonia table I). Therefore, the fre-

Experimental EmpyemaAnimal models of pleural empyema lack many of the fea

tures of human disease [55, 56]. Empyema in man is usuallymonomicrobial, whereas it is difficult to produce disease inanimals without injection of multiple pathogens and concomitant use of foreign bodies like umbilical tape. Empyema didnot occur after tape placement and injection of guinea pigswith 4 log cfu ofBacteroidesfragilis; however, similar preparations and injection with 4 OglO cfu of Staphylococcus aureusproduced empyema in 20 of animals, and concomitant injection with both B fragilis and S. aureus produced empyema in>50 [55]. More than 6 OglO cfu of E coli and B fragilisare required to produce empyema in 50 of animals. Umbilicaltape did not affect lethality of disease induced by coli andB fragilis but addition of blood did increase lethality in thatmodel [56].Empyemahas been produced in rabbits by injection of Strep-

tococcus pneumoniae or Klebsiella pneumoniae into a pleuralexudate induced by turpentine [57]. Those lesions will healspontaneously and therefore do not appear analogous to humandisease. That model has been used to assess the effect of streptokinase injection on experimental empyema. Although streptokinase effectively reduced the incidence of adhesion, it increased the volume of effusion, possibly because pleural fluidwas not drained [58]. Shohet and co-workers used the turpentine-induced empyema model to study gentamicin efficacyagainst K pneumoniae infection in the pleural space [59]. Curerates were reduced when animals were treated with gentamicinalone, but 100 of animals were cured when placed in anoxygen chamber, despite the fact that the pharmacokinetics ofgentamicin were unchanged. These studies add further proofof the suppressive effect of the abscess environment on theactivity of aminoglycosides used as single-drug therapy.

lowering concentrations of iron and zinc. Pneumococci andperhaps other organisms may undergo autolysis in overtly purulent empyema fluid, thus accounting for a portion of the 12 18 rate of sterility of empyema fluid. Late in the course ofinfection, the inflammatory response leads to loculation of pusand occasionallyto its spontaneous drainage by erosion throughthe chest wall i.e., empyema necessitatis, which currently represents failure of diagnostic, medical, and surgical care).Bacteria within empyemas are relatively unresponsive to an

tibiotics. In that milieu bacteria may release ,B-lactamase enzymes capable of degrading ,B-lactamase-susceptible ,B-lactamantibiotics [49]. Similarly, microbial enzymes in pus may degrade chloramphenicol. Overtly purulent empyema fluid maybe quite acidic, even in the absence of esophageal rupture.Since aminoglycoside incorporation by bacteria is ordinarilyoxygen-dependent and acid-inhibitable, aminoglycoside efficacy is suppressed in the hypoxic and acidic milieu of pleuralempyema [50]. Furthermore, the calcium and magnesium concentrations in pus, the avid binding of aminoglycosides to theDNA in pus, and the reduced bacterial metabolism in pus mayinhibit aminoglycoside activity in empyema fluid [50, 51].Bacteria within abscesses or involved in chronic inflamma

tory states multiply slowly, with generation times that mayreach 8-24 hours [52]. Tuomanen and co-workers found thatthere was a direct relationship between the multiplication rateof Escherichia coli and their death rate after exposure to cephalosporins in vitro-i.e., rapidly multiplying organisms werekilled quickly, whereas slowly growing organisms were killedless rapidly in proportionto their growth rate [53]. When killingcurves were expressed in relationship to the doubling time ofthe bacteria exposed to antibiotics, there was a linear relationship between cell division and the rate at which bacteria werekilled by ,B-lactam agents [53].The mechanisms by which growth rates of bacteria modify

their susceptibility to ,B-lactamantibiotics are incompletely understood. Stevens and colleagues demonstrated a progressivereduction of penicillin-binding proteins in streptococci as theyentered a stagnant phase of growth [54]. It appears likely thatthe rate of bacterial division affects the quantity and type ofpenicillin-binding proteins that are available to interact with,B-lactam antibiotics. This may in part explain why bacteria inpus are refractory to antibiotics and why it is necessary to giveprolonged antibiotic therapy to patients with poorly drained,suppurative infections [54].Prolonged therapy may be needed because slowly growing

organisms in pus require prolonged contact with ,B-lactamantibiotics in order to induce sufficient cell wall injury to killbacteria. Fortunately, this impediment can be circumvented byabscess drainage, which removes large numbers of metabolically inert bacteria and their toxins and removes inflammatorycomponents of the empyemic milieu that are capable of suppressing bacterial responsiveness to antibiotics and injuringhost tissues. In addition, there are both new and better waysto achieve adequate drainage of pleural pus [6- 9, 15- 21].

