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Review Article
Pleurodesis: technique and indications*
MARCELO COSTA VAZ1, EVALDO MARCHI2, FRANCISCO SUSO VARGAS3
ABSTRACT
Recurrent pleural effusion, which is commonly seen in clinical practice, compromises patient quality of life, especially in
patients with advanced malignant disease. The therapeutic approach to the pleural space involves a wide range of
techniques, including aggressive procedures such as pleurectomy. Among such techniques, pleurodesis is the most frequently
used. Pleurodesis can be induced through the insertion of pleural catheters, as well as through major surgical procedures
(such as thoracotomy). There are various recommended sclerosing agents, including talc (which is the most widely used),
silver nitrate and, recently, proliferative cytokines. This article summarizes the principal approaches to the treatment of
recurrent pleural effusion, pleurodesis in particular, addressing the indications for, as well as the advantages and
disadvantages of, their application in daily pulmonology practice.
Keywords: Pleural effusion, malignant/prevention & control; Pleural neoplasms; Pleura/surgery; Pleurodesis/methods;
Silver nitrate; Talc; Recurrence
* Study carried out by the Pleura Group of the Pulmonology Department, Instituto do Coração (InCor, Heart Institute),Universidade de São Paulo (USP, University of São Paulo) School of Medicine - São Paulo, Brazil.
1. Ph.D. Professor in the Pulmonology Department of the Universidade de São Paulo (USP, University of São Paulo)School of Medicine - São Paulo, Brazil. Attending physician in the Pulmonology Department of the Instituto do Coração(InCor, Heart Institute) of the Universidade de São Paulo (USP, University of São Paulo) School of Medicine Hospital dasClínicas - São Paulo, Brazil2. Tenured Professor in the Pulmonology Department of the Universidade de São Paulo (USP, University of São Paulo)School of Medicine - São Paulo, Brazil. Associate Professor, Chief of the Department of Thoracic Surgery at theFaculdade de Medicina Jundiaí (FMJ, Jundiaí School of Medicine) - Jundiaí, Brazil3. Full Professor in the Pulmonology Department of the Universidade de São Paulo (USP, University of São Paulo) Schoolof Medicine - São Paulo. Brazil. Director of the Pulmonology Department of the Instituto do Coração (InCor, HeartInstitute) of the Universidade de São Paulo (USP, University of São Paulo) School of Medicine Hospital das Clínicas - SãoPaulo, BrazilCorrespondence to: Francisco Suso Vargas. R. Itapeva, 500, 4C, Bela Vista - CEP: 01332-000, São Paulo, SP, Brazil. E-mail: [email protected]; [email protected]: 3 January 2006. Accepted, after review: 12 January 2006.
INTRODUCTION
hemodynamic alterations that can ultimately resultin respiratory distress syndrome or hemodynamic Recurrent pleural effusion is commonly seen in shock. The pleural fluid removal, performed with all clinical practice, and results from the anatomic or the necessary precautions, is well tolerated and functional impairment of the pleural surfaces by significantly improves the dyspnea caused by the benign or malignant processes. Among the wide effusion. Nevertheless, since the fluid can rapidly re- range of clinical entities responsible for the accumulate, performing multiple thoracenteses production of these effusions are the transudates becomes a temporary alternative in the control of (resulting, in particular, from heart, liver or kidney recurrent pleural effusion. The need for multiple failure), and the exudates (principally generated by punctures is physically and emotionally invasive, nonspecific infections, tuberculosis or neoplasms).
resulting in evident protein and electrolyte depletion.
In this context, we must highlight the significant The second option to be considered is prolonged predominance of cancer, which accounts for drainage to maintain the pleural cavity free of fluid.
