Review of literature CHAPTER (1): ANATOMY OF THE PLEURA Definition

In human anatomy, the pleural cavity is the potential space between the two pleura (visceral and parietal) of the lungs. The pleura is a serous membrane which folds back onto itself to form a two-layered membrane structure. The thin space between the two pleural layers is known as the pleural cavity and normally contains a small amount of pleural fluid. The outer pleura (parietal pleura) is attached to the chest wall. The inner pleura (visceral pleura) cover the lungs and adjoining structures, viz. blood vessels, bronchi and nerves. The parietal pleura is highly sensitive to pain, while the visceral pleura is not, due to its lack of sensory innervation. (Moore, Keith L.; Dalley, Arthur F.; 2006)

Vasculature and sensation

The parietal pleura receive its blood supply from systemic capillaries. Small branches of the intercostal arteries supply the costal pleura, whereas the mediastinal pleura is principally by the pericardiophrenic artery. The diaphragmatic pleura is supplied by the superior phrenic and musculophrenic arteries. The blood supply of the visceral pleura originates from the systemic circulation via the bronchial arteries. The venous drainage of the parietal pleura is through the intercostal veins (systemic veins) while the visceral pleura drains to pulmonary veins. The lymphatics of the parietal pleura drain the pleural fluid and any noxious particles that reach the pleura to nodes along the internal thoracic artery and to the internal intercostal nodes (along the heads of the ribs posteriorly). The parietal pleural lymphatics can remove about 20 times the fluid formed under normal conditions (up to 0.2 mL per kg per hour).
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The visceral pleura drain through two systems a superficial system that floats over the surface of the lung towards the hilum, and a deep system that penetrates the lung parenchyma to reach the hilar nodes. Sensory nerves endings are present in the costal and diaphragmatic parietal pleura. The intercostal nerves supply the costal pleura and the peripheral part of the diaphragmatic pleura. In contrast, the central portion of the diaphragmatic pleura is innervated by the phrenic nerve, and stimulation of this part of the pleura causes pain that is referred to the ipsilateral shoulder. The visceral pleura contains no pain fibers. (Halafawy A.; 2001)

Pleural Membrane Function

The pleural space plays an important role in respiration by coupling the movement of the chest wall with that of the lungs in 2 ways. First, a relative vacuum in the space keeps the visceral and parietal pleurae in close proximity. Second, the small volume of pleural fluid, which has been calculated at 0.13 mL/kg of body weight under normal circumstances, serves as a lubricant to facilitate movement of the pleural surfaces against each other in the course of respirations. This small volume of fluid is maintained through the balance of hydrostatic and oncotic pressure and lymphatic drainage, a disturbance of which may lead to pathology. (Noppen M. 2001)

Development
Initially the intraembryonic coelom is one continuous space. the cranial, section of the intraembryonic coelom consists of a middle part, the pericardial cavity, and two thin canals laterally, the pericardioperitoneal canals. They connect the pericardial cavity with the
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part of the intraembryonic coelom that is open towards the outside, the future peritoneal cavity. At this point no pleural cavity yet exists because the lungs have not yet begun to develop. The lung buds grow into the pericardioperitoneal canals and dent them. Thereby the pericardioperitoneal canals are subdivided on both sides by these lung buds that are sprouting in from the medial direction. With the increase in size of the lung anlage the pericardioperitoneal canal widens to become the pleural cavity that is separated from the pericardial cavity by the pleuropericardial membrane and from the peritoneal cavity by the pleuroperitoneal membrane. The lungs become covered by the visceral layer of the pleural cavity, the pleura visceralis. Towards the outside, the pleural cavity is bounded by the parietal layer, the pleura parietalis. Through their rapid increase in size the two lungs, left and right, enclose the heart that is in their middle. (Adamson JYR.; 1997)

Pleural fluid
Pleural fluid is a serous fluid produced by the normal pleurae. Most fluid is produced by the parietal circulation (intercostal arteries) via bulk flow and reabsorbed by the lymphatic system. Thus, pleural fluid is produced and reabsorbed continuously. In a normal 70 kg human, a few milliliters of pleural fluid is always present within the intrapleural space. (Widmaier, Eric P. et al.; 2006) Larger quantities of fluid can accumulate in the pleural space only when the rate of production exceeds the rate of reabsorption. Normally, the rate of reabsorption increases as a physiological response to accumulating fluid, with the reabsorption rate increasing up to 40 times the normal rate before significant amounts of fluid accumulate within the pleural space. Thus, a profound increase in the production of pleural fluid
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or some blocking of the reabsorbing lymphatic systemis required for fluid to accumulate in the pleural space. Localized pleural fluid effusion noted during pulmonary embolism (PE) results probably from increased capillary permeability due to cytokine or inflammatory mediator release from the platelet-rich thrombi. (Porcel, J.M.; R.W. Light 2008) When accumulation of pleural fluid is noted, cytopathologic evaluation of the fluid, as well as clinical microscopy, microbiology, chemical studies, tumor markers, pH determination and other more esoteric tests are required as diagnostic tools for determining the causes of this abnormal accumulation. Even the gross appearance, color, clarity and odor can be useful tools in diagnosis. The presence of heart failure, infection or malignancy within the pleural cavity is the most common causes that can be identified using this approach. (Shidham, Vinod B.; Atkinson, Barbara F.; 2007) Pleural fluid parameters .Unilateral pleural fluid volume: 8.4 +/- 4.3 mL .Total pleural fluid volume: 0.26 +/- 0.1 mL/Kg .Cell count: WBC: 1716x103 cells/ml. RBC: 700x103 cells/ml .Macrophages:75% Lymphocytes: 23% .Mesothelial cells, neutrophils and eosinophils:2% (David Feller-Kopman.; 2009 )

