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Pleurodesis for the Therapy of Malignant Pleural Effusions: Should It Be an Inpatient Procedure? Con: Inpatient Procedure

Sterman, Daniel MD; Kruklitis, Robert MD, PhD; Lund, Mark MD; Musani, Ali MD

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From the Interventional Pulmonology Program, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA (Drs. Sterman, Kruklitis, Lund, and Musani).

Reprints: Daniel H. Sterman, MD, Director, Interventional Pulmonology Program, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, U.S.A., (e-mail: Sterman@mail.med.upenn.edu).

Malignant pleural effusions (MPEs) are an increasingly important issue in medicine, because they complicate many advanced malignancies and result in significant dyspnea and chest discomfort. Non-small-cell lung cancer accounts for over one third of MPEs, followed by breast cancer, lymphoma, mesothelioma, ovarian cancer, and gastric and esophageal cancer. 1–3 In general, MPEs portend a poor overall prognosis with a mean survival time of approximately 6 months. 4 Therefore, an appropriate therapeutic goal in patients with MPEs would be to provide palliative relief of debilitating respiratory symptoms.

Various procedures are available for the management of MPEs. The initial procedure of choice remains needle thoracentesis. Whereas this is often required to make a diagnosis, thoracentesis alone is insufficient for the definitive treatment of MPEs as a result of the rapidity of fluid reaccumulation. In fact, one study reported symptomatic fluid reaccumulation within 4.2 days of initial therapeutic thoracentesis. 5 Therefore, effective palliative therapy for symptomatic MPEs necessitates not only the removal of pleural fluid, but also the induction of an “effective” sclerosis of the pleural space to prevent reaccumulation. The American Thoracic Society (ATS) defines “complete” or “effective” pleural sclerosis as “long-term relief of symptoms related to a pleural effusion with absence of fluid reaccumulation on chest radiographs until death.”6

The most common procedure for the induction of pleural sclerosis in MPE involves large-bore thoracostomy tube drainage followed by chemical pleurodesis with various agents such as talc, bleomycin, quinacrine, or doxycycline typically performed in an inpatient setting. 2,4,7 Pleural symphysis has been demonstrated in up to 80% to 90% of patients with MPEs undergoing talc slurry instillation; however, not all patients are optimal candidates for this approach. 7–9 In particular, a subpopulation of patients might fail to achieve pleurodesis such as those patients with “trapped lung” syndrome. More invasive modalities to achieve pleural symphysis include thoracoscopy with mechanical pleural abrasion and/or chemical sclerosis or pleurectomy/decortication. 8,10–16 Although the aforementioned techniques might achieve pleurodesis with high degrees of success, they can entail significant morbidity, including prolonged inpatient hospitalization, limited mobility from the pleural drainage apparatus, fever from pleural inflammation, and significant pain from the chest tube, surgical incision, and/or the sclerosing agent. In addition, the sclerosing agents themselves can be associated with significant morbidity and even mortality, as in the case of talc-induced adult respiratory distress syndrome (ARDS). Sclerosing agents such as bleomycin can be quite costly, not to mention the costs of operating room time, anesthesiology, and a several-day inpatient admission. 7 Because many patients with MPEs have already experienced significant morbidity from chemotherapy and/or radiation therapy, it would be ideal to minimize hospitalization and patient discomfort in the process of relieving respiratory symptoms and controlling fluid reaccumulation.

For these reasons, small-bore pleural catheters have been used for outpatient drainage and sclerosis of MPEs, and their success has been reported in several case series. 17–20 These early descriptions contributed to the development of a small-bore, flexible, tunneled pleural catheter (PC) (Pleurx®, Denver Biomedical, Golden, CO) that allows for periodic home drainage of MPEs. Several studies have demonstrated that PCs are as effective as chest tubes when used for chemical pleurodesis with significantly less pain, cost, and hospitalization. 21–26 In addition, tunneled pleural catheters have proven effective in the management of refractory MPE in patients who cannot achieve pleurodesis because of “trapped lung” syndrome. 27 These catheters have significantly altered the nature of MPE management because they can be inserted on an outpatient basis with minimal postprocedure discomfort, thereby obviating the need for hospitalization. Furthermore, patients can drain the MPE at home on a scheduled or symptomatic basis, preventing fluid reaccumulation, and potentially achieving pleurodesis without significant pain or hospitalization.