approximately 50% of the total number of these It should be noted that leaving a drain in place for deposits.(1) It is estimated that there are approximately long periods (a month or more) can, in itself, result 200,000 new cases of malignant pleural effusion per in symphysis of the pleural surfaces, which is highly year in the USA.(2) In Brazil, despite the lack of precise positive. Nonetheless, prolonged drainage results in epidemiological surveys, it is believed that, due to great nutritional deprivation,(3) increases the risk of the common characteristics of the two countries, the pleural infections and can decrease survival.(3) Until number of patients with malignant pleural effusion recently, such drainage was performed with large- caliber tubular thoracic drains (34 to 40 F), which The treatment for recurrent pleural effusion is have been currently replaced by small-caliber complex and is aimed at arresting band preventing catheters (maximum, 16 F). There are very effective fluid collection, maintaining the pleural cavity free pleural catheters in the market, such as the pig-tail from new fluid accumulation. The first step is to or pleurex, which are highly functional, although their address the pathological process responsible for the equally high cost can be an obstacle. Commercial formation of the effusion. In the case of transudates, production of these catheters has just recently begun the treatment is aimed at treating the heart, kidney in Brazil (Figure 1). This will certainly decrease costs, or liver failure, whereas it is aimed at treating the simplify the procedure and benefit our patients.
infection or cancer in the case of exudates. However, The third option is using a pleuroperitoneal shunt, when the systemic treatment of the condition which is nothing more than a thin catheter with a responsible for the formation of the effusion does receptacle (a unidirectional valve) at its midpoint. The not control the fluid accumulation and does not extremities of the shunt are placed in the pleural and prevent its recurrence, local treatment should be peritoneal cavities, and the catheter, including the recommended, allowing the free expansion of the receptacle, follows a subcutaneous trajectory (Figure lung with subsequent functional improvement. The 2). When the patient presents worsening of symptoms methods in reference include initial thoracentesis, (basically dyspnea), the receptacle is repeatedly pleural drainage, pleuroperitoneal shunt, compressed, removing fluid from the pleural cavity and, by virtue of its unidirectionality, sending it to the The objective of the initial thoracentesis is the peritoneal cavity. The inconvenience of this system removal of fluid from the pleural cavity in order to lies in the small volume of the valve chamber (+ 2 ml), achieve lung expansion and subsequent functional which can require an exhaustive number of improvement. However, due to the potential risks of compressions of this compartment. For the removal this procedure, caution is called for regarding the of 400 ml pleural fluid, more than 200 compressions volume to be removed from the pleural cavity.
are necessary. Other negative aspects of the system Therefore, it is recommended that, even in large are the high valve obstruction rate, the risk of neoplastic effusions, fluid removal should not exceed 1200 ml implantation in the abdominal cavity(4) and the high (maximum, 1500 ml), since the removal of larger cost, which makes it practically unviable in Brazil.
volumes of fluid increases the risk of developing pulmonary edema, in addition to respiratory or undoubtedly the most effective procedure.
Figure 1 - Catheter for pleurodesis (manufactured in Brazil); A) drainage/pleurodesis kit and components; B)
introduction of the guidewire into the catheter; C) catheter ready to be introduced into the pleural cavity and D)
simulation of the assembled kit draining the pleural fluid
However, it has been contraindicated due to the fluid. This has been the procedure most often used in the case of complete pulmonary expansion and mortality.(5) In fact, the high risk of complications the general condition of the patient is good. It is is justifiable since it is major surgery and the currently the best option for the control of recurrent candidates are patients with impaired general health status. It represents highly aggressive It is important to mention that pleurodesis only treatment of a group of patients with limited r e p r e s e n t s t h e l o c a l t h e r a p y o f a c l i n i c a l manifestation, which is generally the treatment for Finally, there is pleurodesis, that is, the dyspnea. Therefore, the objective of this procedure intentional collapse of the pleural surfaces (visceral is not to change the progression of the cancer, and parietal) resulting in the symphysis of the and it is not aimed at prolonging patient survival.
pleural space, which hinders the accumulation of In view of this, pleurodesis reduces the dyspnea caused by fluid accumulation in the pleural spaceand consequently results in greater functionalcapacity and better quality of life.
OBJECTIVE
Our intention is to discuss the strategies for inducing pleurodesis in patients with recurrentpleural effusion, especially that of neoplastic origin.
We endorse certain methods of execution cited inthe medical literature.
In this review, due to the current tendency toward simplification of the pleurodesis procedure,we discuss the integration of the skills of clinicalpulmonologists, thoracic surgeons and oncologistsin a joint analysis of the patients, in order to promoteeffective and minimally invasive pleurodesis.