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Pleural pressure Pleural elastance is the change in pleural pressure with removal of a given volume of pleural fluid. It is calculated by dividing the change in pleural pressure by the volume removed. A normal pleural elastance is estimated to be <14.5 cm H2O/L. (Heidecker J, Huggins JT, 2006) The main indications for pleural pressure monitoring during thoracentesis include: Identifying visceral pleural processes that prevent lung expansion when pleural fluid is removed (e.g., lung entrapment and trapped lung). Determining whether lung entrapment will prevent successful pleurodesis for a malignant effusion. Identification of trapped lung as a cause of an undiagnosed pleural effusion. Guiding fluid removal during therapeutic (large volume) thoracentesis. (Daniels CE, Ryu JH. 2011)

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Review of literature CHAPTER (2): MALIGNANT PLEURAL EFFUSION Introduction

Pleural effusions are a significant public health problem. Diagnosis of over 1 million pleural effusions is estimated to occur yearly in the United States. Patients with pleural effusions are frequently symptomatic with dyspnea and loss of function. Treatment goals for these patients should focus on relief or elimination of dyspnea, restoration of normal activity and function, minimization or elimination of hospitalization, and efficient use of medical care resources. (Antunes G, Neville E. 2000)

Prevalence
Malignant pleural effusions occur commonly in patients with cancer. The malignancies responsible for more than 75% of all of pleural effusions in order of frequency are lung, breast, lymphoma, and ovarian cancer. In a general hospital setting, 25% of all pleural effusions are malignant. In patients with an existing diagnosis of cancer, this increases to 30 to 70% if the fluid is an exudate. (Putnam JB. 2002)

Incidence
Malignant pleural effusions are a common clinical problem in patients with neoplastic disease. In one postmortem series, malignant effusions were found in 15% of patients who died with malignancies (1). Although there have been no epidemiologic studies, the annual incidence of malignant pleural effusions in the United States is estimated to be greater than 150,000 cases (Table 1) (2-17). Malignant pleural effusion is also one of the leading causes of exudative effusion; studies have
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demonstrated that 42 to 77% of exudative effusions are secondary to malignancy. (American Thoracic Society 2000)

Etiology and Pathogenesis

Pleural effusions occur between two membranes: the visceral (inner) layer of the pleura attached to the lungs, and the parietal (outer) layer attached to the chest wall. The pleural space normally is nonexistent and is lubricated by a slight amount of pleural fluid (1020 cc) that provides lubrication between the pleura. Fluid (sera) continuously moves from the parietal pleura through the pleural space to be absorbed by the visceral pleura. The fluid is then drained into the lymphatic system. The fluid in the pleural space is minimized by a balance of Starling forces, oncotic pressure in the circulation, and negative pressure in the lymphatics of the lungs. (Joe B. Putnam Jr, MD.; 2002) In patients with primary malignancies, metastasis to the pleural space may cause significant shifts or fluid imbalance from derangements in the Starling forces that regulate the reabsorption of fluid within the pleural space. Movement of pleural fluid across the pleural space may involve over 5 to 10 L/d, and derangements in this movement may increase the normal amount of pleural fluid from 5 to 50 cc to a more significant amount. Other disease processes may also significantly affect the ability of the body to manage its intrapleural fluid. (Joe B. Putnam Jr, MD 2002) Pleural effusions may occur in patients with: 1. Increased capillary permeability caused by inflammation, infection, or pleural metastasis.
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2. Increased hydrostatic pressure as results from congestive heart failure. 3. Decreased oncotic pressure from hypoalbuminia. 4. Increase in the normal negative pressure (more negative intrathoracic pressure) secondary to atelectasis. 5. Impaired or decreased lymphatic drainage secondary to obstruction of the normal lymphatic channels by tumor, radiation, or chemotherapy induced fibrosis. (Mountain CF. 1997)

Diagnostic Approaches 1. Clinical Manifestations

History A detailed medical history should be obtained from all patients presenting with a pleural effusion, as this may help to establish the etiology. History of chronic hepatitis or alcoholism with cirrhosis suggests hepatic hydrothorax or alcohol-induced pancreatitis with effusion. Recent trauma or surgery to the thoracic spine raises the possibility of a CSF leak. The patient should be asked about a history of cancer, even remote, as malignant pleural effusions can develop many years after initial diagnosis. An occupational history should also be obtained, including potential asbestos exposure, which could predispose the patient to mesothelioma or asbestos pleural effusion. The patient should also be asked about medications they are taking. (Sahn SA. 2006)