CausePulmonary infectionSurgeryTraumaEsophageal perforationComplication of thoracentesis/chest tube placementSubdiaphragmatic infectionSpontaneous pneumothoraxSepticemiaOther or unknownTotal

No. Yo)of patients301 56)119 22)20 4)21 4)21 4)15 3)7 1)8 I)30 5)542 100)



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Childhood Empyema

Table 2. Bacteria isolated from nontuberculous pleural empyemafluid in various studies.

Nelson reported that 54 of the empyemas in children ;;;6months of age were caused by S. aureus and only 6 weresterile [75]. Empyemas in children in the age groups of0.5 2 and 2 5 years were caused by S. aureus in 20 , byS. pneumoniae in ~ 25 , and by H. influenzae in 20 and

Approximately one-quarter of empyemas are associated withtrauma or surgery [61, 70]. As shown in table 2, there is adisproportionate increase in staphylococcal infection and a decrease in anaerobic infection in such patients [70]. Ill-advisedor incomplete resection of lung nodules or cavities containingcryptococci or spontaneous rupture of coccidioidomycosisassociated lung cavities into the pleura may lead to fungalempyemas. Similarly, instrumentation or surgery causing injuryor perforation of the esophagus or stomach may lead tomediastinitis or subdiaphragmatic infection that can extend tothe pleura [2]. Sinus drainage from the skin and pleural involvement are suggestive of infection caused by ctinomycesspecies, Mycobacterium tuberculosis or Nocardia species. Empyema may also occur with Entamoeba histolytica infection butis rare in the United States [71-74].

305243413101323 8

26 8818 3789 55 556 512 16

1627

Percentage of patients with empyema[reference]

In combined series Following trauma[2 29 31] n 217) [6] n 31)

AerobicStreptococcus speciesStreptococcus pneumoniaeStaphylococcus aureusStaphylococcus epidermidisEscherichia coliEnterobacter speciesProteus speciesKlebsiella speciesPseudomonas aeruginosaOther gram-negative bacillusAerobic organisms only

AnaerobicBacteroides speciesClostridium species ctinomycesspeciesEubacterium speciesProprionibacterium speciesVeillonella speciesFusobacterium speciesMicroaerophilic streptococciPeptostreptococcus speciesAnaerobic organisms onlyNo organisms

Bacteria isolated

quency with which certain microbes cause parapneumonic empyema in different patient groups reflects the frequency withwhich the vulnerable patients in those groups are exposed to,become colonized with, and fail to clear aspirated secretionscontaining those bacteria. Immunocompromised patients areprone to pleural involvement with fungal or aerobic gramnegative bacillary infection [30, 31 41 61]. In patients with amalignancy, fungal or tuberculous foci may be reactivated andempyema may develop. Similarly, fungal or mycobacterial empyema may develop in transplant recipients and patients withAIDS, but usually because of disseminated disease.The microbe-specific factors favoring development of empy

ema as a complication of pneumonia have special clinical relevance. In overtly healthy adults, the bacteria most commonlycausing pleural empyema are S. aureus S. pneumoniae andStreptococcuspyogenes [1, 62]. Although pneumococcal pneumonia may present with parapneumonic pleural effusions in40 of patients, empyema occurs in ;;;5 of patients withpneumococcal pneumonia [1]. Group A streptococcal pneumonia occurs much less frequently than pneumococcal pneumoniabut is associated with a higher frequency of large pleural effusions that progress rapidly to produce empyema and sepsis[62,63].

t is well appreciated that klebsiella pneumonia and empyema may occur in alcoholic males with multiple host defensedefects that impair containment of or perception of diseaseuntil it is well advanced [64, 65]. t is not clear which hostdefense defects are the most important causes of gram-negativebacillary pneumonia in such patients, but the proteolytic enzyme-mediated removal of fibronectin from the nasopharynxand the subsequent ability of gram-negative bacilli to colonizethe exposed nasopharyngeal membranes are probably two ofthe key determinants of ultimate infection [66]. Likewise, thefetid mouth and a predisposition to aspiration are clearly theforerunners of the fetid lung, lung abscesses, and/or anaerobicempyema [2, 67, 68]. Such infections are usually polymicrobicand linked to pyorrhea or gingivitis and altered consciousness.Extensive local tissue injury and bacterial synergistic infectionare hallmarks of anaerobic pneumonia and empyema.The frequency of aerobic and anaerobic isolates seen in three

combined series is shown in table 2 [2 29 31]. t is likely thatthe role and frequency of anaerobic organisms are substantiallyunderestimated by such reports. Bartlett and Finegold foundexclusively anaerobic organisms in 35 of 83 medical servicepatients with empyema, anaerobic plus aerobic pathogens in41 , and aerobic pathogens alone in 23 [67].S. aureus is a relatively common cause of empyema in other

wise healthy adults, in children, and in patients who have hadchest trauma or surgery. S. aureus pneumonia and empyemahave been linked to prior influenza A virus infection [69].Empyema complicating traumatic hemothorax predisposes patients to infection with S. aureus whereas pneumothoraces orserouseffusions are often secondarily infected by aerobic gramnegative bacilli.



