Jordan Kazakov and Moishe Liberman
The pleural cavity is a slit-like space surrounded by the parietal and visceral pleural surfaces, which exist in all mammals, except the adult elephant. Normally, the human pleural space contains a small amount (0.26 mL/kg) of fluid, which maintains a distance of 10 to 12 μm between the chest wall/diaphragm and the lung and allows for easy movement of the lung and mechanical coupling during the respiratory cycle. The pleural fluid volume is the result of complex interplay between hydrostatic–osmotic pressure, vascular permeability, and pleuro-lymphatic drainage. Fluid volume may increase significantly in pathologic conditions.
Pleurodesis (pleur(o)—pleura, rib, side; desis—fixation) is a procedure that aims to fuse the pleural space. This is achieved with mechanical (abrasion, tunneled indwelling catheter) or chemical (injection of sclerosing agent) injury of the pleura, which leads to fibrous tissue formation and symphysis of the parietal and visceral pleural layers. The injury causes mesothelial denudation, induction of inflammation, coagulation cascade activation, and angiogenesis.
IL-8, TNF-α, NO, MCP-1, adhesion molecules, and transforming growth factor-beta (TGF-β), among other factors, play important roles in the inflammatory process and fibrous tissue formation. TGF-β has a strong profibrotic effect and the direct administration of human recombinant TGF-β into rabbit and sheep pleural space induces pleurodesis faster than talc slurry with lower pleural markers of inflammation than pleurodesis with talc or doxycycline. The cellular component of the inflammation consists mainly of mesothelial cells, which can undergo epithelial–mesenchymal transformation becoming fibroblast-like cells, and myofibroblasts, which migrate into the pleural space after injury and deposit proteins. Other important participants in the generation and proliferation of the inflammatory response are the macrophages and neutrophils. The importance of inflammation for the success of pleurodesis is emphasized by the finding that corticosteroids decrease the effectiveness of talc pleurodesis. It appears that mechanisms other than inflammation may also play role. This has been observed in the experimental work with TGF-β, where the coadministration of corticosteroids did not inhibit pleurodesis.
Pleural inflammation is likely responsible for the symptoms associated with pleurodesis, namely pain (severe in more than 50% of patients who receive intrapleural tetracycline) and fever (up to 62% of patients who receive intrapleural talc).
INDICATIONS/CONTRAINDICATIONS
Malignant Pleural Effusion
Many malignancies have been associated with pleural effusion, the most common being lung and breast cancer. In a prospective study by Villena et al., neoplasm was the most common cause (36%) of pleural effusion in 1,000 consecutive patients who underwent diagnostic thoracentesis. The most common place of origin of the tumor was the lung, followed by pleural mesothelioma. Rodriguez-Panadero et al. found pleural metastases in 29% of 191 patients with one or more malignant tumor elsewhere in the body; pleural effusion was present in 55% of the patients with pleural involvement. A prospective study of 278 consecutive patients with malignant pleural effusion showed a median survival of 211 days. Three factors predicted worse survival—leucocytosis, hypoxemia, and hypoalbuminemia. Patients with pleural effusion from breast carcinoma have better survival.
Malignancy can cause pleural effusion by one or a combination of the following mechanisms: Direct involvement of the pleura (breast, lung), seeding of the tumor to the pleural space via lymphatic and hematogenous routes, involvement of the mediastinal lymph nodes and lymphatic vessel embolization, involvement of the superior vena cava or the pericardium, and obstruction of the ipsilateral mainstem bronchus.
Pleural effusion associated with malignancy may be transudate or exudate. Low glucose (less than 60 mg/dL [3.33 mmol/L]) and low pH (less than 7.3) are associated with increased tumor burden, higher yield of pleural cytology, poorer response to pleurodesis, and shorter survival. The type and the mechanism of the pleural effusion are important for the management of the pleural effusion and the outcome of the procedure. Pleurodesis is less likely to be successful in the presence of bronchial obstruction or extensive tumor infiltration of the ipsilateral lung or pleura in which cases reexpansion of the lung after effusion drainage is unlikely. Other important factors to consider before making a decision regarding the best therapeutic option for pleural effusion are presence of treatment options for the malignancy, presence of symptoms and response to therapeutic thoracentesis, speed of reaccumulation of the effusion, size of the effusion, expected survival, the performance status, the social milieu of the patient, personal preference of the patient, clinician experience, and local availability. Based on these factors there are different clinical scenarios. If the effusion is small and the diagnosis points to a tumor sensitive to chemotherapy (breast, ovary, small-cell lung cancer, lymphoma, etc.) the best choice would be to administer systemic chemotherapy. Mediastinal radiation may be helpful in lymphoma and lymphomatous chylothorax. Further therapy may not be necessary if the effusion disappears or remains stable and well tolerated.