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Dyspnea Dyspnea is the most common symptom associated with pleural effusion and is related more to distortion of the diaphragm and chest wall during respiration than to hypoxemia. In many patients, drainage of pleural fluid alleviates symptoms despite limited improvement in gas exchange. Drainage of pleural fluid may also allow the underlying disease to be recognized on repeat chest radiographs. Note that dyspnea may be caused by the condition producing the pleural effusion, such as underlying intrinsic lung or heart disease, obstructing endobronchial lesions, or diaphragmatic paralysis, rather than by the effusion itself. (Khaleeq G, Musani AI. 2008) Cough Cough in patients with pleural effusion is often mild and nonproductive. More severe cough or the production of purulent or bloody sputum suggests an underlying pneumonia or endobronchial lesion. (Khaleeq G, Musani AI. 2008) Chest pain The presence of chest pain, which results from pleural irritation, raises the likelihood of an exudative etiology, such as pleural infection, mesothelioma, or pulmonary infarction. Pain may be mild or severe. It is typically described as sharp or stabbing and is exacerbated with deep inspiration. Pain may be localized to the chest wall or referred to the ipsilateral shoulder or upper abdomen, usually because of diaphragmatic involvement. Pain often diminishes in intensity as the pleural effusion increases in size. (Froudarakis ME. 2008)
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Additional symptoms Other symptoms in association with pleural effusions may suggest the underlying disease process. Increasing lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea may all occur with congestive heart failure. Night sweats, fever, hemoptysis, and weight loss should suggest TB. Hemoptysis also raises the possibility of malignancy, other endotracheal or endobronchial pathology, or pulmonary infarction. An acute febrile episode, purulent sputum production, and pleuritic chest pain may occur in patients with an effusion associated with pneumonia. (Wong CL, Holroyd-Leduc J.; 2009) Physical Examination Physical findings in pleural effusion are variable and depend on the volume of the effusion. Generally, there are no physical findings for effusions smaller than 300 mL. With effusions larger than 300 mL, findings may include the following:

Dullness to percussion, decreased tactile fremitus, and asymmetrical chest expansion, with diminished or delayed expansion on the side of the effusion, are the most reliable physical findings of pleural effusion. (Wong CL, Holroyd-Leduc J, 2009) Mediastinal shift away from the effusion - This is observed with effusions of greater than 1000 mL; displacement of the trachea and mediastinum toward the side of the effusion is an important clue to obstruction of a lobar bronchus by an endobronchial lesion, which can be due to malignancy or, less commonly, to a nonmalignant cause, such as a foreign body.
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Diminished or inaudible breath sounds. Egophony ("e" to "a" changes) at the most superior aspect of the pleural effusion.

Pleural frictions rub. (Kalantri S, et al. 2007)

Other physical findings, as follows, may suggest the underlying cause of the pleural effusion:

Peripheral edema, distended neck veins, and S3 gallop suggest congestive heart failure. Edema may also be a manifestation of nephrotic syndrome; pericardial disease; or, combined with yellow nails, the yellow nail syndrome. Cutaneous changes with ascites suggest liver disease. Lymphadenopathy or a palpable mass suggests malignancy. (Sahn SA. 2006)

2. Imaging Techniques
Chest CT scanning with contrast should be performed in all patients with an undiagnosed pleural effusion, if it has not previously been performed, to detect thickened pleura or signs of invasion of underlying or adjacent structures. The 2 diagnostic imperatives in this situation are pulmonary embolism and tuberculous pleuritis. In both cases, the pleural effusion is a harbinger of potential future morbidity. In contrast, a short delay in diagnosing metastatic malignancy to the pleural space has less impact on future clinical outcomes. CT angiography should be ordered if pulmonary embolism is strongly suggested. A study by Gurung et al involving 41 consecutive patients with hepatic hydrothorax indicated that hepatic hydrothorax virtually always presents with ascites that can be
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revealed by ultrasonography or computed tomography (CT) scanning. (Gurung P, et al.; 2011) Most patients presenting with malignant pleural effusions have some degree of dyspnea on exertion and their chest radiographs show moderate to large pleural effusions ranging from approximately 500 to 2,000 ml. While only 10% of patients have massive pleural effusions on presentation, malignancy is the most common cause of massive pleural effusion. Massive pleural effusions are defined as those effusions occupying the entire hemithorax. About 15% of patients, however, will have pleural effusions < 500 ml in volume and will be relatively asymptomatic. An absence of contralateral mediastinal shift in these large effusions implies fixation of the mediastinum, main stem bronchus occlusion by tumor (usually squamous cell lung cancer), or extensive pleural involvement (as seen with malignant mesothelioma). (American Thoracic Society 2000) Computerized tomography (CT) scans of patients with malignancies may identify previously unrecognized small effusions. They may also aid in the evaluation of patients with malignant effusions for mediastinal lymph node involvement and underlying parenchymal disease, as well as in demonstrating pleural, pulmonary, or distant metastases; identification of pleural plaques suggests asbestos exposure. Ultrasonography may aid in identifying pleural lesions in patients with malignant effusions and can be helpful in directing thoracentesis in patients with small effusions and avoiding thoracentesis complications. (Benard F, et al.; 1998) The role of magnetic resonance imaging (MRI) in malignant effusions appears limited, but MRI may be helpful in evaluating the extent of chest wall involvement by tumor. There is little information available on the
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utilization of fluorodeoxyglucose positron emission tomography (PET scanning) in malignant pleural effusions, although it has been reported as helpful in evaluating the extent of disease in malignant mesothelioma. (Bittner RC, Felix R.; 1998)