This review is consistent with the line of research pursued by the Pleura Group of the PulmonologyDepartment of the University of São Paulo Schoolof Medicine, and our objective is quite clear: thecomprehensive evaluation of patients suffering from Figure 2 - "Pleuroperitoneal shunt": A) catheter with interposed
pulmonary diseases. We believe that patients with receptacle (unidirectional valve); B) insertion of one of the extremities lung cancer should be submitted to holistic treatment into the pleural cavity; and C) shunt in position, draining fluid from by the pulmonologist, rather than being referred to the pleural cavity and directing it toward the abdominal cavity the oncologist immediately after confirmation of thediagnosis. Therefore, we disagree with those whorecommend referring such patients to a surgeon Register; and the Evidence-Based Medicine for the induction of pleurodesis immediately after Cochrane Database of Systematic Reviews. The recurrent pleural effusion has been confirmed.
search terms used were 'pleurodesis' and 'pleural Thanks to recent technological advances and effusion'. We limited our search to articles that simplification of procedures, the physician should focused on efficacy and safety, ruling out case develop the necessary skills to create continuity in descriptions, letters to the editor and editorials.
the treatment of these patients, as well as tocoordinate clinical-surgical-oncological integration, INDICATIONS
in order to offer the best treatment options topatients with neoplasms. (See our proposal regarding Recurrent benign pleural effusions
minimally invasive outpatient pleurodesis performed The performance of pleurodesis in recurrent benign (transudative) pleural effusion is controversial Therefore, the aim of this discussion is to answer and should be regarded as a procedure reserved the following questions: What are the indications for pleurodesis? What is the best agent for pleurodesis? What is the best method for the comparative studies evaluating the efficacy and safety of pleurodesis in benign processes. Thefindings of observational studies suggest that, in these situations, pleurodesis is efficacious and safe.
However, there is the theoretical fear that, after pleurodesis of the transudates, the pleural fluid will bibliographic searches of the following electronic begin to accumulate in other tissues, such as those databases: Medline; the Cochrane Controlled Trials Therefore, the performance of pleurodesis in effusion (radiological regression of the effusion recurrent benign pleural effusion is only acceptable and decreased number of thoracenteses to promote in those rare situations in which there is absolute dyspnea relief) is preceded by the performance of failure of the clinical treatment of the underlying one or two cycles of chemotherapy (after two to three months or even at the end of the chemotherapy Among the causes of recurrent benign pleural treatment). Although there are factors in favor of and effusion, we should mention liver, kidney and heart against these approaches, both indications are failure, as well as hypoproteinemia and myocardial decided, other factors that, despite not enjoying a Recurrent malignant pleural effusions
consensus, can modify the indication criteria The main indication for pleurodesis resides in should be considered, since they can interfere with this group of patients. However, not all the patients the result expected. Therefore, acid pH (< 7.3),(10) with malignant pleural effusion benefit from the low glucose level (< 60 mg/dl) and incidence of procedure. In some situations, there is a consensus chylothorax have been related to worse prognosis regarding the induction of pleurodesis (Chart 1); and worse efficacy of pleurodesis, independently in others, it is absolutely controversial.
of the technique and of the drug used (5) (Chart 3).
Once these conditions have been considered, The presence of lymphangitis and a performance status index lower than 70 have been associated with procedure should be analyzed. Some authors worse clinical evolution of the patient after the defend the idea that pleurodesis should be induction of pleurodesis.(5) Finally, lung entrapment, performed as soon as possible after the diagnosis either due to pleural loculations or to a lack of has been confirmed.(9) Others recommend its pulmonary expansion, reduces the efficacy of performance only if chemotherapy fails to control pleurodesis, as well as increasing the risk of infections the pleural effusion. However, there is no evidence in the pleural space.(3) Therefore, pleurodesis is not to support the use of the latter strategy. In this situation, the analysis of the control of the pleural PERFORMANCE OF PLEURODESIS -
Chart 1 - Indications for pleurodesis
METHODOLOGY
Types of procedures
Indications
Pleurodesis can be achieved through the use of Failure of oncological treatment to control pleural various stimuli: direct physical lesion (abrasion); instillation of caustic or irritating chemical substances Dyspnea relief after drainage of the pleural cavityFull pulmonary expansion (chest X-ray) (talc, doxycycline, silver nitrate or bleomycin) into Karnofsky performance status index > 70 the pleural space; or immunological induction with Corynebacterium parvum, transforming growth factor-beta (TGF-ß) or interferon-alpha 2 (IFN-a 2).