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PLEURX® PLEURAL CATHETER

The Pleurx® pleural catheter is a 66-cm long, 15.5 French silicone rubber catheter with fenestrations along the distal portion (Fig. 1). A valve at the proximal end of the catheter prevents fluid or air from entering the catheter until accession by its unique drainage line. A polyester cuff helps to secure the catheter in place within the subcutaneous tunnel, and thereby minimizes the risk of infection. After placement, pleural fluid can be drained periodically from the chest into vacuum bottles by connecting the drainage line access tip to the valve. 27

FIGURE 1.

FIGURE 1.

Pleurx® catheter placement is typically performed as an outpatient procedure under local anesthesia with the use of intravenous midazolam and/or fentanyl for conscious sedation, if needed. The patient's blood pressure, pulse oximetry, and heart rate and rhythm are monitored continuously throughout the procedure. The catheter is placed using a modified Seldinger technique in the midaxillary line, as described elsewhere (see ref. 27), and tunneled under the skin along the chest wall. After catheter insertion, 1000 to 1500 mL of pleural fluid is drained immediately and a chest radiograph is obtained to evaluate catheter position. Before discharge, patients and/or their caregivers receive detailed written and oral instructions for drainage and care of the catheters at home. Pain medications are prescribed as needed, although the use of oral narcotics for chest wall discomfort beyond 24 to 48 hours after catheter insertion is uncommon. 27

Visiting nurses trained initially with an instructional videotape and a handbook on catheter maintenance assist with catheter care and drainage and provide additional teaching to patients. Home pleural drainage of up to 1000 mL per session is performed with the assistance of the visiting nurse. Patients are evaluated at follow up for improvement in respiratory symptoms and pleural effusion on chest radiographs, and for complications of the pleural catheter placement. Visits are scheduled on an outpatient basis weekly for the first 2 weeks and then as clinically indicated. 27

Our institution has extensive experience with the outpatient management of MPEs using indwelling PCs such as the Pleurx®. In our series, the majority of patients with symptomatic MPEs undergoing PC insertion achieved complete or partial pleural symphysis, allowing PC removal 4 to 6 weeks from catheter insertion. Regardless of whether patients with MPE ultimately attained complete pleural symphysis, nearly all achieved symptomatic relief of respiratory distress. The success rate and/or the rapidity of pleurodesis engendered by PC insertion could be ameliorated through instillation of a sclerosing agent (such as doxycycline) after a predefined period of outpatient drainage of the MPE.

Several mechanisms can be proposed as to how pleural symphysis is attained without the use of chemical or physical irritants. First, physical separation of the visceral and parietal pleural surfaces by a MPE prohibits pleurodesis until the 2 surfaces can appose one another. Daily drainage of the MPE can permit sufficient apposition of the visceral and parietal pleurae to allow for eventual pleural symphysis. Second, daily drainage of the MPE can remove protein, cellular debris, or other factors within the MPE that could interfere with the ability of the visceral and parietal pleura to appose one another. Third, certain inflammatory mediators (IL-2, TNF-α, TGF-β) potentially released by the pleural surfaces or tumor cells into the MPE can serve as endogenous sclerosing agents once the visceral and parietal pleura are apposed. Finally, the PC itself can act as a physical irritant to stimulate inflammatory responses and permit pleural symphysis. Pleural symphysis through the PC is invariably multifactorial, possibly involving several of the mechanisms proposed and others not yet understood.

A distinct advantage that PCs have over standard chest tube drainage with chemical pleurodesis relates to the decreased morbidity to patients who already have experienced both surgical and medical therapy for their primary malignancy. Current American Thoracic Society consensus guidelines for MPE suggest an initial thoracentesis to establish a diagnosis of MPE followed by standard chest tube drainage with subsequent talc slurry instillation. This approach requires an average of 4 to 5 days of inpatient hospitalization and is associated with significant pain, limited mobility, and separation from the home environment. Although this approach is quite effective in treating MPEs, 7–9 inpatient hospitalization is costly and can be distressing for patients and their families who likely already have experienced multiple hospitalizations related to their underlying malignancy.

