dummy, factorially randomized trial MIST-2 evaluated the effectiveness of t-PA and the DNAse. They found the combination of t-PA 10 mg twice daily and DNAse 5 mg instilled for 1 h via clamping the thoracostomy tube twice daily, for 3 days improved their primary outcome of improved pleural drainage as measured by changes in pleural opaci cation as a percentage of hemithorax via chest X-ray (CXR) on day 7 [15]. They also found a reduction in their secondary outcomes of surgical referral at 3 months (4% vs. 16% in placebo), reduced hospital length of stay (mean difference of 6.7 fewer days in t-PA + DNAse group compared to placebo), and reduced fever on day 7, but no change in mortality at 3 or 12 months. The question of when to consider thrombolytics versus proceed with operative management is still a topic of considerable debate, which MIST-3, comparing thrombolytics to early video-assisted thoracoscopic surgery (VATS) will attempt to address [5].

Prognostication

Multiple studies have attempted to identify prognostic factors associated with empyema. In 1999, Davies et al. sought to identify clinical predictors for failure of medical treatment. They found an absence of frank purulence on sampling of the pleura to be useful for predicting success for medical therapy (positive predictive value 93%). While the presence of purulence was seen more often in treatment failure (77% vs. 40%), it had a poor positive predictive value of 26% for predicting failure [35]. Bacteremia seemed, with a non-­ signi cant trend toward predicting medical failure. Interestingly, they found no difference in medical treatment successes or failures for delays in antibiotics, delays for chest drainage, pleural fuid biochemistry or bacteriology, or pleural fuid collection size.

Later, Rahman. et al. continued this work, but instead of identifying risk factors for medical treatment failure, they evaluated 22 baseline characteristics from the patient in the MIST-1 cohort to see which were associated with a high-­ risk of death. From these 23 characteristics, they

derived the RAPID (renal, age, purulence, infection, and dietary) score [17]. Patients were given an aggregate score from 0–78 based on renal function (BUN in mg/dL, 0 points for <14, 1 point 14–23, or 2 points >23), age (0 for <50, 1 50–70, 2 for >70), purulence (0 for present, 1 absent), infective source (0 for CAP, 1 for HAP), and dietary evaluation (1 points for albumin <2.7, 1 for albumin <2.7). Of these 5 risk factors, hypoalbuminemia and elevations in urea were the only statistically signi cant predictors for mortality at 3 months (odds ratio of 2.8 and 3.96, respectively), while the others demonstrating strong effects but not signi cance. Compared to the 1999 Davies et al. retrospective analysis, Rahman et al. found the absence of purulence to be risk factor for worse outcomes.

Based on their aggregate score, patients were then grouped into risk low (0–2), medium (3–4), and high (5–7) risk categories. These risk categories were then prospectively applied to the Second Multicenter Intrapleural Sepsis Trial (MIST-2) patient cohort. They found the RAPID score predicted mortality well, with an area under the curve (AUC) of 0.88 but did not predict requiring surgery at 3 months (AUC 0.36). When evaluating the individual risk groups, the RAPID score described a signi cant difference in mortality, with 3-month mortality in the low-risk group of 1–3%, compared to the medium risk 3-month mortality of 9%, and the high-risk group mortality of 31%. Interestingly, this importance of nutrition refects the 1918 U.S. Army Empyema Commission ndings, where nutritional needs, estimated via 24-hour urine and chest tube aspiration nitrogen quanti cation, were estimated between 3300 and 3500 calories [12].

Surgical Management

The two essential goals when managing parapneumonic effusions and empyema are draining the pleural fuid and achieving pulmonary re-­ expansion, thereby resolving the infection and restoring pulmonary function. Exudative effusions are best managed with thoracentesis and antibiotic therapy. The majority of those with

brinopurulent effusions can be successfully treated with pleural drains and intrapleural brinolytic therapy with t-PA—DNase. Yet a signi - cant proportion of those with brinopurulent effusions, and most with effusions in the organization stage, will have suboptimal results with intrapleural brinolytic, manifested as incomplete drainage, inadequate pulmonary re-­ expansion, or clinical deterioration. These patients require a surgical drainage procedure. Such individuals often can be identi ed early in their clinical course by suggestive ndings on chest CT, including multiple loculations and contrast­ enhancement of the parietal pleura suggesting a “peel” or “rind,” indicative of the organization stage.