Chart 2 - Ideal moment for the performance of pleurodesis
Indication
Makes oncological treatment more difficult Greater risk of empyemaPoorer performance status Chart 3 - Prognostic factors of the efficacy of
the ideal sclerosing agent (Chart 4).
Chemical stimulation has the advantage of allowing various routes of access to be combined.
Worse prognostic and least efficacy
The most important aspect, in this particular case, is that pleurodesis can be achieved surgically or Presence of chylothorax Presence of lymphangitis efficacious sclerosant. When compared with other agents, it presents a relative risk of 1.34 fortherapeutic success (95% confidence interval: 1.16to 1.55) and a success rate of over 90% in moststudies.(11) However, in a recent multicenter study Mechanical stimuli
conducted in Europe, talc was found to be Among the mechanical stimuli, abrasion is the efficacious in 71% to 78% of the patients submitted principal method. Abrasion is carried out during a to pleurodesis, all of whom survived for more than surgical intervention, whether conventional or 30 days after the procedure.(12) Talc has been video-assisted, in which the surgeon exfoliates the considered the agent of choice, since it presents pleural mesothelium, creating friction with a rough- many of the characteristics cited in the definition surfaced material (gauze, for example). This of an ideal agent (low cost, wide distribution, easy irritation results in the desquamation of the administration, high efficacy and low rate of side mesothelium and activation of the inflammation effects). It can be administered, either by and coagulation pathways, with subsequent insufflation during thoracotomy or through drains proliferation of fibroblasts and collagen deposition, of various calibers, in the form of so-called talc slurry (talc suspension in saline solution). Despite Pleural abrasion is not currently used in the its low rate of complications, its use has been control of recurrent neoplastic pleural effusions associated with acute respiratory distress syndrome, due to its lesser efficacy, as well as to the high risk which affects 1.2%(7) to 9% of patients(13) and can of bleeding in the regions involved and to the be fatal. It is believed that this complication is possibility of tumor dissemination. These two risks related to the size of the talc particles. The smaller are related to the direct manipulation of the tumor ones would be more easily absorbed from the w i t h l e s i o n o f n e w l y f o r m e d v e s s e l s a n d pleural cavity and distributed throughout the embolization of tumor cells that are released circulation, resulting in a greater risk of remote during the manipulation of the tumor mass.
complications.(14) Due to the severity of this type Another inconvenience of pleural abrasion is that of complication, other drugs again began to be it requires surgical intervention. Its indication has been currently recommended only for selectedcases of recurrent pneumothorax.
Chart 4 - Characteristics of the ideal sclerosant agent
Chemical stimuli
Characteristics
Pleurodesis induced by chemical stimuli was first carried out at the beginning of the last century.
There are references to the fact that, in 1901, Spengler injected silver nitrate into the pleural cavity for the control of recurrent pneumothorax.(5) Apparently, talc was first introduced into the pleural cavity, with the objective of collapsing the existing residual space after pulmonary resection, by Bethune in 1935.(5) Since then, various Minimal, easily controlled morbidity Near 100% efficacy substances have been used to induce pleurodesis,although there is as yet no consensus regarding Doxycycline has proven efficacious and safe efficacy of this agent has not been reproduced in for the induction of pleurodesis. However, it is not Brazil, and there are currently difficulties in its available in many countries (including Brazil). In production, and there is no distribution network.
