Malignant pleural effusion frequently complicates both solid and hematologic malignancies and is associated with high morbidity, mortality, and health care costs. Although no pleura-specific therapy is known to impact survival, both pleurodesis and indwelling pleural catheter (IPC) placement can significantly alleviate symptoms and improve quality of life. The optimal choice of therapy in terms of efficacy and particularly cost-effectiveness depends on patient preferences and individual characteristics, including lung expansion and life expectancy. Attempting chemical pleurodesis through an IPC in the outpatient setting appears to be a particularly promising approach in the absence of a nonexpandable lung.
Key points
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Malignant pleural effusion frequently complicates both solid and hematologic malignancies, typically recurs, and is associated with high morbidity, mortality, and health care costs.
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Chemical pleurodesis and indwelling pleural catheter (IPC) placement are 2 minimally invasive palliative approaches.
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Attempting chemical pleurodesis through an IPC appears to be a particularly promising approach in the absence of a nonexpandable lung.
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Specific management strategies should focus on patient-centered outcomes, optimizing quality of life and cost-effectiveness.
Introduction
In humans much like most mammals (the elephants being a notable exception), each lung is surrounded by the visceral and parietal pleura. The visceral pleura lines the lung parenchyma (including the fissures), and the parietal pleura lines the chest wall and diaphragm. Relatively speaking, the parietal pleura is more richly vascularized than the visceral pleura, and the corresponding Starling forces typically result in net production of a small amount of serous, transudative fluid into the pleural space. The robust lymphatic infrastructure on the parietal surface is responsible for maintaining a physiologic amount of pleural fluid, measuring approximately 0.26 mL/kg of body weight, within each pleural cavity. Lymphatic drainage can increase by 28-fold in order to limit pleural fluid accumulation. The presence of more than a small amount of pleural fluid implies either a major increase in pleural fluid production, a reduction in pleural fluid drainage, or a combination of both processes. Malignant pleural effusion (MPE) refers to accumulation of pleural fluid as a consequence of an underlying malignancy and is most commonly due to lung or breast cancer. A patient is diagnosed as having MPE using either pleural fluid cytology (that has a limited sensitivity of around 60%) or pleural biopsy, which, when performed thoracoscopically, has a sensitivity of around 95%. At times, MPE is presumed in the setting of a suggestive fluid biochemical profile in a patient with known underlying malignancy. Ultrasonographic characteristics (parietal pleural thickening >1 cm, diaphragmatic thickening >7 mm, and presence of diaphragmatic nodules) or radiographic findings (such as nodular pleural thickening or mediastinal pleural thickening) can also suggest MPE ( Fig. 1 ). ,
MPE accounts for a considerable public health burden in both inpatient and outpatient settings. Almost all patients are symptomatic, with dyspnea and chest pain being the most common symptoms, and the disease has a significant impact on health-related quality of life (HR-QOL). , Approximately 50% of patients with lung cancer will develop a pleural effusion, and according to 1 postmortem case series, 15% of patients dying from any malignancy had MPE. MPE accounts for more than 150,000 hospital admissions annually in the United States alone, with an estimated inpatient health care expenditure of greater than $5 billion each year. MPE commonly recurs after an initial thoracentesis, and as such, definitive and early pleural palliation is recommended.
Prognosis
MPE carries a poor prognosis. Variable estimates of survival have been published, but the most robust and prospectively gathered data point to a median survival of approximately 6 months with a range of 3 to 12 months. Table 1 illustrates the 2 prognostic scores currently available for clinical use. The LENT score is a prospectively validated score that estimates median survival for patients with MPE. It only requires 4 parameters for calculation (namely, pleural fluid lactate dehydrogenase levels, performance status, serum neutrophil-to-lymphocyte ratio, and tumor type) and is therefore very pragmatic. It was shown to perform reasonably well in a subsequent validation study, but clinicians and randomized trial investigators have continued to struggle in terms of consistently identifying patients with very low survival. The more recently developed and validated PROMISE score is a risk-stratification system (A = lowest risk, D = highest risk) that combines a pleural fluid biomarker (TIMP1) with clinical factors (namely, history of chemotherapy or radiotherapy, serum hemoglobin, serum C-reactive protein, serum white blood cell count, performance status, and tumor type) and appears to perform significantly better based on initial analyses. TIMP1, a glycoprotein that stands for tissue inhibitor of metalloproteinases 1, has been previously identified as a regulator of the extracellular matrix structure and a promoter of antiapoptotic activity. In the absence of pleural fluid TIMP1 testing, only the clinical variables can be used to calculate a clinical PROMISE score with reasonably good test performance based on initial validation (C statistical value of 0.89). Further investigation is needed for external validation.