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em 1996;22 (May) Pleural Empyema 75110 , respectively [75]. Among older children there was a 7-fold higher incidence of empyema fluid culture sterility thatprobably reflected autolysis of pneumococci or possibly deathof emophilus strains in purulent secretions.

Prior antibiotic therapy reduces the frequency of positivecultures [76]. Hoff and co-workers reported that 71 of patients with sterile empyemas had received antibiotics beforecultures were performed, as compared with 41 of patientswhose empyema fluid contained viable bacteria P < .05) [76].These differences would probably be even more striking if thesusceptibility of specific bacteria, the potency and duration ofantibiotic therapy, and the problem of antibiotic carryoverinto culture media could be subjected to multivariant analysis.In the past, H injluenz e infection has occurred principally inchildren aged


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Table 3. Clinical radiological and laboratory clues to the possibility of pleural empyema.Clinical clues

History Chills, fever, dyspnea, chest pain, or referred pain; recent pulmonary or contiguous infection in the oropharynx, mediastinum, or subdiaphragmaticarea; symptoms suggesting adjacent tissue infection extending to the pleura, i.e., dysphagia, dyspepsia, hiccups, or pharyngeal, abdominal, back, or shoulderpain; recent instrumentation, surgery, or trauma of the chest, oropharynx, esophagus, or abdomen; delayed or incomplete response to appropriate medicaltherapy for an infection that could extend to the pleura; comorbid diseases such as alcoholism, malnutrition, immunodeficiency, immunosuppression, ordiabetes.

Physical examination Diminished breath sounds or basilar dullness to percussion; pleural friction rub; bronchophony or egophony above effusion oradjacent to pneumonia; tracheal or mediastinal shift; scoliosis following a respiratory infection in children); focal chest wall heat, erythema, swelling, and/orpain rare); draining dermal sinuses rare); hyperpyrexia, shock, tachypnea >30 respirations/min), and lor altered consciousness all of which may beindicative of disproportionately severe infection).

Clinical course Rapid onset of clinical deterioration and sepsis with respiratory failure; persistent fever, sepsis, and/or organ failure despite appropriateantibiotic therapy in a susceptible patient); worsening clinical and laboratory indicators of infection despite appropriate antibiotic therapy.

Radiological clues imaging method)Pleural fluid conventional or lateral decubitus radiography); pleural effusion loculation lateral decubitus radiography, ultrasonography, or CT); evidence of

pleural effusion and contiguous infection ultrasonography or CT); pleural mass conventional radiography); hemothorax, pleural air, amoebic abscess, orcontiguous infection extending to pleura; bronchopleural fistula and empyema CT).Laboratory clues

Pleural fluid Cloudy, bloody, or purulent; WBC count, ;;>50,000 X 109I L usually); pH level, ,7.1 or ;;>0.3 lower than serum pH); lactic dehydrogenaselevel, ;;>1 000 lUlL; glucose level,


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ern 1996;22 May Pleural Empyema 753Table 4. Classification and treatment of parapneumonic effusions and empyema.

Pleural fluidindices of suppuration Mode of therapy requiredWidth of Bacteria Loculation(s) Thora-effusion Lactic in gram of pleural Clinical status coscopy Fullon lateral dehydro- stain fluid noted decorti-

Class of effusion or decubitus Glucose genase and/or Frank in radiologic Stable or Anti- Needle Tube Throm- decorti- cationempyema radiograph pH (mgldL) (lUlL) culture pus studies improving Sepsis biotics aspiration drainage bolysis cation procedureI: Nonconsequential

pleuraleffusion 1 em ;;,7.2 >40 40 >1,000 + + +*

4: Moderatelycomplex .;7.0 1,000 + + + + + +*

5: Extremelycomplex


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UltrasonographyUltrasonographic devices are widely available, provide real

time guidance for thoracentesis or pleural catheter placement[4], and can be transported to the bedside of unstable or critically ill patients. This imaging adjunct is particularly usefulfor sampling fluid that does not layer freely on decubitus films,and it reduces the incidence ofpneumothorax during thoracentesis [99, 100]. The sonographic appearance of pleural fluidcollections is quite variable, ranging from anechoic (completelyecho-free or sonolucent) to very echogenic. When highly echogenic, the collections may be mistaken for consolidated lungor pulmonary abscess [101]. n such instances it is importantto coordinate sonographic and radiographic interpretations.