When there is no response to systemic therapy, the effusion is progressing or recurring, when the initial effusion is large and there is amelioration of the clinical signs and reexpansion of the lung after therapeutic thoracentesis, the patient should be considered for pleurodesis or indwelling pleural catheter (IPC). Exception of this rule is slowly (more than 1 month) recurring and short (less than 3 months) expected survival where the effusion can be managed with repeat thoracentesis. Diagnostic and possibly therapeutic bronchoscopy is mandatory before an attempt at pleurodesis when malignant airway obstruction is suspected. If pleurodesis or IPC are considered they should be carried out as early as possible before the development of trapped lung.
Benign Pleural Effusion—Congestive Heart Failure, Hepatic Hydrothorax, and Chylothorax
Cardiac disease is a common cause for recurrent pleural effusion. Specific etiologies include congestive heart failure, and acute and chronic pericarditis. The effusion in congestive heart failure is more often bilateral and of transudative type (diuresis may change the appearance of the fluid to exudative), whereas the effusion related to pericardial disease is more often left-sided and more likely to be an exudate.
Increased left atrial pressure and pulmonary capillary wedge pressure are essential for the development of pleural effusion associated with congestive heart failure. The mechanisms responsible for pleural effusion associated with pericarditis include simultaneous involvement of the pleura from the same process causing the pericarditis, contiguous inflammation, and involvement of the mediastinal lymphatics.
The treatment for pleural effusion due to cardiac disease is the treatment of the underlying cardiac problem itself combined with diuretic therapy in the case of congestive heart failure or anti-inflammatory agents in the case of pericarditis. In a case of a refractory symptomatic effusion, pleurodesis with talc or doxycycline may be considered. Unilateral pleurodesis may worsen the effusion on the opposite side. Placement of indwelling pleural catheter or pleuroperitoneal shunt can be considered as alternatives to pleurodesis.
Pleural effusion due to hepatic cirrhosis with portal hypertension in the absence of primary pulmonary, pleural, or cardiac disease is called hepatic hydrothorax. The incidence of hepatic hydrothorax is less than 5% of all cirrhotic patients. It usually appears in the presence of ascites, which is believed to cross the diaphragm via diaphragmatic defects. Huang et al. classified the defects to four types: type I, no obvious defect; type II, blebs lying on the diaphragm; type III, broken defects (fenestrations); and type IV, multiple gaps in the diaphragm. In as many as 20% of the patients with hepatic hydrothorax ascites cannot be identified even with ultrasound, hence the presence of ascites is not required for the diagnosis. The effusion is transudative in nature. In most of the cases, the hepatic hydrothorax is right-sided, followed by left-sided, and bilateral.
Treatment of hepatic hydrothorax is similar to treatment of ascites. Sodium restriction and diuretics may be effective. Patients who are compliant with the low sodium diet and have recurrent effusion are considered to have refractory hydrothorax. Treatment options for this group include repeated thoracentesis, peritoneovenous shunt, pleurodesis, video-assisted thoracoscopic surgery (VATS) repair of diaphragmatic defects, transjugular intrahepatic portosystemic shunt, and liver transplantation. Chest tube placement as a sole treatment may cause massive fluid shifts with electrolyte and protein depletion, bleeding, renal failure, and death and is not recommended. Huang et al. described 10 patients who underwent thoracoscopic pleura or mesh onlay repair of diaphragmatic defects with no postoperative recurrence of the effusion and improved pulmonary function. Pleurodesis in hepatic hydrothorax is complicated by the rapid passage of fluid between the abdomen and the chest, which does not allow for close contact between the parietal and visceral layers of the pleura. Nevertheless, successful pleurodesis with tetracycline and thoracoscopic talc pleurodesis have been described. Milanez de Campos et al. described 18 patients who underwent 21 VATS talc pleurodesis procedures with immediate success in 48% of the procedures. The success rate of the procedure increased to 60% when it was combined with suture of the diaphragmatic defect. High morbidity (57.1%) and mortality (38.9%) in the 3-month follow-up period were described. Ferrante et al. attempted VATS talc pleurodesis in 15 patients with successful control of hepatic hydrothorax in 53% after a single procedure and in 73% after two procedures.