the past, some health facilities in Brazil utilized oral tetracycline/doxycycline derivatives to induce interleukin 2-alpha, staphylococcal superantigen pleurodesis. Nevertheless, there are doubts as to and TGF-β. In a comparative, randomized, whether the sclerosing effect observed is due to prospective, parallel study carried out in 2004, IFN- the agent used or to the excipient (talc). In a 2b was found to be less efficacious than addition, we should also be concerned with the bleomycin,(17) and its use was not indicated for sterilization of the agent introduced in the pleural pleurodesis induction. Staphylococcal superantigen cavity, since the capsules are in fact commercially seems to be a promising agent, despite having been distributed for oral ingestion and their content is little studied. In a study carried out in 2004,(18) not sterile and are therefore not recommended for staphylococcal superantigen was instilled in fourteen patients with low performance status Silver nitrate was the first substance utilized in indices. It was successful in eleven patients (71%), the induction of pleurodesis, being abandoned, without any side effects. Its principal advantage is for reasons that remain unclear, in the 1980s. Our ease of administration, not requiring hospitalization group recently posited that the adverse effects or thoracic drainage. Since these results are still observed in the past were secondary to the high preliminary, further studies of efficacy and safety concentrations of silver nitrate used (from 1% to are required. Finally, TGF-β is a cytokine that 10%), and we therefore suggested that the use of stimulates tissue proliferation and collagen lower concentrations would be safer and more formation, without inducing an inflammatory efficacious.(15) In studies with laboratory animals reaction or tissue lesion. The major concern (rabbits), 0.5% silver nitrate proved highly efficacious regarding its use is related to its systemic and presented a low rate of complications.(16) The absorption, with development of fibrosis in other pathophysiological mechanism involved in the organs, including the lung. It was successfully induction of pleurodesis seems to be, to a certain tested in experimental animals with low short-term extent, different from that observed with the talc, complication rates.(19) However, studies analyzing since, in this rabbit model, the corticosteroid did its efficacy and safety in humans have yet to be not reduce the efficacy of the pleurodesis obtained carried out. It is rather unlikely that TGF-β will with silver nitrate, in contrast to what occurs with prove to be the ideal sclerosing agent, since its the talc. A recently published study involving cost is higher than that of other agents.
human subjects with neoplastic pleural effusion Therefore, we can conclude that, despite the and utilizing 0.5% silver nitrate, demonstrated lack of consensus, talc, in the dosage of five to efficacy indices similar to those found for talc, with ten grams, remains the most accepted agent.
low rates of side effects.(15) Naturally, furthercomparative studies of the safety and efficacy of Route of access
silver nitrate in humans are required.
Route of access is defined as the method by Bleomycin is an antineoplastic agent that was which the sclerosing agent is given access to the used to induce pleurodesis in past decades. However, pleural space, either through classical thoracotomy, its low efficacy and high cost have significantly through video-assisted surgery, through thoracic drainage with local anesthesia or through thoracicdrainage with thoracic puncture and a small-caliber Immunological stimuli
Chief among the immunostimulants is C.
All of these techniques present advantages and parvum. Its principal advantage is that it does not disadvantages that can interfere with the final require surgical intervention or pleural drainage result of the procedure (Chart 5). Among the and can be introduced into the pleural space advantages, we can cite the complete drainage of through a simple puncture. However, the described distribution of the sclerosing agent in the pleural and can be more easily introduced, being currently space, less aggressiveness of the procedure and recommended as an option for the initial approach less need for hospitalization. These factors to recurrent pleural effusion and for the induction influence the choice of the technique that is most Small-caliber drains have been successfully In these past few years, the route of access for used in the performance of rapid pleurodesis. In pleurodesis has been thoroughly studied. There is this new form of pleurodesis induction, the a tendency to reduce the aggressiveness of the pleural catheter is put in place, the sclerosant is treatment, migrating from talc insufflation during instilled, the drain (with a unidirectional valve thoracotomy to video-assisted insufflation and system that allows the outflow of the fluid but eventually to the instillation of sclerosant through does not allow the air to get in and prevents a thoracic drain. Even when the thoracic drain is backflow of the fluid into the pleural space) is used as a route of access to the pleural cavity, left open, and the drain is generally removed there is a tendency toward reducing its complexity within 48 h.(21) The combination of small-caliber and morbidity (pain). Therefore, we have evolved drains with a valve system, such as the Heimlich from using large-caliber to using small-caliber valve, which is a unidirectional valve system that drains and ultimately to the use of pleural catheters.