Sonography can distinguish solid from liquid pleural abnormalities with 92 accuracy (vs. the 68 accuracy of chestroentgenography). With combined use of radiography and sonography, the accuracy rises to 98 [8]. The ability of ultrasonography to detect variation in the shape ofpleural fluid collections during respiration is helpful in excluding a solid lesion.Similarly, evidence of fluid bronchograms in cases of consolidated lung is another distinguishing feature detectable byultrasonography [102].

Discrete intrapleural septations can be demonstrated sonographically in up to 74 of exudative effusions [103], andsome may appear mobile on real-time examination [104]. Ultrasonography may show limiting membranes suggesting the presence of loculated collections, even when they are invisibleby CT. The presence of septations has prognostic importancebecause loculated collections (Light's class 5 or higher; seetable 4) require drainage and are usually larger than simplecollections [105]. Anechoic collections may be exudative ortransudative [7].

omputed TomographyThe development of rapid, newer-generation CT scanners

has revolutionized the evaluation and treatment of thoracicempyema. Empyemas usually appear well-defined, smooth, andround or elliptical on CT scans. Their margins are composedofinflamed visceral and parietal pleura that often have a markedlythickened appearance and enhance after administration of intravenous contrast material. The visceral and parietal layers areseparated by the interposed empyema fluid, giving rise to thesplit pleura sign of empyema [106]. When air is introducedinto the empyema cavity, either iatrogenically following thoracentesis or in association with a bronchopleural fistula, theinner aspect of the visceral and parietal margins is usuallysmooth. The extrapleural or subcostal fat external to the thickened parietal pleura and deep to the ribs is also noted to thickenin both acute and chronic empyema. This clearly discerniblefatty hyperplasia has imaging characteristics similar to thoseof subcutaneous fat and is much lower in CT attenuation thanthe thickenedpleura itself. Conventional chest radiographs can-

not distinguish pleural thickening that reflects pleural fluidaccumulation from that due to accentuation of this fatty layer.

Empyema is frequently associated with nearby pulmonaryconsolidation and sometimes lung abscess. Alternatively, alung abscess can resemble effusion or empyema [106]. Differentiation between these diagnostic possibilities is often difficult, if not impossible, with use of clinical and conventionalradiographic approaches. Fortunately, CT usually allows definitive diagnosis. Lung abscesses are often poorly defined,roughly spherical, and surrounded by irregularly consolidatedlung. They often contain one or more cavities with shaggyintramural contours. When abutting a pleural surface, abscessesform acute angles with the adjacent chest wall. Because theyarise within and occupy consolidated lung, they rarely appearto displace adjacent pulmonary structures such as peripheralairways and vessels. Empyemas may form acute or obtuseangles yet have the other CT characteristics mentioned in thepreceding paragraph.

TreatmentEffective therapy for an empyema requires control of infec

tion, drainage of pus, and expansion of the lung. Occasionally,procedural or surgical correction of adjacent infection is required. Empirical antimicrobial therapy is initiated on the basisof its anticipated bactericidal activity against the suspectedmicrobial pathogens and is changed when the susceptibilitiesof the infecting microorganism(s) are known.Drug delivery to the pleura is not a problem. In general, (3lactam agents are given in high doses for 2 4 weeks, buttherapy may need to be prolonged if drainage is not optimalor if an adjacent abscess or osteomyelitis is present. Nafcillinis the drug of choice for S. aureus infection, and penicillinis the drug of choice for penicillin-susceptible streptococcalinfections. Infection due toS.pneumoniae with high-level resistance to penicillin (MIC, >2 flg/mL) and to ceftriaxone orcefotaxime (MIC, flg/mL) should be treated with vancomycin. Cephalosporin-susceptible pneumococci with intermediatesusceptibility to penicillin should be treated with ceftriaxoneor cefotaxime.Monotherapy with an aminoglycoside is contraindicated because of its poor activity in pus and the risks of toxicity [49].The synergistic activity of aminoglycosides with (3-lactamdrugs has justified their use in combination therapy for Pseu-domonas aeruginosa Enterobacter cloacae Serratia marces-cens and Acinetobacter calcoaceticus infections, because (3lactam antibiotics appear to overcome the suppressive effectof the hypoxic and acidic abscess environment on incorporationof the aminoglycoside by bacteria [50]. Ciprofloxacin is a logical alternative to aminoglycosides for use in combined therapyagainst those pathogens in early infection and can be givenorally during later stages of infection. lmipenem is the drug ofchoice for E cloacae infection and should be used in conjunc-