Video-assisted thoracoscopic surgery (VATS) should be the therapeutic maneuver after unsuccessful intrapleural brinolytic therapy, or whenbrinolytic therapy is unlikely to be successful. Thoracoscopy has been used for endoscopic examination of the pleural space since the middle of the nineteenth century. Progress in video technology led to its expanded use in the 1980s. The indications for VATS have broadened considerably in the past three decades. VATS was initially utilized for minor pleural procedures such as pleural biopsy, drainage of effusions or hemothoraces, pleurodesis, and limited pulmonary procedures including bullectomy and wedge resection. Increasing application to major thoracic procedures has emerged and VATS is employed for a host of operations such as: anatomic pulmonary resections including segmentectomy, lobectomy, and pneumonectomy; esophageal procedures such as myotomy and minimally invasive esophagectomy; and mediastinal surgery. VATS has several advantages over thoracotomy, for example, decreased pain, fewer perioperative complications, shorter chest tube duration, decreased length of stay, faster return to functional status, and improved oncologic outcomes.

VATS affords the ability to visualize the infected pleural space and determine when complete drainage of all empyema fuid and disruption of all adhesions and loculations have been accomplished. If lung entrapment is present, decortication is indicated. Performed early before

collagen deposition on the visceral pleura and entrapment of the lung, VATS can be used to disrupt brinous adhesions, completely drain all infected fuid, debride the parietal and visceral pleura, and precisely locate chest tubes. As with all interventions for parapneumonic effusions and empyema, VATS must accomplish the two key therapeutic goals of establishing a uni ed pleural space via thorough fuid drainage and ensuring total re-expansion of the lung with obliteration of the pleural cavity. When VATS provides inadequate visualization due to the complexity of loculations, if debridement is insuf cient, or if the time required to adequately perform the operation is excessive, thoracotomy is indicated. The earlier that VATS is employed, the more likely it is to be successful, thus avoiding thoracotomy. Hence, VATS should occur promptly if intrapleural brinolytic therapy is unlikely to be successful or if it has failed to clear the pleural space effectively and re-expand the lung.

On VATS examination of the pleural space, a determination is made as to whether all fuid can be drained and the extent of lung entrapment. When the lung is not entrapped, debridement, irrigation, and disruption of all adhesions and loculations can be accomplished in a straightforward manner. Two or three large-bore (24 Fr to 28 Fr) chest tubes are placed using video assistance and left to suction drainage until outputs diminish, sometimes within 2 days. When the output is suf ciently low and the drained fuid is clear, rather than purulent, chest tubes can be removed. Success using VATS usually depends on whether the lung is entrapped by a thick visceral peel (organized phase of empyema). Thebrinopurulent, multiloculated stage of empyema is particularly amenable to thoracoscopic management. If the lung is found to be entrapped, conversion to thoracotomy for decortication is more often required. Decortication using VATS can result in parenchymal lung injury and bleeding, may inadequately remove the peel, and is frequently time-consuming.

Decortication via a thoracotomy should be performed when the organization stage of empyema is suggested by a CT scan that reveals vis-

ceral pleural enhancement without brin septation in multiple areas of loculation. It should also be considered if the lung does not re-expand after thorough fuid drainage. Entrapment should be suspected when this has occurred, particularly when the pleural process is known to have been ongoing for greater than 2 weeks. After creating a thoracotomy, a complete decortication can be performed with wider exposure. The videoscope can still be used through the incision, or through planned chest tube sites, to better access the hard-­ to-­reach areas. The rst objective of the operation is to remove all purulent fuid, brinous debris, and thickened parietal pleura. Hemostasis is critical or a resulting hemothorax may occur, defeating the initial purpose. The second objective, more technically challenging but most critical task, is to resect the visceral pleural peel. A plane of separation between the peel and visceral pleura must be established. This is accomplished with scissors, knife, and curettes. Blunt dissection can result in parenchymal injury, and should be utilized cautiously. When the proper plane is established, the peel is stripped completely from the entire lung. The lung must be freed entirely from the chest wall, mediastinum, and diaphragm. All of the brotic visceral peel should be removed, even within the lung ssures. The costophrenic angle should be re-established. Complete re-­ expansion of all lung parenchyma is the goal. Decortication is achieved most easily through thefth or sixth intercostal space, which allows access from the diaphragm and costophrenic angle to the apex. This is a major operation and results in signi cant morbidity and mortality rates, especially among debilitated patients and those with signi cant medical co-morbidities.