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MANAGEMENT OF MPE WITH `TRAPPED LUNG'

The patients with MPE who are least likely to benefit from pleural drainage and chemical sclerosis are those with so-called “trapped lung.” These patients often have a dense peel of malignant tissue encasing the visceral pleura and fail to exhibit complete lung reexpansion after drainage of the effusion. 28 Because apposition of the pleural surfaces cannot be achieved, sclerosis attempts are rarely successful and management for these patients has proved challenging. Therapeutic options include repeated thoracenteses, long-term thoracostomy drainage, pleurectomy with decortication, and pleuroperitoneal shunting. 29 Each of these techniques, however, carries with it specific risks and liabilities, and some might not be feasible for all patients.

Serial thoracenteses can provide immediate relief for symptoms resulting from chronic MPE and trapped lung, and has traditionally remained an option for patients felt to be unsuitable candidates for other therapies, especially those with limited life expectancy. However, as MPE usually recurs quickly, these patients could require frequent intervention. With repeated procedures, they are at increased risk for complications, including pneumothorax, empyema, loculation of pleural fluid, and hypoproteinemia. Long-term tube thoracostomy drainage offers some of the advantages that are conferred by the Pleurx® catheter, namely, the capacity for use in the home setting. However, a semirigid chest tube, sutured to the chest wall at the point of entry into the pleural space, can cause discomfort and increase the risk of infection. Additionally, patients might not have significant control over the timing or duration of drainage, requiring constant connection to a relatively bulky portable water seal drainage system. Accidental disconnection from the system can lead to a tension pneumothorax. Because of these considerations, extended-term tube thoracostomy drainage is infrequently used in the management of patients with MPE. 29

Pleuroperitoneal shunting might also allow some patients who are not candidates for definitive therapy with pleurectomy and decortication to achieve palliation of symptoms arising from recalcitrant MPE. 30 These shunts can be placed under general or local anesthesia and are tunneled subcutaneously, decreasing the risk of infection. Patients are required to perform manual compression of the pump chamber multiple times during the day for effective evacuation of the pleural space and to keep the shunt patent, requiring a time commitment of at least 20 to 40 minutes daily. 31 Potential complications include infection, malignant peritoneal seeding, and small bowel obstruction. 32 Shunt occlusion resulting from tumor ingrowth or fibrin debris has also been reported. 33,34 Contraindications to pleuroperitoneal shunt placement include inability to operate the pump, multiple loculations, or an obliterated peritoneal space. 33–35

Pleurectomy and decortication are generally considered to be definitive palliative therapy in the management of recurrent MPE with “trapped lung.” The high perioperative morbidity and mortality of pleurectomy and decortication preclude consideration of these procedures for most patients. Those who do undergo the procedure tend to have excellent preoperative functional status and significant life expectancy, having nevertheless failed other attempts at palliation. 27

In our experience, placement of a permanent pleural catheter for repeated drainage of symptomatic pleural fluid accumulations provides a convenient, effective alternative to the procedures currently in use for patients with refractory MPE and “trapped lung.” Most patients experienced relatively minor, if any, problems with chronic catheter use. Skin breakdown and insertion site infection typically respond promptly to wound care and oral antibiotics. Catheter infection and occlusion are potentially serious complications for which patients should be vigilantly monitored. As a relatively noninvasive procedure, pleural catheter placement can be performed reasonably in patients in whom other invasive procedures are contraindicated as a result of, for example, somewhat limited life expectancy or metastatic abdominal disease. The pleural catheter is usually placed in the outpatient setting and can be maintained largely at home, minimizing time spent at office visits and in the hospital. 27

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COMPLICATIONS RELATED TO PLEURAL CATHETER INSERTION

The complications related to the placement and maintenance of the catheters are generally infrequent and easily managed. Adverse events occurring during PC placement are unusual given proper physician training, supervision, and nursing assistance. Occasionally, PCs will require repositioning because of tube compression against an adjacent rib or attachment to a pleural drainage container because of air entry through the thoracostomy. The most common postprocedure complications include cellulitis localized to the insertion site; bacterial superinfection of the MPE; development of a symptomatic, loculated MPE; and incisional tumor growth, although these occur in a minority of patients. Each of these complications can be managed conservatively with antibiotic, removal of the PC, insertion of a standard thoracostomy tube, or additional antineoplastic therapy. This list of postprocedural complications is not much different from that seen with chest tube drainage and talc slurry instillation, particularly the development of loculations, occasionally requiring surgical intervention through video-assisted thoracic surgery (VATS) or decortication.