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tion with at least one other effective antibiotic for treatment ofempyema caused by that pathogen.Patients with chronic pleural empyemas that are poorly

drained may require prolonged antibiotic therapy. Similarly,empyemas caused by ctinomycesor Nocardia species, mycobacteria, or fungi require protracted therapy. Anaerobic empyema can be treated like anaerobic suppurative infection at othersites; however, metronidazole is minimally active against streptococci, ctinomyces and propionibacteria and less apt to beeffective for partially drained infections because it is notmetabolized to its active derivative in partially oxygenated environments [50].Since many anaerobic infections are polymicrobic, therapy

is usually selected from among clindamycin, ,8-lactamaseinhibitor combination drugs, and imipenem on the basis of thespecific concomitant aerobic and/or microaerophilic organismspresent in pus. Neither chloramphenicol nor tetracycline shouldbe used to treat anaerobic empyema. Anaerobic and polymicrobic anaerobic empyemas that have extended to the pleurafrom adjacent sites of infection often require surgical treatmentof the primary site of infection. Patients with pleuropulmonaryamebiasis should receive metronidazole (usually 750 mg pothrice daily for 10 days), and drainage should be performed asappropriate [71]. Severely ill patients may also require brieftherapy with dehydroemetine or chloroquine [71, 92]. Thosewith polymicrobic pleuropulmonary amebiasis should receiveantibiotics appropriate for the concomitant bacteria and mayrequire large-chest-tube drainage if the empyema fluid is especially thick. The treatment of choice for pleuropulmonary paragonimiasis is praziquantel [73].

If the causative organisms are susceptible, tuberculosisrelated pleural effusions respond well to the usual antituberculous regimens and rarely require drainage. In practice, the organisms susceptibilities may not be known until patients arewell into their second month of treatment with a four-drugregimen of isoniazid, rifampin, ethambutol, and pyrazinamide.Thereafter, patients infected with susceptible strains receiveisoniazid and rifampin for 4 months.Patients with multidrug-resistant tuberculosis require indi

vidualized regimens based on antimicrobial susceptibility findings [107]. If possible, all patients should receive directly observed therapy. Patients with pleuropulmonary rifampinresistant tuberculosis require ~ 18 months of therapy with twoormore effective drugs. Frankly purulent tuberculous empyemais (fortunately) rare and usually follows a long history ofunsuccessful medical and/or surgical therapies. The pleura is usuallyquite thick, is occasionally calcified, and often has high concentrations of mycobacteria. Therapy should be initiated with repeated thoracentesis and multidrug regimens [107, 108]. Tubedrainage shouldbe avoided in order to prevent secondary bacterial infection of a tuberculous empyema [109]. Control of infection may require decortication or tailoring procedures such asthoracoplasty or surgical correction of associated bronchopleural fistulae [l08].

mpyema rainageDrainage of pus is still a major component of adequate treat

ment of pleural empyema. Serous pleural fluid that is not loculated, is devoid of microorganisms on microscopic examination, or has ambiguous indicators of suppuration (such as ahigh pH, a glucose concentration of ~ mg/dL, and a lacticdehydrogenase level of < 1,000 lUlL) can be treated with antibiotics and reevaluated, with repetition of thoracentesis in12 18 hours (table 4). Patients with loculated fluid, frank pus,or smear-positive purulent fluid with a pH of


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empyemas are often small and loculated [110] and thereforeideal for treatment with small catheters under CT guidance.Alternatively, after placement of skin markers, drainage canbe completed under fluoroscopy. Some authors favor the useof ultrasonography in management of pleural fluid collections,especially those that are large [4, 9, 27, 100]. Ultrasonographyis usually quicker and more convenient to perform but is moreoperator-dependent than CT. Empyema collections occasionally may be difficult to identify or to distinguish from nearbyconsolidated lung by ultrasonography if they contain air orthick pus with extensive echogenic debris [27].

Several recent reviews provide detailed descriptions of thetechniques for percutaneous pleural catheter placement [27, 35,110, 113]. Two general approaches can be taken. The first isa direct trocar technique, in which the catheter is advancedunder imaging guidance over a stiff coaxial cannula, enteringthe collection at the site of a preliminary diagnostic thoracentesis [27]. The second method uses a modified Seldinger technique, in which an 18-gaugeneedle is placed into the collectionunder imaging guidance and a guide wire is advanced throughthe needle; serial subcutaneous fascial dilations are then performed over the guide wire with dilators of progressively largerdiameter, and finally the catheter is placed and anchored to askin dressing.