In conclusion, VATS talc pleurodesis for hepatic hydrothorax is effective in 40% to 75% but may result in significant morbidity and mortality. Better results are seen in patients who undergo closure of the diaphragmatic defect than in patients without demonstrable defect. Some reports suggest CPAP may be helpful with chemical pleurodesis or alone by decreasing the pressure gradient between the chest and the abdomen and thereby decreasing the transfer of ascites.
Chylothorax is the presence of chyle in the pleural space due to leakage from the thoracic duct or its tributaries. The diagnosis is supported by triglyceride concentration greater than 110 mg/dL; an intermediate level between 50 and 110 mg/dL should be followed by lipoprotein electrophoresis of the pleural fluid—chylothorax contains chylomicrons; levels less than 50 mg/dL excludes the diagnosis of chylothorax. Pseudochylothorax is a chyliform effusion with high concentration of cholesterol that occurs in the setting of chronic pleural inflammation.
The thoracic duct ascends from the cisterna chyli at the level of first or second lumbar vertebra in a rightward position. It enters the thoracic cavity from the abdomen through the aortic hiatus and then ascends between the thoracic aorta and the azygos vein until it reaches the fifth thoracic vertebra where it crosses the midline and continues in the left posterior mediastinum to reach the left jugular or subclavian vein. Occasionally, there are two thoracic ducts in the mediastinum or a single thoracic duct empties in the right-sided veins. The level of the injury to the thoracic duct determines the side of the chylothorax.
The etiology of the chylothorax could be traumatic (surgical or nonsurgical) or nontraumatic. The nontraumatic chylothorax may be further separated into malignant (lymphomatous and nonlymphomatous) and nonmalignant. Exudative effusion is the most common finding but transudative chylothorax has been reported.
Computed tomography of the thorax and abdomen and pleural fluid analysis are the initial tests for evaluation of patients with chylothorax. Lymphangiography or lymphoscintigraphy may be utilized in patients with uncertain diagnosis, recurrent chylothorax after thoracic duct ligation, and suspected anomalous thoracic duct anatomy.
Treatment of the underlying condition is attempted if possible. Dietary measures include modified enteral nutrition (high protein-low fat diet) with supplementation of medium chain triglycerides and fasting with total parenteral nutrition. Intermittent drainage with thoracentesis can be employed for relief of dyspnea. Chest tube placement is used in traumatic (surgical and nonsurgical) chylothorax or with rapidly accumulating effusion. Tube drainage should be limited to 14 days to minimize the risk of immunosuppression due to loss of lymphocytes and immunoglobulins. Surgical treatment should be considered for patients with chyle loss exceeding 1 to 1.5 L/day for more than 5 days in an adult or more than 100 mL/day in a child. The access side depends on the side of the effusion, the course of the thoracic duct, the side of the initial surgery, and the presence of gastric conduit. Laparoscopic approach may be used for subdiaphragmatic leak. The thoracic duct ligation can be combined with mechanical or chemical (talc) pleurodesis. Talc pleurodesis without duct ligation may also be performed with varying results. Maldonado et al. reported experience with 77 adult patients. Fifty-seven patients (77%) had initial nonsurgical treatment. The rate of resolution after the initial treatment was 27% for patients with nontraumatic chylothorax and 50% for those with traumatic chylothorax. The rate of recurrence after additional therapeutic maneuvers was 50% for the first group and 13% for the second. In another study Paul et al. reported experience with 29 patients who underwent surgical procedure for a high output (more than 1 L/day) or recurrent chylothorax. Twenty-two patients underwent thoracic duct ligation and six underwent pleurodesis. The success rate after initial thoracic duct ligation was 95% and after pleurodesis was 83%. Mares et al. treated 24 thoraces in 19 consecutive patients with recurrent chylothorax as a complication of lymphoma. They utilized medical thoracoscopy for talc insufflation pleurodesis with 100% success rate.
