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Dr. Light is Director of the Pulmonary Disease Program, Saint Thomas Hospital.
Correspondence to: Richard W. Light, MD, FCCP, Director of Pulmonary Disease Program, Saint Thomas Hospital, 4220 Harding Rd, Nashville, TN; e-mail: RLIGHT98{at}yahoo.com
At the present time, talc is the agent for pleurodesis that is preferred by the majority of chest physicians in the United States and England. The reason for this preference is that talc, administered either by an aerosol (insufflation) or in a suspension (slurry), is effective, inexpensive, widely available, and associated with minimal side effects in most reports.
Concerns, however, remain about the safety of talc. The primary worry is the observation that ARDS can develop after its intrapleural administration. There are least at 42 cases of ARDS following intrapleural talc administration in the literature, 24 following the use of talc slurry and the remaining 18 following talc insufflation.1 2 3 4 5 6 7 8 9 10 In some cases, the patients presented with respiratory failure and required mechanical ventilation. Eleven of the patients died.1 4 6 8 9 10 The reports of this complication seem to be increasing recently. In one recent article from New Zealand, Brant and Eaton10 reviewed their experience with 33 pleurodesis procedures in 29 patients. They reported that major complications (ie, hypoxemia and hypotension) occurred in seven patients and that two of the patients died.10 In another recent report, Scalzetti11 reported that 16% of 108 patients undergoing pleurodesis developed a transient interstitial process in the lung ipsilateral to the treated pleural space.
What is talc? Talc is a pulverized, natural, foliated, hydrated magnesium silicate that has the approximate chemical formula of Mg3(Si2O5)2(OH)2.12 There are many talc deposits scattered throughout the world, and every talc deposit is unique with regard to both chemistry and morphology. In general, the companies that produce the talc that is used for pleurodesis do not know the origin of their talc. There are variable amounts of calcium, aluminum, and iron present in different talc preparations. Non-talc minerals associated with commercial talc vary from deposit to deposit and may include calcite, magnesite, dolomite, chlorite, serpentine, quartz, and others. Talc is processed by being passed through mesh to eliminate the larger talc particles. Accordingly, the mesh size sets the upper limit for the size of the talc particles in the final preparation.
The mechanism responsible for ARDS following intrapleural talc administration is unknown. The incidence of ARDS following intrapleural talc administration has varied widely from study to study. For example, at one extreme in Seattle, Rehse and coworkers5 retrospectively reviewed their experience of 89 talc pleurodesis procedures in 78 patients and reported that 9% of their patients developed ARDS requiring mechanical ventilation. At the other extreme, Cardillo and associates13 recently reported in Italy that there were no cases of ARDS in 611 patients who received 5 g insufflated talc intrapleurally. It has been hypothesized that the onset of ARDS following talc administration is dose-dependent, occurring in patients receiving > 5 g.14 15 However, this hypothesis is probably wrong since de Campos and coworkers9 have reported that acute respiratory failure developed in 7 of 550 patients (1.3%) who received only 2 g insufflated talc for either recurrent pleural effusion or pneumothorax. Four of these seven patients died of respiratory failure.
Another hypothesis is that the acute pneumonitis is due to the systemic absorption of talc with the subsequent elaboration of inflammatory mediators. Support for this hypothesis is provided by studies in both humans and animals. In the four cases reported by de Campos and coworkers9 and in the case reported by Rinaldo and associates,1 there were large quantities of talc in the BAL fluid of patients who developed ARDS following talc pleurodesis. Moreover, at the autopsy of one patient who died from ARDS, talc particles were present in almost every organ, including the ipsilateral and contralateral lung, brain, liver, kidney, heart, and skeletal muscle.9 After the intrapleural administration of talc in rabbits, talc particles were detected in 17% of the mediastinal ganglia, 17% of the kidney specimens, and the 49% of the splenic specimens.16 Talc particles were detected in every organ of 40 rats that were killed 24 and 48 h after the talc was administered intrapleurally.17
If the systemic absorption of talc particles is responsible for the acute pneumonitis, then a reasonable subhypothesis is that talc preparations with smaller median sizes would be more likely to be absorbed and, therefore, would be more likely to produce ARDS. Indeed, we have shown previously that the mean diameter of the talc particles in eight different talc preparations varied from 10.8 to 33.6 µm.18 Interestingly, talc preparations from the United States, the country with the highest incidence of ARDS following talc administration, had the smallest mean diameter. It should be noted that in sheep the mean diameter of the stomata, which are the openings to the lymphatics in the pleural cavity, are 8 to 10 µm.19
The article by Fraticelli and workers in this issue of CHEST (see page 1737) examined whether there was systemic dissemination of talc after the intrapleural administration of talc with a median particle size of 33.6 µm and a mean particle size of 31.3 µm. After a relatively large dose of this talc was injected intrapleurally into rats, talc particles were found in only 4 of 198 samples of the right lung, brain, liver, spleen, kidneys, and blood when talc was searched for in the entire organ. However, it is interesting that 75 particles were found in the liver of one rat. The authors hypothesized that these particles were due to contamination of the liver by other talc-containing tissue since the size of the talc particles was similar to that from the intrapleurally injected calibrated talc. Alternatively, the talc could have been absorbed. It is possible that interindividual variation in talc absorption might explain the sporadic occurrence of ARDS after intrapleural talc.