When the operative risk of thoracotomy with decortication is prohibitive, a lesser open drainage procedure may be considered. The Eloesser fap originally was described as a drainage procedure for tuberculous empyema. A U-shaped fap of skin and subcutaneous tissue is formed and then sewn into the most dependent portion of the empyema cavity after resecting a portion of the underlying two or three ribs and attached intercostal muscles. With the fap acting as a tubeless,

one-way valve, air is allowed to egress against less resistance than air entering. The lung may then gradually re-expand and obliterate the cavity. Alternatively, when a smaller window is suf cient to achieve drainage, a short segment single rib resection can be performed. A silicone salivary bypass drain is inserted with the fange secured to the skin with sutures and a colostomy apparatus used to collect the drainage. These lesser open drainage procedures are more effective when a unilocular empyema is present and located inferiorly or laterally. The procedure can be accomplished under local anesthesia with intravenous sedation in a high-risk surgical patient.

Survivorship

For those patients who survive treatment, many have been found to have residual pleural defects. In 2003, Castro et al. evaluated the prevalence of persistent pleural thickening 6 months after infection, and risk factors associated with its development. They de ned persistent pleural thickening as pleural thickness ≥ 10 mm, measured at the lateral chest wall at the level of an imaginary line tangential to the dome of the diaphragm on a posterior-anterior lm. Of 348 patients with parapneumonic effusion or empyema, 13.79% had residual pleural thickening (RPT) at 6 months [21]. Patients with RPT had signi cantly larger effusions, lower pleural fuid pH levels, and higher pleural fuid LDH and leukocyte levels. Pleural leukocyte counts had the highest diagnostic accuracy for RPT, with patients with pleural fuid leukocytes >1000 per mm3, having an AUC of 0.78 (compared to volume effusion AUC 0.63, pleural fuid glucose 0.47, and pleural fuid pH 0.61). Despite this, when comparing patients with and without RPT, there was no statistically signi cant differences in forced vital capacity values at 6 months, nor in the Borg dyspnea index. Patients without RPT, however, did experience signi cantly higher improvement in FVC between discharge and 6 months compared to those with RPT, suggesting that RPT has limited functional impact.

Summary and Recommendations

With increasing incidence, evolving bacteriology, and persistently high morbidity and mortality, the early involvement of an interventional pulmonologist or thoracic surgeon is recommended. Early evaluation by ultrasound or chest CT can better evaluate potential effusions, and imagingguided tube thoracostomy with thoracentesis or small-bore chest tube is the diagnostic and initial therapeutic procedure of choice. Evaluation by pleural chemistry combined with fuid culture with gram stain coupled with inoculation of blood culture bottles currently offers the best diagnostic yield, with next-generation biomarkers and microbiological analysis providing future hope for better pathogenic identi cation. For complicated parapneumonic effusion, current best practice favors appropriate antibiotics and intrapleural thrombolytics with t-PA and DNase, with further studies are pending to identify which patients would bene t with earlier surgical intervention via VATS with decortication. In patients with evidence of an organized parapneumonic effusion, the early involvement of thoracic surgery allows for expedient pulmonary re-expansion.

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Defnition and Pathogenesis

Malignant pleural effusion (MPE) is the accumulation of pleural uid (PF) caused by malignant involvement of the pleural cavity. It is an ominous fnding that usually signifes widespread metastatases [1]. Most pleural metastases arise from tumor emboli to the visceral pleura, with secondary seeding to the parietal pleural [2, 3]. Direct extension of tumor from the lung, chest wall, mediastinal structures, or diaphragm and hematogenous metastasis to the parietal pleura are other mechanisms of malignant pleural involvement (Fig. 33.1) [2, 4]. In addition to direct tumor involvement of the pleura, MPEs can result from lymphatic blockage anywhere between the parietal pleura and the mediastinal lymph nodes [3, 5]. Increased pleural permeability caused by tumor involvement and over production of local factors, such as vascular endothelial growth factor (VEGF), play a signifcant role in the formation of MPE [6–8]. Among VEGF homologs, VEGF-D showed a 92.6% rate of positive expression in a study of MPE [9]. The unbalance created by the