Pneumothorax—Recurrent, Persistent Air Leak
Pneumothorax occurring without an inciting event is defined as “spontaneous.” It can be further divided to primary—occurring in patients without previous lung disease, and secondary—occurring in patients with known lung disease.
The primary spontaneous pneumothorax (PSP) is more common in tall, thin males and varies geographically. Typically, the patients are young or middle aged (20 to 40 years old) and at rest at the time of the occurrence of the pneumothorax. Predisposing factors for PSP include family history, Marfan syndrome, Birt–Hogg–Dubé syndrome, homocystinuria, smoking, and thoracic endometriosis. The recurrence rate is highest during the first year and varies between 25% and more than 50%. Risk factors for recurrence are continuing smoking, female sex, height, and low body weight.
Treatment options for PSP include observation, pleural aspiration, chest tube insertion, VATS, pleurodesis, and thoracotomy. Observation with supplemental oxygen is indicated for small (less than 3 cm between the lung and the chest wall on a chest radiograph) uncomplicated pneumothorax. The patient may be discharged home after 6 hours if follow-up x-ray shows no progression and the patient has quick access to emergency medical services. Pleural aspiration with an 8- to 9-French (Fr) catheter can be performed manually in clinically stable patients with large pneumothorax. Chest tube insertion is indicated in clinically stable patients with large pneumothorax or persistent symptoms like dyspnea or pain. In clinically unstable patients, a chest tube should be inserted without delay, and if not immediately available, a 14-gauge intravenous catheter can be used to decompress the pleural space until more definite treatment is possible. Small- and large-bore tubes are comparable in effectiveness in the treatment of pneumothorax but large-bore tube thoracostomy is preferable in mechanically ventilated patients, patients with very large leak, and hemothorax. Patients with good lung re-expansion and persistent air leak (more than 3 days) after tube thoracostomy can have their tube attached to a Heimlich valve and discharged home. Thoracoscopy is the preferred treatment modality for PSP with concurrent hemothorax, persistent air leak, failure of the lung to reexpand, and recurrent PSP. Chemical pleurodesis is employed if the patient is unwilling or unable to undergo surgical procedure or VATS is not available. Tetracycline, doxycycline, and talc have been used successfully for pleurodesis after spontaneous pneumothorax and can be performed via the tube thoracostomy or during VATS. Light et al. compared tetracycline pleurodesis with no treatment and found significant decrease (41% to 25%) in the recurrence rate of spontaneous pneumothorax in the pleurodesis group. Olsen et al. observed 16% recurrence after tetracycline pleurodesis in 390 patients who underwent thoracoscopy. Györik et al. performed talc pleurodesis via thoracoscopy in 112 patients with persistent air leak or recurrence after PSP. Fifty-nine patients were followed for median 118 months with success of the primary procedure in 95% and recurrence rate of 5%.
Contraindications
Talc pleurodesis may cause deterioration of the respiratory function, which may not be tolerated in patients with severe lung disease and hypoxic respiratory failure. Pleurodesis is also contraindicated when close contact between the parietal and visceral pleura cannot be achieved (lung entrapment and insufficient drainage). Treatment with steroids will decrease the effectiveness of the pleurodesis and they should be stopped, if possible, 24 to 48 before the procedure. Contraindications to indwelling tunneled pleural catheter include infection of the skin at the insertion site, infected pleural effusion or empyema, inability of the patient to tolerate the procedure, and inability to manage the catheter. Contraindications for thoracoscopy include anatomic limitations and inability of the patient to tolerate surgical procedure.
Choice of Agent and Modality
Chemical
Multiple agents have been used for chemical pleurodesis—talc, doxycycline, minocycline, erythromycin, bleomycin, florouracil, mitomycin C, cisplatin, cytarabine, doxorubicin, etoposide, iodopovidone, silver nitrate, Corynebacterium parvum with parenteral methylprednisolone acetate, and Streptococcus pyogenes A3 (OK-432).