Diagnostic Thoracentesis
Background Thoracentesis (thoracocentesis) is a core procedural skill for hospitalists, critical care physicians, and emergency physicians. With proper training in both thoracentesis itself and the use of bedside ultrasonography, providers can perform this procedure safely and successfully. Before the procedure, bedside ultrasonography can be used to determine the presence and size of pleural effusions and to look for loculations. During the procedure, it can be used in real time to facilitate anesthesia and then guide needle placement. (Duncan DR, Daniels CE. 2009) Indications Thoracentesis is indicated for the symptomatic treatment of large pleural effusions (see the images below) or for treatment of empyemas. It is also indicated for pleural effusions of any size that require diagnostic analysis. (Porcel JM. 2009)

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Figure (1): chest X-ray showing large left pleural effusion before and after thoracocentesis. Image of a 48-year-old Chest radiograph after of the shown patient

woman with cancer and large thoracentesis left pleural effusion (2.5 liters cancer were removed). The patient above. was tachypneic, hypoxic, and reported pleuritic chest pain.

Transudative effusions result from decreased plasma oncotic pressures and increased hydrostatic pressures. Heart failure is by far the most common cause, followed by liver cirrhosis and nephrotic syndrome. (Chaiyakunapruk N. et al.; 2002)

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Exudative effusions result from local destructive or surgical processes that cause increased capillary permeability and subsequent exudation of intravascular components into potential spaces. Causes are manifold and include pneumonia, empyema, cancer, pulmonary embolism, and numerous infectious etiologies. (Chaiyakunapruk N. et al.; 2002)

Contraindications Relative contraindications to diagnostic thoracentesis include a small volume of fluid (< 1 cm thickness on a lateral decubitus film), bleeding diathesis or systemic anticoagulation, mechanical ventilation, and cutaneous disease over the proposed puncture site. Mechanical ventilation with positive end-expiratory pressure does not increase the risk of pneumothorax after thoracentesis, but it increases the likelihood of severe complications (tension pneumothorax or persistent bronchopleural fistula) if the lung is punctured. (Duncan DR, 2009) Complications Complications of diagnostic thoracentesis include pain at the puncture site, cutaneous or internal bleeding, pneumothorax, empyema, and spleen/liver puncture. Pneumothorax complicates approximately 12-30% of thoracentesis but requires treatment with a chest tube in less than 5% of cases. Use of needles larger than 20 gauge increases the risk of a pneumothorax complicating the thoracentesis. In addition, significant chronic obstructive or fibrotic lung disease increases the risk of a symptomatic pneumothorax complicating the thoracentesis. (Duncan DR, 2009)

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Review of literature 3. Closed Pleural Biopsy

Historical view Pleural diseases involve the parietal and visceral pleura and may be of either inflammatory or malignant origin, often resulting in pleural effusions. The diagnostic evaluation of pleural effusions includes chemical and microbiological studies, as well as cytological analysis, which can provide further information about the etiological disease process. However, 40% of pleural effusions remain undiagnosed after an initial thoracocentesis. (Salyer WR, 1975) Pleural biopsy is recommended for evaluation and exclusion of infectious etiologies such as tuberculosis or malignant disease, particularly malignant mesothelioma. Connective tissue disorders such as rheumatoid disease can also present with pleural involvement, requiring pleural biopsy for diagnosis. In addition, pleural thickening in the absence of pleural effusion may require further histological evaluation. It is important to understand that the etiology of pleural effusion remains unclear in nearly 20% of cases. (Prakash UB, Reiman HM. 1985) Various biopsy techniques are available to diagnose pleural disease. These range from older techniques, such as blind or closed pleural biopsy, to newer techniques including image-guided and thoracoscopic biopsy. The latter techniques have higher diagnostic yield and provide better diagnostic sensitivity. In addition, the use of immunohistochemistry provides increased diagnostic accuracy. (Koss MN, 1998)

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Indications and results Indications for pleural biopsy include the following:

Recurrent pleural effusion of unknown etiology. Pleural mass or thickening. (Ernst A, 2003) Normal Results The pleural tissues appear normal, without signs of inflammation, infection, or cancer. Normal value ranges may vary slightly among different laboratories. Talk to your doctor about the meaning of your specific test results. (Broaddus VC, Light RW. 2010)

Abnormal Results Abnormal results may reveal cancer (including primary lung cancer, malignant mesothelioma, and metastatic pleural tumor), tuberculosis, a viral disease, a fungal disease, a parasitic disease, or collagen vascular disease. (Broaddus VC, Light RW. 2010) Complications