allows the replacement of the water-seal (Figure In parallel with the reduced aggressiveness, the 2), has facilitated pleurodesis induction, allowing efficacy of the treatment must be maintained. The greater patient mobility and comfort, as well as ideal route of access for striking a balance between a l l o w i n g p l e u r o d e s i s t o b e p e r f o r m e d i n efficacy and safety in pleurodesis has yet to be defined. Unfortunately, many studies comparingroutes of access have not employed the same CONCLUSIONS AND RECOMMENDATIONS
sclerosing agent for each route, thereby making itdifficult to interpret the isolated effect of the route of access to the pleural space. A meta-analysis indicated in benign pleural effusions, with carried out in 2004(11) by the Pain, Palliative Care restrictions. The principal indication for pleurodesis and Supportive Care Group of the Cochrane is recurrent malignant pleural effusions, with full Database of Systematic Reviews (112 patients), pulmonary expansion, in patients with good evaluated the efficacy of talc pleurodesis using video-assisted surgery or using drainage/talc slurry Pleurodesis via chemical stimulus, especially talc (talc in suspension). The authors showed that the pleurodesis, remains the first option for the instillation through video-assisted surgery was treatment of recurrent malignant pleural effusion.
more efficacious, with favorable relative risk of Silver nitrate seems to be a reasonable option for 1.19 (95% confidence interval: 1.04 to 1.36) and use in Brazil, although more studies of its safety similar mortality in the two groups. Unfortunately, in this meta-analysis, it was not possible to The most efficacious route of access is video- compare the adverse effects of the two treatments assisted surgery. However, the use of small-caliber due to the lack of pertinent data in the studies thoracic drains (catheters) provides a good cost- involved. Despite the fact that video-assisted effectiveness/comfort ratio, especially for patients surgery was found to be more efficacious than in advanced stages of neoplastic disease.
slurry pleurodesis, the level of success for both The most significant aspect to be considered is that pleurodesis has become a procedure to can be carried out in outpatient clinics by physicians.
The current evidence suggests there is no This simplifies its execution considerably while difference between the use of large-caliber thoracic maintaining the indices of efficacy. Therefore, there drains and small-caliber thoracic drains (catheters).
is no need for hospitalization, which would deprive Although a consensus has yet to be reached, small- patients, during this difficult phase of their life, of caliber drains provides more comfort to the patient Chart 5 - Techniques employed in the performance of pleurodesis
Technique
Hospitalization requiredComplicates use of soluble drugs Hospitalization requiredComplicates use of soluble drugs Hospitalization requiredTalc slurry not possible Feasible with lower performance statusSoluble drugs can be used Chart 6 - Proposal/protocol for outpatient pleurodesis by a physician or surgeon
• Confirm the diagnosis of neoplastic pleural effusion through cytological or anatomopathological study.
• Confirm lung expansion after initial thoracentesis (X-ray or tomography).
• The better the general status of the patient (Karnofsky > 60), the better the result.
• Introduce small-caliber catheter/drain, connect Heimlich valve draining into collection bag (or colostomybag).
• The patient can go home after detailed explanation about special care and how to change the collectionbag. Provide guidance on access to medical treatment in case of emergency. Patient can return after sevendays.
• Induce pleurodesis. There are basically two options, injecting through the catheter: a) 5 g of talc insuspension with 100 mL of saline solution; or b) 20 ml of a solution of 0.5% silver nitrate.
• Confirm the diagnosis of neoplastic pleural effusion through cytological or anatomopathological study.
• There is no need for analgesia. The procedure is well tolerated. However, it is convenient to have access toan opioid (morphine, meperidine or tramadol), since significant pain can be observed, which will be reducedby the medication, allowing the proposed procedure to continue.
• After the intrapleural introduction of the sclerosant agent, inject 20 ml of saline solution to wash thecatheter, clamp it for one hour, and then open it to allow the drainage of the fluid. Leave it open. There isno need to move (rotate) the patient while the catheter is clamped.
• The patient can be discharged after receiving guidance regarding necessary care. In general, commonpainkillers (dipyrone or equivalent) are sufficient. More potent drugs are rarely necessary, and we suggesttramadol or opioids. Avoid the use of nonsteroidal anti-inflammatory drugs or corticosteroids, since they canreduce the efficacy of the pleurodesis. Ask the patient to write down the volume drained daily, and schedulean appointment for the following week.
• If the drainage is inferior to 100 ml/day, and there is no sign of obstruction of the catheter or of pleuralloculation, remove the catheter. Conduct clinical follow-up evaluation and follow-up imaging studies (X-ray,ultrasound or tomography).
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