| Biomarker | LENT Score | PROMISE Score |
|---|---|---|
| Pleural fluid lactate dehydrogenase | ☒ | |
| Eastern Cooperative Oncology Group performance status | ☒ | ☒ |
| Serum neutrophil-to-lymphocyte ratio | ☒ | |
| Serum white blood cell count | ☒ | |
| Tumor type | ☒ | ☒ |
| History of chemotherapy or radiotherapy | ☒ | |
| Serum hemoglobin | ☒ | |
| Serum C-reactive protein | ☒ | |
| Pleural fluid TIMP1 | ☒ |
Discussion
Overview of Management
The foremost aim of MPE management is improving dyspnea and quality of life while minimizing need for additional pleural procedures.
This goal can be achieved through the 3 following major strategies:
- A.
Thoracentesis
- B.
Pleurodesis
- C.
Indwelling pleural catheter (IPC)
Thoracentesis
Thoracentesis can offer a quick and minimally invasive way to improve dyspnea in patients with MPE. However, it neither mitigates the risk of effusion recurrence nor helps address it when it does occur. Although thoracentesis represents the least invasive and least risky of all procedures, it is associated with a higher cumulative risk of complications, including pneumothoraces and emergency room visits, when used for patients with rapidly recurring MPE.
In addition to necessitating repeated interactions with the health care system and potentially multiple needle sticks, complications associated with thoracentesis include a dry tap (ie, unsuccessful aspiration of fluid), pneumothorax, bleeding, and reexpansion pulmonary edema (RPE). , Uncommonly, an unresolving pneumothorax/persistent air leak has also been observed following thoracentesis. With the advent of point-of-care ultrasonography, both dry tap and pneumothorax rates have substantially decreased to approximately 2% to 3% each, whereas rates of pneumothorax needing tube thoracostomy have been reported to be down to around 1%. Although historical convention was to limit maximum fluid removal to 1.5 L in order to limit the incidence of RPE, an observational study of 185 patients undergoing large-volume thoracentesis (ranging from 1000 to 6550 mL) found a very low rate of clinically evident RPE (1 patient, or 0.5%) with no evidence to suggest an association with the amount of fluid removed.
Bleeding is an infrequent complication of thoracentesis. Although the convention has been to avoid the procedure in a patient with a platelet count less than 50,000/uL, renal insufficiency, use of anticoagulants, or use of nonaspirin antiplatelet agents such as clopidogrel, a prospective observational study of 312 patients undergoing thoracentesis (with 130 of them identified as having one or more of the afore-mentioned risk factors) found no occurrences of hemothorax over a 30-day follow-up period. On the other hand, knowledge of anatomy and careful attention to anatomic landmarks are key when performing the procedure; the foremost anatomic fact to keep in mind is that the costal groove, which typically houses the intercostal vessels and nerve, is located near each rib’s inferior surface. That said, the intercostal artery does not always lie within the confines of this costal groove. In general, entering the soft tissues immediately adjacent the rib’s superior surface and entering more than 6 cm lateral to the spine helps avoid the intercostal artery, which tends to be more tortuous among elderly patients and in more cephalad rib spaces according to computed tomographic characterization of 47 patients in a UK-based study. , According to a Japanese study of 33 patients (25 men, mean age 74 years), the risk of a tortuous and exposed intercostal artery is significantly lower 9 to 10 cm lateral to the spine compared with only 5- to 6 cm lateral to the spine. Some investigators have advocated for routine preprocedure use of ultrasound in order to screen for aberrant intercostal vessels, including collaterals, , whereas others have advocated for postprocedural ultrasonography (preferably along with color Doppler imaging) in order to promptly identify an iatrogenic bleeding complication.