C. A. Jiménez (*) · V. R. Shannon

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center,

Houston, TX, USA

e-mail: cajimenez@mdanderson.org; vshannon@mdanderson.org

Fig. 33.1  Pathogenesis of pleural metastases. Modifed from Rodriguez-Panadero F [4]. Visceral pleural is seeded via tumor embolization or direct invasion. The parietal pleura is affected by neoplastic spread across the pleural cavity from the visceral pleura along areas with pleural adhesions, and by exfoliated malignant visceral pleural cells attaching to the parietal pleural. Hematogenous metastases to the parietal pleural occur with some malignancies (i.e., ovarian or breast origin)

abnormal excess production and decreased absorption of PF results in a surplus accumulation of PF (Fig. 33.2) [10]. Seventeen percent of all pleural effusions in patients with cancer are “paramalignant,” a term used for effusions that occur in the setting of cancer that is not caused by direct malignant involvement of the pleural space [11]. These effusions develop as a result

of local or systemic effects of the tumor, complications of cancer therapy, or concurrent nonmalignant disease [12]. Lymphatic obstruction is associated with both malignant and paramalignant effusions and is the most common cause of paramalignant effusions. Other common causes include bronchial obstruction, trapped lung, and pulmonary embolism.

Parietal pleura

5

VEGF

4

Parietal

capillary 1 pressure

Interstitial

lymphatic

Lymphatic stoma

3

Net flow of transpleural fluid

Pulmonary interstitial space

Visceral pleura 5

VEGF

4

2Pulmonary capillary pressure

Interstitial

lymphatic

Fig. 33.2  Pathophysiology of malignant pleural effusion. (Modifed from Zocchi L. [10]). VEGF vascular endothelial growth factor (elevated). π = pleural space oncotic pressure (increased). (1) Elevated parietal pleural starling

fltration. (2) Impaired starling absorption. (3) Obstruction of lymphatic stoma. (4) Hampered electrolyte-couple liquid out ow. (5) Disturbed vesicular ow of liquid accompanying protein transcytosis

Clinical Manifestation, Imaging

Studies, and Diagnosis

Between 20% and 40% of patients with a malignant pleural effusion claim to be symptom free [13, 14]. Most of them have very small amounts of PF. Unsurprisingly, the commonest symptom is progressive exertional dyspnea. The physiopathology of breathlessness associated with a pleural effusion continues to be a subject of debate. Recent evidence supports prior fndings suggesting dyspnea is related to increased breathing effort due to impaired respiratory mechanics. Compromised diaphragmatic function associated with a caudal displacement of the dome of the diaphragm, rather than compression of the lung parenchyma or hypoxemia, is the pathophysiologic mechanism responsible for impaired respiratory mechanics and dyspnea [15, 16]. In fact, patients presenting with hypoxemia and pleural effusion should undergo further workup to determine an alternative cause to explain the hypoxemia, even if the pleural effusion is large [15].

a

Cough or chest discomfort is reported in approximately 50% of the patients [17]. Associated symptoms of hemoptysis and chest wall pain suggest malignant endobronchial disease and tumoral invasion of the chest wall [18]. Constitutional symptoms are common signals of advanced malignant disease, and thus malaise, weight loss, and poor appetite will become more frequent complaints as the patient’s overall condition worsens [18].

Standard chest X-rays and ultrasonography of the chest provide critical information in the initial evaluation of pleural effusions, including effusion size, position of the mediastinum and diaphragms, presence of loculations, or air uid levels within the pleural space and characteristics of the underlying lung parenchyma. Knowledge regarding the position of the mediastinum is imperative in therapeutic decision-making. Large pleural effusions with contralateral mediastinal shift typically require prompt therapeutic thoracentesis (Fig. 33.3a, b) [4, 18]. When a centered or ipsilateral shift of the mediastinum is seen

b

Fig. 33.3  (a) 66-year-old man with pancreatic adenocarcinoma. Anteroposterior view of the chest with complete opacifcation of the left hemithorax and contralateral mediastinal shift caused by a large pleural effusion. (b) Posterioanterior chest view after drainage of 5350 cc of

pleural uid. There is complete lung expansion with a small apical left pneumothorax and small residual right and left pleural effusions. There are bilateral opacities more prominent on the left hemithorax and bilateral nodular lesions

with a large pleural effusion, other disease processes need to be considered, including a frozen or fxed mediastinum associated with malignant mesothelioma or lymphoma, atelectasis related to occlusion of the ipsilateral central airway, or extensive tumoral infltration of the ipsilateral lung simulating a large effusion [4, 18, 19].