The choice of technique may be individualized to the patient's requirements. Collections with tenacious pus and thickmargins often require a direct trocar placement to provide themechanical advantage needed for entry and to prevent bucklingof the catheter in the subcutaneous tissues. Trocar placementis also generally quick to perform and can be done withoutassistance. Exchanges over a guide wire require two operators.Fluid is aspirated through the catheter, followed by local irrigation with saline until clear. The catheter is then attached to astandard underwater-seal drainage system for continuous suction at the bedside.

ranscatheter ntrapleural hrombolytic herapyDespite catheter placement and drainage of empyema fluid,

patients may still have residual pockets of undrained fluid anddisplay signs and symptoms of persistent infection [60, 80].This is not surprising, since empyema fluid is often loculated.The act of placing a catheter over a guide wire is helpful inbreaking down at least some loculations, but additional measures may be required to achieve complete drainage. One approach has been to place additional catheters [4, 27, 35, 110,113]. In addition, there has been renewed interest in thrombolytic therapy.

Loculation(s) may form early during development of eithercomplicated parapneumonic effusion or empyema [1]. Theirappearance indicates that the effusion has progressed to thefibropurulent stage, with extensive deposition of fibrin on thepleural surfaces. Pleural fibrosis will occur unless the loculatedcollections are drained and appropriate antibiotics are given.

Strange and colleagues used an animal model of pleural empyema to show that the initial dense fibrin layer began to bereplaced by a network of connective tissue elements by thefifth day [58].When fibrinwas not removed promptly, fibrinousstrands became firmly anchored to the pleural surfaces. Theauthors postulated that fibrin deposition enhances the development of subsequent fibrosis by creating a diffusional barrier tooxygen, since pleural fluid hypoxia and lactic acidosis havebeen shown to enhance fibroblast collagen production in anempyema [58]. These findings support the clinical urgency ofdraining empyema fluid to prevent the formation of intrapleuralfibrosis, which often requires surgical extirpation. talso provides a rationale for therapies specificallydirected at preventionof deposition and removal of intrapleural fibrin early in thecourse of an empyema.

Streptokinase and streptodornase, derived from streptococcalsources, were first used to help drain loculated pleural pus byTillett and Sherry in 1949 [117]. Initial enthusiasm was laterdampened by concern about allergic reactions to the agents.Currently, there is renewed enthusiasm for intrapleural fibrinolysis in cases of complicated parapneumonic effusions andempyema, in part because of the availability of urokinase,which is nonantigenic and nonpyrogenic [15, 16, 19, 20]. Although purified forms of streptokinase are now available[17,21], these have been documented to produce an antibodyresponse [118]. The antibody response is responsible for thefebrile reaction to the agent, which may falsely mimic persistence of empyemas [20]. Urokinase is produced by the humankidney and does not cause an allergic or febrile reaction.We usually perform intrapleural urokinase instillation according to methods of Moulton et al. [19] and Robinson et al.[20]. Each dose consists of 100,000 units given in 100 mL of0.9 sterile saline solution. The 100-mL aliquot is left in thepleural space for at least 2 hours. The catheter or chest tube isthen unclamped and suction restored. This process can berepeated as needed.

Robinson and colleagues suggest that the instillation beginin the evening and continue overnight while the patient sleeps[20]. Unused portions of the urokinase solution should be refrigerated between instillations. While it is possible to giveurokinase by transmurally injecting the solution into an indwelling surgical chest tube, it is more efficient to introduceit through a radiologically placed pleural catheter via a threeway stopcock, which is then turned off in the direction of thecatheter. Use of the catheter ensures that the agent reaches andstays within the pleural collection. The larger de d spaceof surgical chest tubes decreases the effective dose instilledinto the pleura and may decrease the efficacyof a given instillation. The pleural catheter may be repositioned as needed (seefigure 1).

Use of urokinase in the pleural space is safe. Systemic sideeffectshave notbeenreported. Thetotaldosegivenintothe pleuralcavity is approximately one-tenththe doseof the agent commonlygivenintravascularly to lyseclots.Urokinasehasan averageserum



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half-life of 20 minutes. The presence of a bronchoplcural fistulais considered by some authors to contraindicate the use of intrapleural urokinase [16, 19]. However, no adverse effects associated with its use in that setting have been do umented Indeed,empyema and bronchopleural fistula have been effectively managed without complications with use of streptokinase [18]. Urokinase therapy is much less expensive than surgical debridement andmay successfully ir umvent the added morbidity and mortalityassociated with thoracoscopy or thoracotomy [20, 119].