Talc (hydrated magnesium silicate) is the most commonly used and most effective agent. Talc can be delivered as slurry via a chest tube or as insufflation during thoracoscopy. Talc insufflation was shown to be more effective than slurry in a prospective nonrandomized trial by Stefani et al. A prospective randomized trial by Dresler et al. showed similar efficacy overall but higher efficacy of insufflation in patients with either a lung or breast primary. The choice of a modality should be made based on the condition of the patient and additional diagnostic or therapeutic goals. The success rate of talc pleurodesis varies between 60% and 90%.
Doxycycline is another commonly used agent. The success rate of doxycycline pleurodesis is lower than the success rate of talc pleurodesis with recurrence rate of 13% to 35%.
Mechanical
IPCs and VATS can be used for management of pleural effusion. Both modalities may achieve pleurodesis by mechanical irritation of the pleural layers with inflammation and connective tissue formation. These modalities may also be used for application of pleural sclerosant such as talc.
IPCs should be considered in patients with recurrent pleural effusion. They offer the convenience of outpatient procedure, ease of care, fast symptom relief, and improved quality of life. IPCs are the preferred modality for patients with lung entrapment or nontreatable endobronchial obstruction. Van Meter et al. reported a rate of spontaneous pleurodesis of 45.6% with indwelling catheters. In a study by Tremblay et al. spontaneous pleurodesis was achieved in 70% of the cases with mean time to pleurodesis of 90 days. For patients who do not achieve spontaneous pleurodesis, the catheter can be used to administer pleural sclerosing agent. Data from an unblinded randomized controlled trial comparing IPCs with talc pleurodesis showed no difference in dyspnea scores until 6 months, chest pain, and quality-of-life scores. Although, there were more nonserious adverse events such as pleural, skin infection, and catheter blockage in the IPCs group, there was no significant difference in the serious adverse effects between both groups. The IPC group had shorter initial hospital stay, and decreased need for additional pleural procedures. A multi-institutional prospective randomized study compared IPCs with doxycycline pleurodesis in the management of malignant pleural effusions. The patients in the IPC group had shorter hospital stay, less late recurrence of the effusion, and comparable symptomatic improvement in dyspnea and quality of life.
VATS employs minimally invasive surgical procedures for diagnosis and treatment of thoracic diseases including pleural effusions. VATS (thoracoscopy) with pleurodesis can be performed as a primary diagnostic and therapeutic procedure or after an initial negative thoracentesis or failed pleurodesis by other method. The efficacy of VATS talc pleurodesis approaches 90%. A retrospective review by Hunt et al. comparing tunneled pleural catheters (TPCs) to VATS talc pleurodesis for treatment of malignant pleural effusion showed significantly fewer reinterventions for recurrent ipsilateral pleural effusions in the TPC group, shorter length of stay, and postprocedure length of stay; no difference was found in the complication rate or in-hospital mortality.
PREOPERATIVE PLANNING
Surgery
Pleurodesis via Chest Tube
Talc slurry—50-mL sodium chloride 0.9% is injected in the bottle containing 5 g of sterile talc. After assuring good mixing, the content of the bottle is aspirated back in one syringe or divided in two syringes and further diluted with sodium chloride. The slurry should be injected within 12 hours of mixing. After clamping the chest tube, the slurry is injected in the pleural cavity and the catheter is kept clamped for 1 hour and the patient is rotated. Suction is then reapplied (−20 cm H2O). The chest tube is removed when the pleural fluid drainage is less than 150 mL per 24 hours.
Doxycycline—500 mg in 50-mL sodium chloride 0.9% is injected in the pleural cavity via the chest tube. The chest tube is clamped for 4 hours and the patient is rotated. Suction is than reapplied. The chest tube is removed after 24 hours if the drainage volume is less than 100 mL. If the drainage remains above 100 mL for more than 4 days, doxycycline is readministered. Continued high chest tube output for more than 4 days after the second doxycycline administration is considered as a treatment failure and other modalities for pleurodesis should be sought. Local anesthetic such as lidocaine (25 mL, 1% solution) or mepivacaine (20 mL, 2% solution) could be added to the doxycycline solution for local analgesia.
The rotation of the patient does not increase the likelihood of successful pleurodesis. There is no evidence that waiting for the drainage output to decrease, is better than removing the tube after 24 hours regardless of the amount of fluid drainage.