The flexible-rigid pleuroscope is considered to be a safe procedure, with no morbidity or mortality observed in a study of 51 patients. The major concern of the procedure is pleural hemorrhage from underlying intercostal blood vessels. (Lee P, Hsu A, 2007) Immediate pressure using forceps and a small piece of gauze can be applied to control bleeding. If bleeding is significant, an additional incision should be considered to access the pleural cavity in order to perform tissue cauterization. If bleeding is not controlled with direct pressure and cauterization, ligation of the bleeding vessels with endoclips
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should be considered. Ongoing bleeding may require thoracotomy. Other common complications include prolonged air leak, subcutaneous emphysema, post procedure wounds infections including empyema, and chest wall metastasis from mesothelioma. (Lee P, Mathur PN, 2010)

4. Medical Thoracoscopy
Medical thoracoscopy/pleuroscopy is a minimally invasive procedure that allows access to the pleural space using a combination of viewing and working instruments. It also allows for basic diagnostic (undiagnosed pleural fluid or pleural thickening) and therapeutic procedures (pleurodesis) to be performed safely. This procedure is distinct from video-assisted thoracoscopic surgery, an invasive procedure that uses sophisticated access platform and multiple ports for separate viewing and working instruments to access pleural space. It requires one-lung ventilation for adequate creation of a working space in the hemithorax. Complete visualization of the entire hemithorax, multiple angles of attack to pleural, pulmonary (parenchymal), and mediastinal pathology with the ability to introduce multiple instruments into the operative field allows for both basic and advanced procedures to be performed safely. (Chen LE, et al. 2002) Complications of medical thoracoscopy/pleuroscopy are uncommon. They include bleeding, infection of the pleural space, and injury to intrathoracic organs, atelectasis, and respiratory failure. (Seijo LM, Sterman DH. 2001) Physicians performing this procedure should have ample experience, excellent knowledge of pleural and thoracic anatomy, mature judgment in interpreting radiographic images related to pleural disease, and sufficient surgical skill. Trainees should perform at least 20 procedures in a
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supervised setting to establish basic competency. To maintain competency, dedicated operators should perform at least 10 procedures per year. (Wilsher ML, Veale AG. 1998)

5. Bronchoscopy
Introduction Bronchoscopy allows a doctor to examine inside your airway for any abnormality such as foreign bodies, bleeding, a tumor, or inflammation. The doctor uses either a rigid bronchoscope or flexible bronchoscope. (Prakash UB. 1999) Indications Common reasons to perform a bronchoscopy for diagnosis are:

Lung growth, lymph node, atelectasis, or other changes seen on an x-ray or other imaging test Suspected interstitial lung disease Coughing up blood (hemoptysis) Possible foreign object in the airway Cough that has lasted more than 3 months without any other explanation

Infections in the lungs and bronchi that cannot be diagnosed any other way or need a certain type of diagnosis

Inhaled toxic gas or chemical To diagnose a lung rejection after a lung transplant (Kraft M. 2011)

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You may also have a bronchoscopy to treat a lung or airway problem, such as to:

Remove fluid or mucus plugs from your airways Remove a foreign object from your airways Widen (dilate) an airway that is blocked or narrowed Drain an abscess Treat cancer using a number of different techniques Wash out an airway (therapeutic lavage) (Kraft M. 2011)

Risks The main risks from bronchoscopy are:

Bleeding from biopsy sites Infection Arrhythmias Breathing difficulties Fever Heart attack, in people with existing heart disease Low blood oxygen Pneumothorax Sore throat (Reynolds HY. 2011)

When a biopsy is taken, there is a risk of severe bleeding (hemorrhage). Some bleeding is common. The technician or nurse will monitor the amount of bleeding. There is a risk of choking if anything

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(including water) is swallowed before the numbing medicine wears off. (Kupeli E, 2010)

6. Surgical Biopsy
Video-assisted thoracic surgery (VATS) procedures usually require general anesthesia and single-lung ventilation. The surgeon may undertake a more extensive procedure than medical thoracoscopy, using several ports, and often combining diagnosis with treatment. VATS is contraindicated and open biopsy is preferred when the patient cannot tolerate single-lung ventilation (e.g., patient undergoing mechanical ventilation, prior contralateral pneumonectomy, or abnormal airway anatomy precluding placement of double-lumen endotracheal tube), if the pleural space contains adhesions that would prevent the safe insertion of the examining thoracoscope, and if there is insufficient expertise to deal with the complications of the procedure. Adhesions may be evident preoperatively on chest radiographs or on pleural ultrasound and may lead to the decision to undertake open biopsy. Often, however, this situation is appreciated for the first time at a VATS examination, and the surgeon must therefore be ready to convert to an open procedure. Adhesions frequently result from previous pleurodesis attempts but may also follow repeated thoracentesis for diagnosis or therapy. (McKneally MF, Lewis RJ.; 1992)