One significant limitation to the tunneled PC is its ability to effectively drain loculated effusions. Chest computed tomography (CT) scans, or transthoracic ultrasound, should be performed in all patients with malignant pleural effusions before placement of the PC to rule out the presence of loculated effusions, especially if there is a history of previous pleural intervention. Although standard chest tube drainage of MPE has similar limitations, some loculations can be physically disrupted either by the individual placing the chest tube or by the chest tube itself as it is inserted into the thoracic cavity. Certainly, intrapleural loculations can be lysed effectively at the time of video thoracoscopy. In a handful of cases, our interventional radiology colleagues have placed pigtail catheters for multiloculated effusions. These patients were deemed unsuitable for chest-tube mediated pleurodesis as a result of location of their loculations or a history of failure by chest tube drainage. Fortunately, many MPEs are not loculated and often only become loculated after a failed attempt at chemical or physical pleurodesis. In this manner, although PC-directed pleurodesis might take longer to occur, the incidence of loculated effusions can be reduced compared with that of other methods.

Although MPEs can contain a significant amount of protein, there have been no published reports of protein malnutrition during the period of repeated pleural fluid drainage. This complication could be envisioned if pleurodesis was not attained and large-volume daily drainage was required over an extended period. This proved not to be a significant problem in patients with lung entrapped by malignancy. 27 Furthermore, in our experience, no patients developed reexpansion pulmonary edema with the PC because the quantity of fluid drained could be tightly regulated, unlike the situation often encountered with placement of standard chest tubes as a result of the technical aspects of a larger portal of entry and rapidity of tube placement.

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CONCLUSION

The development of MPEs in advanced malignancies can cause significant morbidity and can lead to progressive respiratory failure and death. Adequate drainage of MPEs with subsequent pleural symphysis can provide significant palliation for these patients. Several approaches are available to provide palliation, including repeated thoracentesis, chest tube drainage with chemical pleurodesis, VATS with chemical or mechanical pleurodesis, and surgical pleurectomy/decortication. As mentioned previously, each of these modalities has its limitations, and a more effective and less invasive approach for treating MPEs would be desirable.

It is our opinion that tunneled, indwelling PCs are a cost-effective and desirable approach to the management of MPEs. They can be inserted on an outpatient basis without the subsequent pain, constitutional symptoms, and hospitalization required for chest tube-mediated chemical pleurodesis. The MPEs can then be drained at home by a visiting nurse, and after appropriate training, by a family member. At subsequent follow-up outpatient visits, the pleural fluid output is evaluated, along with the patient's respiratory symptoms and catheter-related problems. Even patients with acute respiratory distress from MPEs can potentially be managed as outpatients using these devices. Before PC use at our institution, these patients would have undergone standard chest tube management of these MPEs. All of these advantages would represent not only a significant cost savings, but also a less invasive and more acceptable palliative approach to the management of MPEs. We do, however, acknowledge a potential selection bias in the fact that the sickest patients might have been excluded from our clinical experience because they were likely admitted for surgical management of their MPEs.

Our experience at the University of Pennsylvania Medical Center suggests that insertion of tunneled, indwelling PCs for outpatient management of MPEs provides a minimally invasive, cost-effective approach for this common clinical problem compared with current strategies for the management of MPEs. In the United States, the Cancer and Leukemia Group B (CALGB) is currently conducting a phase III randomized, controlled trial comparing current recommended guidelines of chest tube drainage with talc slurry pleurodesis with that of outpatient PC-mediated MPE control, which will include quality-of-life comparisons between the 2 groups. Ultimately, this multicenter study might provide the answer as to the best overall approach to the management of the patient with symptomatic MPE.

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