Indwelling Pleural Catheter
The patient is positioned in lateral decubitus position or in semirecumbent position. Ultrasound should be used to locate the most dependent area of the effusion. The chest is prepped and draped in the usual sterile fashion. After the appropriate intercostal space is identified local anesthetic is applied at the insertion site, along the tunnel track, and on the exit site. The insertion site is usually located on the anterior axillary line and the exit site is 5 to 8 cm anterior to it. The guidewire introducer needle is then inserted in the appropriate interspace just above the lower rib. The guidewire is inserted through the guidewire introducer into the pleural cavity. A 1-cm incision is performed over the guidewire insertion site and a second incision, 5 to 8 cm inferior and anterior to the first one. Next, the catheter is inserted with a tunneler in the direction from the exit site to the insertion site and the cuff advanced approximately 1 cm beyond the anterior incision. A 16F peel-away introducer sheath is advanced over the guidewire into the pleural space. The guidewire and the dilator are then removed and the proximal fenestrated end of the catheter is inserted through the peel-away sheath until all the fenestrations are inside the pleural space. The sheath is peeled away while ensuring the catheter remains in place and lays flat without any kinks. The insertion and exit sites are sutured and the catheter is secured to the skin. The stitch is usually removed after 2 weeks. Once the catheter is in place it is connected to the drainage system and 1 to 1.5 L fluid removed. The patient and/or family members should be taught about catheter care, drainage, and signs of infection. Visiting nurse arrangement should be made if the patient and the family members are not able to manage the catheter independently. The initial instructions are for catheter drainage every 1 to 2 days, not more than 1 L/day until less than 50 mL is removed at three consecutive sessions at which point removal of the catheter should be considered.
Video-assisted Thoracoscopic Surgery (VATS)
The patient is positioned in lateral decubitus position with the costal margin of the patient placed at the break of the operating table. Appropriate padding at the pressure points is required, as well as head and operative side arm support. The chest is prepped and draped in the usual sterile fashion. A single port is sufficient in most cases of diagnostic thoracoscopy and pleurodesis. A 10- to 15-mm incision is made at the anterior axillary line and the soft tissues are dissected bluntly or using electrocautery. The choice of camera and instruments depends on the preference of the surgeon and the expected procedure. Pleurodesis can be achieved with insufflation of 3 to 5 g of talc powder or pleural abrasion. A chest tube is placed via the same incision and the wound is closed primarily. The chest tube is placed on negative pressure postoperatively and is removed after the output decreases below 100 to 150 mL for 24 hours.
Complications
Inflammation/infection—systemic inflammatory reaction with fever, increased white blood cell count, and C-reactive protein is common. Empyema and local site infection are uncommon complications.
Pain—pain is a common complication of pleurodesis. Talc pleurodesis in patients with spontaneous pneumothorax is particularly painful. Local anesthetics such as lidocaine 1% and mepivacaine 2% may be administered in the pleural space. Oral and intravenous opiates may be necessary to control pain.
Respiratory failure—dyspnea is a common symptom after pleurodesis. Respiratory failure is more common with talc pleurodesis, preparations with higher proportion of smaller particles (<5 to 10 microns in diameter), higher total talc doses, bilateral pleurodesis, and presence of factors that increase systemic absorption of talc particles (inflammation, pleural defects) are associated with more severe local and systemic inflammatory reaction. Respiratory failure and ARDS are rare if less than 5-g size-calibrated talc is used. The type of talc preparation (slurry or insufflation) has no importance for the development of respiratory failure.
IPC complications can be related to the technique—pneumothorax, lung injury, bleeding, and infection, or can be delayed; infection at the insertion site, empyema, catheter obstruction, accidental dislodgement, pleural fluid leakage around the catheter, catheter fracture with retention of fragments upon catheter removal, metastases along the catheter tract, and symptomatic loculations. In a systematic review by Van Meter et al. including 19 studies and 1,370 patients, complications were seen in 12.5% of the patients.
CONCLUSIONS
There are different modalities for achieving pleurodesis. The choice of procedure should take into account multiple factors including the primary diagnosis, the status of the patient, comorbidities, pleural anatomy, presence of lung entrapment, additional diagnostic and therapeutic goals, and patient preference.
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