Treatment
The patients symptoms, functional status, life expectancy, and the type of tumor responsible for MPE should be kept in mind when considering therapeutic options as discussed later. In MPE associated with breast cancer and small cell lung cancer, chemotherapy may be all that is required. Similarly, radiation may suffice for the MPE associated with
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lymphoma, precluding any further intervention. (Khaleeq G, Musani A. 2008) Therapeutic thoracentesis should be performed in each case, not only to establish a cytological diagnosis, but also to document symptomatic improvement and the presence or absence of trapped lung. Lack of symptomatic improvement after thoracentesis may dissuade one from further interventions. A diagnosis of trapped lung should prompt one to consider strategies other than chest tube insertion and talc pleurodesis, such as indwelling pleural catheters, which are discussed in detail below. Symptomatic, recurrent, and recalcitrant (to chemotherapy or radiation therapy) MPEs should be addressed with a definitive, palliative care plan. (Pien GW, Gant M, 2001)

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CHAPTER (3): TALC PLEURODESIS Historical Background

Bethune in 1935 first introduced talc in the pleural space to produce pleural adhesions preliminary to lobectomy. Subsequently, Chambers in 1958 suggested that intrapleural talc could be used for the palliative treatment of malignant pleural effusions. Since then, many authors have reported their results with this agent and have concluded that it is one of the most effective, simplest, and cheapest methods to produce pleurodesis. (Emad Ibrahim, Marc Noppen; 2010)

Structure
Steritalc is non-soluble and induces permanent pleurodesis. It is guaranteed asbestos and latex free. Steritalc is supplied sterile and has the perfectly adapted and controlled granulometry to minimise the risk of migration across the parietal pleura. Steritalc has side effects similar to cyclines. Any pain occurring can be reduced by using xylocaine 1% administered directly in the pleura or via the slurry. (Emad Ibrahim, Marc Noppen; 2010)

Indications
1. Chronic pleurisy, principally malignant. 2. Spontaneous pneumothorax.
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3. Other cases in which a pleurodesis is indicated. (Kolschmann S, 2005)

Contraindications
Steritalc should not be used if the patient cannot undergo thoracoscopy. In order to avoid systemic migration of the talc, Steritalc should not be applied after a mechanical abrasion of the pleura. Steritalc should not be applied in case of pregnancy or breast-feeding. (Kolschmann S, 2005)

Dosage
Malignant Pleural Effusion Talc pleurodesis is used to be indicated as a sclerosing agent to decrease malignant pleural effusion recurrence in symptomatic patients. It is administered intrapleurally via chest tube after adequate drainage of the effusion. *Sclesol: 4-8 g (1-2 canisters); deliver by manually pressing actuator button; distal end of the delivery tube should be pointed in several different directions, while short bursts are administered to distribute talc powder equally and extensively on all visceral and parietal pleural surfaces. *Sterile Talc Powder dosage is 5 g dissolved in 50-100 mL 0.9% NaCl.

Instructions for use

Contents are sterile unless package is damaged or opened. Remove contents from inner packaging only immediately before use. The respective asepsis standards have to be adhered to when removing the content from the inner packaging. (M. Tschopp, Boutin C, 2002)

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Review of literature Technique

There are many technical differences in thoracoscopic talc pleurodesis but the outcomes usually the same. One method is adopted for pneumothorax by Tschopp et al, where thoracoscopy was carried out in the lateral decubitus position under local anesthesia with 1% lignocaine. A 7-mm trocar was inserted into the fourth or fifth intercostal space in midaxillary line. A 0 optical telescope was inserted and connected to a video camera and monitor. The visceral pleura were carefully inspected using supplemental air insufflation where necessary. No electrocoagulation, stapling or ligation of any parenchymal lesions was carried out. Sterile asbestos-free talc (2 g) was insufflated particularly to the apex. At the end of the procedure a drain (2428 French gauge) was inserted through the sixth intercostal space in the midaxillary line and connected to underwater seal suction with a negative pressure of 20 cmH2O for 2 days or until air leakage stopped. When an air leak persisted for >7 days, another procedure was perfomed and the case was considered as an immediate failure. The authors waited 1 week before proposing a second intervention in order to optimise the chances of success in both groups and to avoid overtreating failed cases of conservative treatment. (M. Tschopp, Boutin C, 2002) Kolschmann et al, used medical thoracoscopy by a pulmonary physician in an endoscopy suite assisted by two trained nurses for pleurodesis in MPE. Patients were placed in the lateral decubitus position. The patients BP, pulse rate, and oxygen saturation were monitored continuously. Supplemental oxygen was given to the patients to maintain oxygen saturation. Lidocaine 2% was used for local anesthesia and sedation was achieved by a combination of midazolam and fentanyl. They used a 6.5-mm thoracoscope (0 and 30; Karl Storz;
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Tuttlingen, Germany) with a single 7-mm trocar. After complete aspiration of all of the remaining fluid, a thorough inspection of the pleural surface was made. The adhesions were taken down with the biopsy forceps, if possible. Biopsy specimens were made for histopathologic examination, if necessary. Under visual control, an average of 8 g of sterile asbestos-free talc (Steritalc; Novatech; France) was distributed onto the pleural surface. After removal of the thoracoscope, a thoracostomy tube (24 Charrire) was inserted. Suction (20 cm H2O) was started after 1 h, and the chest tube was left in place until < 100 mL of fluid was drained in 24 h. Chest radiography was performed the same day after the procedure and before discharge. (Kolschmann S, 2005) Despite the safety of talc pleurodesis still some reported side effects have to be mentioned. Fever up to 102.4 F after talc pleurodesis has been reported to occur in 1669% of patients. Fever characteristically occurs 412 h after talc instillation and may last for 72 h. Empyema has been reported with talc slurry in 011% of procedures, whereas talc poudrage is associated with an incidence rate of 03% of patients. Local site infection is uncommon, and the degree of pain associated with talc has reportedly ranged from nonexistent to severe. Cardiovascular complications such as arrhythmias, cardiac arrest, chest pain, myocardial infarction, or hypotension have been noted; whether these complications result from the procedures or are related to talc per se has not been determined. Acute respiratory distress syndrome (ARDS), acute pneumonitis, and respiratory failure have also been reported to occur after both talc poudrage and slurry. (Kennedy L, 1994) Milanez de Campos et al, reported empyema in 4%, re-expansion pulmonary edema in 2.2%, and respiratory failure 1.3% in talc
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pleurosesis. Kolschmann et al ; studied survival curves after 180 days after talc pleurodesis in MPE and showed significant differences, with best survival in mesothelioma and shortest life expectancy in lung cancer (p = 0.005). Adverse effects included empyema in one case and malignant invasion of the scar. No episode of talc-induced ARDS was observed. (Milanez de Campos JR, 2001)