The need for further closed tube drainage is ass ess ed byquantitation of the volume e xpe ll ed daily and the size of thepleural cavity. Drainage of < 50 mUd and cavities


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Figure 1. This case illustrates the use ultrasonography and CT in identifying and characterizing thoracic empyema, as well as the use imaging-guided catheter drainage and transcatheter intracavitary urokinase for managing empyema. A contrast-enhanced CT image showspleural collection. No septations are visible within the pleural collection since they are the same density as the pleural liquid.B Ultrasonographyreveals dependent, echogenic debris in the effusion and a network clearly defined limiting membranes forming loculations. The largeloculation on the right was targeted for thoracentesis and catheter placement. C and D Posteroanterior and lateral chest radiography was donefollowing catheter placement and the immediate removal of 150 mL of fluid. Only minimal additional fluid was removed over the next 24hours, during which time the catheter remained folded within the loculation. Urokinase was then introduced through the catheter to improvedrainage. and F chest radiographs obtained after the first urokinase treatment show that thewalls the loculation have been lysed, permittingthe catheter to uncoil. G and H serial urokinase treatments and drainages were done over 48 hours and the catheter was repositioned. Thesemaneuvers yielded an additional 1,200 mL of empyema fluid. Reprinted with permission from Mandell GL, ed. Atlas infectious diseases.Philadelphia: Current Medicine, 1996 [in press].



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infection. Patients with compromised host defenses are especially vulnerable to the adverse effects of undrained puse.g., malnutrition, sepsis, and multiorgan failure) and therefore are in urgent need adequate drainage early in thecourse of their infection [13, 81, 127, 128]. Delay in diagnosis generally correlates with an adverse outcome [30, 76, 81,

126]. Hoff and co-workers found that the mean duration ofillness prior to the hospitalization children for empyemawas 4.8 days for those cured with antibiotics alone, 5.8 daysfor those requiring chest tube drainage, and 8.0 days forthose requiring decorti cation [76]. They found scol iosis of 5 in 44 children presenting with empyema. None of



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those children were cured by antibiotics alone, and 17 of 27required decortication. Children with scoliosis secondary toempyema had been ill for an average of 7.3 days prior toadmission. Pleural thickening or opacification of a hemithorax correlated with poor prognosis in their series.

There is controversy over the best criteria and techniques forperformance of pleural fluiddrainage [126, 127].The approachsuggested by Light is supported in principle by many authors(table 4). In general, early intervention by the least noxiousmeans is preferred [1 13 76 81 126]. Storm and co-workersfound that daily infusion of intrapleural antibiotics and irrigation with saline over a 2-week period reduced the need for ribresection or decortication to 6 among 51 patients on theirmedical service [128]. During that period, 77 of 43 patientstreated on a surgical service in that hospital required resectionor decortication [128]. There are insufficient data to evaluatethis approach, and further studies are needed.

Posttraumatic empyema has a poor prognosis, and patientsappear to benefit from early decortication if sepsis is poorlycontained despite antibiotic therapy, iflung entrapment impairsventilatory function, or if pleural drainage is inadequate after2 weeks of therapy [39, 70]. Tube drainage is rarely successfulfor management of an infected hemothorax because clots obstruct the tube.

There is a vicious cycle of delayed diagnosis and therapyfor patients with multiple underlying host defense defects,nosocomial infection, andmultiply resistant organisms that adversely affects prognosis. Such patients may have fewer signsand symptoms of their disease, have increased complicationsof malnutrition and multiple organ failure, and respond poorlyto medical and surgical therapy.

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10 7. I se ma n M D, M ad se n L A. Chr oni c t ub er cu lo us e mp ye ma wi th b ro nchopleural fistula resulting in treatment failures and progressive drugresistance. Chest 1991; 100:124 7.

108. Neihart RE, Hof DG. Successful nonsurgical treatment of tuberculousempyema in an irreducible pleural space. Chest 1985; 88:792 4.

109. Magovern CJ, Rusch VW. Parapneumonic and post-traumatic pleuralspace infections. Chest Surg Clin North Am 1994;4:561 82 .

110. Merriam MA, Cronan Jl, Dorfman GS, Lambiase RE, Haas RA. Radiographically guided percutaneous catheter drainage of pleural fluid collections. AJR Am J Roentgenol1988; 151:1113 6.

III. Goldberg MA, Mueller PR, Saini S, et al. Importance of daily rounds bythe radiologist after interventional procedures of th e a bd om en a ndchest. Radiology 1991; 180:767 70.

112. Stavas J, van Sonneberg E, Casola G, Wittich GR. Percutaneousdrainageof infected and noninfected thoracic fluid collections. J Thorac Imaging1987;2:80 7.

113. Hunnam GR, Flower CDR. Radiologically-guided percutaneous catheterdrainage of empyemas. Clin Radiol 1988; 39: 121 6.114. Kerr A, V as ude van VP, P ow el l S, L ig en za C. P er cu ta ne ou s c at he te r

d ra in ag e f or a cut e em py ema : i mp ro ve d cu re r at e us ing CA T s can ,fluoroscopy, and pigtail drainage catheters. NY State J Med1991; 91:4 7.

115. Ali I, Unruh H. M an ag em en t of empyema thoracis, An n Th or ac S ur g1990; 50:355 9.

11 6. L igh t R W. P ar ap ne um on ic e ff us io ns a nd e mp ye ma . Cl in Che st Med1985;6:55 62.