Because MPE recurs in nearly all patients, one of the more definitive strategies should be used for managing previously diagnosed MPE unless the life expectancy is estimated at 1 month or less. Repeated thoracenteses, besides necessitating multiple interactions with the health care system, are associated with higher rates of emergency room visits and complications, such as pneumothorax.
Pleurodesis
Pleurodesis refers to obliteration of the pleural space resulting in sustained resolution of the pleural effusion. It is typically achieved chemically through intrapleural administration of a sclerosant, such as talc or doxycycline. Administration can be performed either via a chest tube or during medical/surgical thoracoscopy in the form of insufflation/poudrage. Although the exact mechanism of action is unknown, chemical pleurodesis is understood to generate an inflammatory reaction leading to fibrosis and symphysis between the parietal and visceral pleural layers. Data also indicate that talc can inhibit angiogenesis as well as induce selective apoptosis of tumor cells while sparing normal pleural mesothelial cells. , It is hoped that future research will identify the molecular mechanisms responsible for increased pleural fluid formation in MPE as well as mechanisms to decrease production and/or increase resorption.
Historically, chemical pleurodesis has been the mainstay of palliative treatment of recurrent, symptomatic MPE. Most data point to equivalent outcomes between thoracoscopic versus chest tube-guided pleurodesis, although there is some evidence emanating from the post hoc analysis of a single, multicenter randomized trial that the thoracoscopic approach may have superior success rates for MPE patients with lung and breast primaries. The TAPPS (“thoracoscopy and talc poudrage vs pleurodesis using talc slurry”) trial, which directly compares the 2 strategies using a randomized experimental design, is currently ongoing.
Technique for Bedside Talc Pleurodesis via Chest Tube Slurry
Although there is no universally agreed protocol for chemical pleurodesis, the authors describe their typical practice as 1 example of how talc pleurodesis may be performed at the bedside using a previously placed small-bore (≤14 g) chest tube ( Box 1 ):
- 1.
Ensure patency of chest tube by flushing 10 mL sterile saline toward the patient using a 3-way stopcock
- 2.
Although talc pleurodesis typically does not cause pain in patients with MPE (with incidence estimated at approximately 5%–10%), , preemptive analgesia may be considered via either oral, parenteral, or intrapleural administration of a local anesthetic (eg, 10 mL of 0.25% bupivacaine)
- 4.
Suspend 4 to 5 g of sterile talc powder in 50 mL sterile saline and administer it toward the patient using a 3-way stopcock
- 5.
Ensure continued patency of the chest tube by flushing 10 mL sterile saline toward the patient using a 3-way stopcock
- 6.
Clamp the chest tube for 1 hour in order to let the sclerosant dwell in the pleural space
- 7.
Unclamp the chest tube and place it on −20 cm H 2 O continuous suction
- 8.
Flush the chest tube with 10 mL sterile saline every 8 hours in order to ensure continued patency and carefully document chest tube output on a daily basis
- 9.
Remove chest tube when drainage is ≤150 mL/24 hours along with improved patient symptoms and ultrasonographic ± radiographic evidence of pleural fluid resolution
Box 2 lists answers to various questions about chemical pleurodesis that are commonly encountered in clinical practice.
- 1.
Which pleurodesis agent should be used as the first line?
A recent Cochrane Review and metaanalysis of various chemical sclerosant agents substantiate previously published data and expert opinion that talc is the most effective agent, although the metaanalysis authors reported considerable uncertainty in their conclusions because of moderate overall risk of bias across the included studies. ,
- 2.
What chest tube size is preferred?
Data from the TIME1 randomized trial, multiple other studies, and a metaanalysis indicate that small-bore chest tubes are equivalent to large-bore (“surgical”) chest tubes in terms of pleurodesis efficacy, whereas their complication rates also appear to be similar. ,
- 3.
Does the patient need to be rotated after instillation of the pleurodesis agent?
A temporal imaging analysis of patients undergoing instillation of radionuclide-labeled talc slurry indicated that rotation of patients did not appreciably impact distribution of talc across the thoracic cavity. Therefore, rotating the patient is not recommended.
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