Fraticelli and coworkers conclude that the lack of the systemic dispersion of talc particles in their study is probably due to the size of their talc particles, which was larger than sizes in most talc preparations. However, definite proof for this conclusion would require the demonstration of the significant systemic distribution of talc particles after talc particles with a smaller median diameter were injected intrapleurally. It should be noted that 20% of their talc particles had a diameter < 10 µm. If the size of the particle was the only factor governing its systemic distribution, then one would expect a few small particles to be found in nearly every organ.
Another possible mechanism relating the size of the talc particle to the development of ARDS is that talc preparations with smaller median particle size would lead to the generation of more cytokines in the pleural space and the systemic absorption of these cytokines could lead to ARDS. Nevertheless, it should be noted that the evidence is far from conclusive that the occurrence of ARDS is related to the median size of the talc particles. Other possible mechanisms are contaminants of the talc preparations, such as endotoxin, or other organic or inorganic materials.
What is the future for talc as a pleurodesis agent? Talc is basically dirt. It appears to me that in the year 2002, we should be able to find an agent that is more specific for the induction of pleurodesis than is dirt!! Our studies in rabbits and sheep have demonstrated that transforming growth factor (TGF)-ß induces a pleurodesis that is superior to that induced by talc, doxycycline, or bleomycin and that occurs faster.20 21 22 It appears that TGF-ß induces the pleurodesis by stimulating the mesothelial cells to produce collagen and does not require that the pleural surface be injured as it is with talc or doxycycline. Inflammatory indexes in the pleural fluid after the intrapleural administration of TGF-ß are much lower than those after doxycycline or talc administration.20 I would guess that in the future TGF-ß or some similar cytokine will become the agent of choice for pleurodesis. However, such a cytokine is likely to be expensive, and in underdeveloped countries a less expensive agent is desirable. Such an agent may prove to be silver nitrate, which at least in animals is more effective than talc,23 24 and in a preliminary report was effective in humans.25 I believe that the use of talc will diminish due primarily to the fact that ARDS occurs following its administration and that the many sources of talc make the standardization of talc preparations very difficult.
Footnotes
Supported in part by The Saint Thomas Foundation, Nashville, TN.
References
This article has been cited by other articles:
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  A. R. Haas, D. H. Sterman, and A. I. Musani Malignant Pleural Effusions: Management Options With Consideration of Coding, Billing, and a Decision Approach Chest, September 1, 2007; 132(3): 1036 - 1041. [Abstract] [Full Text] [PDF]
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 G. T. Stathopoulos, Z. Zhu, M. B. Everhart, I. Kalomenidis, W. E. Lawson, S. Bilaceroglu, T. E. Peterson, D. Mitchell, F. E. Yull, R. W. Light, et al. Nuclear Factor-{kappa}B Affects Tumor Progression in a Mouse Model of Malignant Pleural Effusion Am. J. Respir. Cell Mol. Biol., February 1, 2006; 34(2): 142 - 150. [Abstract] [Full Text] [PDF]
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I. Kalomenidis, Y. Guo, K. B. Lane, M. Hawthorne, and R. W. Light Transforming Growth Factor-{beta}3 Induces Pleurodesis in Rabbits and Collagen Production of Human Mesothelial Cells Chest, April 1, 2005; 127(4): 1335 - 1340. [Abstract] [Full Text] [PDF]
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 S. Sartori, D. Tassinari, P. Ceccotti, P. Tombesi, I. Nielsen, L. Trevisani, and V. Abbasciano Prospective Randomized Trial of Intrapleural Bleomycin Versus Interferon Alfa-2b via Ultrasound-Guided Small-Bore Chest Tube in the Palliative Treatment of Malignant Pleural Effusions J. Clin. Oncol., April 1, 2004; 22(7): 1228 - 1233. [Abstract] [Full Text] [PDF]
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Y. C. G. Lee, M. H. Baumann, N. A. Maskell, G. W. Waterer, T. E. Eaton, R. J. O. Davies, J. E. Heffner, and R. W. Light Pleurodesis Practice for Malignant Pleural Effusions in Five English-Speaking Countries: Survey of Pulmonologists Chest, December 1, 2003; 124(6): 2229 - 2238. [Abstract] [Full Text] [PDF]
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E. Marchi, L. R. Teixeira, F. Vargas, P. Astoul, A. Fraticelli, A. Robaglia-Schlupp, and P. Cau Talc for Pleurodesis: Hero or Villain? Chest, July 1, 2003; 124(1): 416 - 417. [Full Text] [PDF]
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