Computer tomography (CT) is helpful in identifying loculated effusions; it offers more detailed anatomical information of the chest wall, parietal and visceral pleurae, mediastinal structures, and lung parenchyma, and is especially valuable in delineating alternate diagnoses. CT fndings that suggest malignancy include pleural nodularity, pleural rind, mediastinal pleura involvement, parietal pleura thickening of more than 1 cm, and invasion of adjacent structures [18, 20].

Ultrasonography is more sensitive than chest radiographs detecting PF and discerning pleural effusions from lung consolidation, solid pleural abnormalities or diaphragmatic displacement (Fig. 33.4a–e) [21, 22]. It provides guidance in locating the optimal site for thoracentesis and is particularly helpful in the setting of loculated pleural effusions [22]. In addition, utilizing ultrasound with M mode and strain analysis could be useful in identifying entrapped lung prior to PF drainage, facilitating the selection of those patients suited for pleurodesis [23].

Positron emission tomography (PET) with 18Fuorodeoxyglucose (FDG) and magnetic resonance imaging (MRI) are both helpful in highlighting extra-pleural extension of disease [18]. PET imaging provides valuable information associated with malignant mesothelioma; however, its utility in the evaluation of other malignant pleural diseases has not been established [18].

PF analysis reveals an exudative effusion in most cases, with only 5% of MPE effusions being

transudates [12]. Positive PF cytology, noted in 62–67% of cases, represents the diagnostic cornerstone of MPE [24–26]. However, the yield of PF cytology varies according to tumor type [4, 26]. It is higher in those patients with pleural effusion caused by endometrial cancer (75%), thyroid cancer (77%), adenocarcinoma of the lung (78%), urothelial carcinoma (83%), ovarian cancer (84%), breast cancer (85%), and pancreatic cancer (86%). PF cytology yield is lower on patients with sarcoma (20%), head and neck malignancies other than thyroid cancer (21%), renal cancer (37%), and squamous cell carcinoma of the lung (39%).

The presence of elevated tumor markers in pleural effusions should not be used alone to diagnose malignancy, but should prompt additional invasive procedures to determine a more accurate diagnosis [27, 28]. The diagnostic approach to pleural effusions of patients with suspected or established hematopoietic or lymphoid malignancies requires an excellent clinical evaluation and a prompt PF analysis to detect infection, uid overload, thrombosis, or therapy-related causes [29–33]. If malignant involvement is suspected, it is recommend to use a stepwise approach, implementing increasingly complex techniques such as immunohistochemistry, owcytometry, and electron microscopy in order to increase the diagnostic yield [30, 34].

Pleuroscopic pleural biopsies have a 95% sensitivity in the diagnosis of pleural malignancies, and diagnostic yield increases only incrementally (1%) when combined with PF cytology [24]. Image-guided pleural biopsies have a slightly lower sensitivity (87%) [35]. By contrast, closed pleural biopsy has a diagnostic yield of only 44–47% but improves to 77% when combined with an analysis of PF cytology [24, 35].

Fig. 33.4  (a) 37-year-old woman with breast cancer and extensive metastases. Posterioanterior chest view with opacifcation of the lower half of the right hemithorax. (b) Lateral view of the chest. The right hemidiaphragm cannot be delineated. (c) CT chest axial cut. Enlarged liver with metastatic disease with cephalad displacement of the

right hemidiaphragm. (d) Ultrasound image of the right hemithorax with a moderate size pleural effusion. Starting from the top in a clockwise direction, arrows show the chest wall and parietal pleura, the right hemidiaphragm and the collapsed right lower lobe. (e) Anteroposterior chest view after draining 800 cc of pleural uid