Safety
Talc powder is a household item, sold globally for use in personal hygiene and cosmetics. Some suspicions have been raised about the possibility its use promotes certain types of diseases, mainly cancers of the ovaries and lungs. The studies reference, showed its usage in pulmonary issues, lung cancer, skin cancer and ovarian cancer. One of these, published in 1993, was a US National Toxicology Program report, which found that cosmetic grade talc containing no asbestos-like fibers was correlated with tumors formation in rats (animal testing) forced to inhale talc for 6 hours a day, five days a week over at least 113 weeks. (National Toxicology Program 1993) The US Food and Drug Administration (FDA) considers talc (magnesium silicate) to be generally recognized as safe (GRAS) for use as an anti-caking agent in table salt in concentrations smaller than 2%. (U.S. Food and Drug Administration. 2009)

Adverse effects
They are frequency not defined. It is difficult to distinguish adverse effects of talc from adverse effects of procedures associated with talc administration: 1. Empyema
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2. Hypoxemia 3. Dyspnea 4. Unilateral pulmonary edema 5. Pneumonia 6. ARDS 7. Bronchopleural fistula 8. Hemoptysis 9. Pulmonary emboli 10.Tachycardia 11.Myocardial infarction 12.Hypotension 13.Hypovolemia 14.Asystolic arrest 15.Adverse reactions due to the delivery procedure and chest tube may include pain, infection at the site of thoracostomy or thoracoscopy, localized bleeding, and subcutaneous emphysema (Talc powder, sterile (Rx) 2011)

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CHAPTER (4): POVIDONE-IODINE PLEURODESIS INTRODUCTION Povidone-iodine (PVP-I) is a stable chemical complex of polyvinylpyrrolidone (Povidone, PVP) and elemental iodine. It contains from 9.0% to 12.0% available iodine, calculated on a dry basis. This unique complex was discovered at the Industrial Toxicology Laboratories in Philadelphia by H. A. Shelanski and M. V. Shelanski. They carried out tests in vitro to demonstrate anti-bacterial activity, and found that the complex was less toxic than tincture of iodine in mice. Human clinical trials showed the product to be superior to other iodine formulations. It was first sold in 1955, and has since become the universally preferred iodine antiseptic. (Walter Sneader 2005)

HISTORICAL VIEW First discovered in its elemental form by Courtois in 1812, iodine has been used as a topical antiseptic since the mid-1800s. Of all the chemical species found in solutions studied, free molecular iodine or free iodine is the only species with a concentration proven to correlate with bactericidal activity. Whereas free iodine correlates with bactericidal

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activity, total iodine correlates with a given formulations capacity to kill bacteria. (Gottardi W. 2001) Povidone Iodine or polyvinyl pyrrolidone-iodine, commonly abbreviated as PVP-I was discovered by American scientists H. A. Shelanski and M. V. Shelanski. PVPI was introduced to the pharmaceutical market as an antiseptic agent in the 1950s and is found to be more effective than other iodine formulations and was less toxic. Structure: PVP-I is 2-Pyrrolidinone, 1-ethenyl-, photopolymer, compound with iodine. (Eugene SB, Harry GB. 1998)