11 7. T ill ett WS, Sh er ry S. Th e ef fec t i n pa tie nt s of streptococcal fibrinolysin streptokinase) and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations. J Clin Invest 1949;28:17390.

118. Berglin E, Ekroth R, Teger-Nilsson AC, William-Olsson G. Intrapleuralinstillation of streptokinase: effects on systemic fibrinolysis. J ThoracCardiovasc Surg 1981;29:124 6.11 9. Hu ll er J A, Ha rar i D , B ai mb ri dg e MY . Th e m an ag em en t of empyemathoracis by thoracoscopy and irrigation. Ann Thorac Surg1985; 39:517- 20.

120. Hoover LE, Hsu H-K, Ross MJ, et al. Reappraisal of empyema thoracis:surgical intervention when the duration of illness is unknown. Chest1986;90:511 5.

121. Silen ML, Weber TR. Thoracoscopic debridement of loculated empyemathoracis in children. Ann Thorac Surg 1995;59:1166 8.

122. Ridley PD, Baimbridge MY. Thoracoscopic debridement and pleuralirrigation in the management of empyema thoracis. Ann Thorac Surg1991; 51:461 4.

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OFFI E OF ONTINUING MEDI L EDU TIONU L S HOOL OF MEDI INE

This test affords you the opportunity to assess your knowledge and understanding of the material presented in the preceding clinical article, Pleural Empyema by Bryant andSalmon, and to earn continuing medical education (CME)credit.The Office of ContinuingMedical Education, UCLA School

of Medicine, is accredited by the Accreditation Council forContinuing Medical Education to sponsor continuing medicaleducation for physicians. The Office of Continuing MedicalEducation, UCLA School ofMedicine, certifies that this continuing medical education activity meets the criteria for credithour in Category I of the Physician s Recognition Award ofthe American Medical Association and the California MedicalAssociation Certificate in Continuing Medical Education.To earn credit, read the State-of-the-Art Clinical Article care

fully and answer the following questions. Mark your answersby circling the correct responses on the answer card (usuallyfound toward the front of the issue), and mail the card afteraffixing first-class postage. To earn credit, a minimum scoreof 80 must be obtained.Certificates of CME credit will be awarded on a per-volume

(biannual) basis. Each answer card must be submitted within3 months of the date of the issue.This program is made possible by an educational grant from

Roche Laboratories.

I Which of the following is not a feature of the CT appearance of pleural empyema?A. Thickened visceral and parietal pleural layersB. Pleural enhancement with intravenous contrastC. Extrapleural fat hypertrophyD. Collection appears to occupy rather than displace lungE. Smooth inner pleural margins

2 Which of the following is the chief physiological mechanism for fluid removal from the pleural space?A. Lymphatic drainage through stoma located in the visceral pleura

B Lymphatic drainage through stoma located in the pari-etal pleura

C. Venous drainage through systemic veinsD Venous drainage through pulmonary veinsE. Venous drainage through pulmonary and systemicvems

3. What is the smallest quantity of pleural fluid shown to bedetectable on a lateral decubitus roentgenograph?A. 5 mLB 25 mL

C. 100 mLD 250 mLE. 1,000 mL

4. What quanti ty is usually required to cause a blunting ofthe posterior costophrenic sulcus on an upright lateral chestroentgenograph?A. 5 mLB 25 mLC 250 mLD. 500 mLE. 1,000 mL

5. Which of the following parapneumonic pleural fluid characteristics does not suggest the need for pleural fluid drainage?A pH, 3.5 g/dL

6. Which infectious cause of empyema is unlikely to necessitate chest tube drainage?A. ycobacterium tuberculosisB. Anaerobic organismsC. Several species of microorganismsD Streptococcus pyogenesE. scherichia coli

7. Which infection is associated with marked pleural fluideosinophilia?A. TuberculosisB. Anaerobic/polymicrobic infectionC ntamoeba histolytica infectionD. ParagonimiasisE None of the above

8. Which of the following features of empyema fluid is nothelpful in excluding the disease causing pleural fluid accumulation?A Pleural fluid amylase level- ruptured esophagusB. Positive cytology-malignancyC. Rheumatoid factor or antinuclear antibody titer-rheumatoid effusion

D. CT liver abscess-pleural amebiasisE pH of


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764 CME Test 1996;22 May

A Acid fast smearB. CultureC Smear and culture pleural biopsy specimenD Determination adenosine deaminase level

10 Which the following suggests that pleural fluid drainageis not required?

A. Overt pusB. Fetid odorC Loculation revealed by CT or ultrasonographyD Persistent fever despite appropriate antimicrobial ther-apyE. None the above



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Clin Infect Dis. 1996 Bryant 747 64