USES i. As Skin Disinfectant: The patients skin is a major source of pathogens that cause infection. Traditional aqueous-based iodophors, such as povidone-iodine, are one of the few products that can be safely used on mucous membrane surfaces.6 PVP-I as 10% solution(1% available iodine) is widely used for skin disinfection and 7.5% PVPIodine solution (0.75% available iodine) is used for wound cleansing. The resultant broad spectrum of antimicrobial activity is well documented and its efficacy, particularly in relation to resistant micro-organisms such as methicillin-resistant Staphylococcus aureus, has been shown. (Durani P, Leaper D. 2008) ii. Pre-Operative skin preparation: Procedural and surgical site infections create difficult and complex clinical scenarios. A source for pathogens is often thought to be the skin surface, making skin preparation at the time of the procedure critical. The most common skin preparation agents used today include products containing iodophors. PVP-Iodine products have been widely used for pre-operative skin preparation and in
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various surgical procedures and shown to significantly lower subsequent infection rates. In the aqueous form, most commercially available iodophors require a 2-step application in a scrub-and-paint technique, and their activity is limited by the amount of time the agent is in contact with the skin. (Micah L Hemani, 2009) iii. Topical Application: PVP-I in the form of ointments, sprays, lotions is used to prevent microbial contamination of wounds, ulcers, burns etc. PVP-Iodine effectively controls bacterial growth and protects the developing epithelium. Unlike many antibiotic agents it has the added advantage in that its continued use does not result in the generation of resistant organisms. (Povidone Iodine, 2011) iv. Pleurodesis: It is used in pleurodesis (fusion of the pleura because of incessant pleural effusions). For this purpose, povidone-iodine is equally effective and safe as talc, and may be preferred because of easy availability and low cost. (Das SK, Saha SK, 2008) Out of the 28 patients treated with povidone iodine pleurodesis, bronchogenic carcinoma was present in 21 patients, breast carcinoma in 5 patients, non-Hodgkin's lymphoma and unknown primary malignancy was present in 1 patient each. Pleurodesis with talc showed complete success in 19 patients, partial success in 3 patients and failure in 2 patients. Pleurodesis with povidone iodine showed complete response in 24 patients, partial response in 1 patient and failure in 3 patients. Chest pain occurred in 4 patients of talc pleurodesis and 5 patients of povidone iodine pleurodesis, 3 patients of each group had fever. There was no death in the peripleurodesis period. (Das SK, Saha SK, 2008)

DOSAGE AND EFFICACY

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The pleurodesis solution, containing a mixture of 20 ml of 10% iodopovidone (Betadine Aqueous paint) and 80 ml normal saline, used to be injected into the pleural cavity through the chest tube. Some difficulty was experienced in the form of increased resistance while injecting the total volume of fluid (50 ml lidocaine solution + 100 ml iodopovidone solution) in the patients with recurrent pneumothorax. It is possible that patients with pneumothorax require lower amounts of the sclerosing agent for pleurodesis. (Dey A, Bhuniya S, 2010) A mixture of 20 mL of 10% topical solution of Povidone-iodine and 80 mL of normal saline and 2 mg/kg lidocaine 2% was Instilled into the pleural cavity through thoracostomy tube and then, the tube was clamped for 2 hours. The position of these patients was changed within 2 hours by the medical staff to circulate the mixture. After declamping, the thoracostomy tube was removed as soon as the drainage decreased <100 mL per day. Negative pressure was not applied to any of the patients. After pleurodesis, all patients were assessed via chest X-ray (CXR) after 1 week, 1 and 3 months. Complete response was obtained in 26 patients (72.2%). (Godazandeh G, 2013)

TECHNIQUE Patients underwent insertion of a 28 F chest tube at bedside under local anesthesia; IV opioids were administered when necessary. The next day, povidone-iodine 10 % was diluted to get povidone-iodine 2.5% , to which 5 mL of a 2% lidocaine solution was added and instilled through the chest tube according to the group of the patients. The tube was clamped for 1 h and then connected to a water seal. All patients were admitted to the same ward in the hospital, and underwent the same
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postpleurodesis respiratory therapy and pain control protocols. It is not our policy to use suction after pleurodesis; therefore, none of the patients underwent postoperative chest tube aspiration. Chest X rays were obtained after chest tube removal as the baseline chest X rays. Further chest X ray radiographs were performed on the 30th postoperative day after patients had undergone pleurodesis. The presence of pleural effusion was evaluated with chest X rays. (Ali Asghar Alavi, et al.; 2011)

ADVERSE EFFECTS The only significant side effect of iodopovidone was the occurrence of chest pain. Only two studies have systematically assessed the occurrence of chest pain. Hypotension was reported in two studies and was found associated with chest pain and is likely to be vasovagal in origin. However, iodine can cause severe allergic reactions, especially in patients with allergic diathesis, and thus one should be prepared to deal with this emergency. Iodine may also precipitate thyrotoxicosis in patients with subclinical hyperthyroidism (Jod-Basedow effect). However, in a study with 12 patients, no alteration in thyroid function was noted. There were no deaths or ARDS associated with this agent. There is also a single report of visual loss associated with iodopovidone pleurodesis using 200-500 ml of 10 per cent iodopovidone. (Ritesh Agarwal, et al.; 2012) Many studies have demonstrated that the significant side effects of povidone-iodine are the occurrence of the chest pain, postoperative visual loss and thyroiditis. However patients on the povidone-iodine group reported higher scores of dyspnea in one month follow up. (Wagenfeld L, Zeitz O, 2007)
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