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(Chest. 2001;119:1516-1520.)
© 2001 American College of Chest Physicians

Experimental Pleurodesis in Rabbits Induced by Silver Nitrate or Talc*

1-Year Follow-up

Francisco S. Vargas, MD, FCCP; Lisete R. Teixeira, MD; Leila Antonangelo, MD; Marcelo A. C. Vaz, MD; Alipio O. Carmo, PharmD; Evaldo Marchi, MD and Richard W. Light, MD, FCCP

* From the Laboratory of Pleura (Drs. Vargas, Teixeira, Antonangelo, Vaz, Carmo, and Marchi), Division of Respiratory Diseases, Heart Institute (InCor), University of São Paulo Medical School, Brazil; and Department of Medicine of Saint Thomas Hospital and Vanderbilt University (Dr. Light), Nashville, TN.

Correspondence to: Richard W. Light, MD, FCCP, Director of Pulmonary Disease Program, Saint Thomas Hospital, 4220 Harding Rd, Nashville, TN 37205; e-mail: rlight98{at}yahoo.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To compare the pleurodesis results from the intrapleural injection of silver nitrate and talc slurry over an observation period of 12 months in rabbits.

Design: Rabbits were randomized to receive 2 mL of 0.5% silver nitrate or 400 mg/kg of talc slurry in 2 mL intrapleurally. Ten rabbits in each group were killed at 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, and 12 months after intrapleural injection. The degree of gross pleurodesis and the amount of microscopic pleural fibrosis and inflammation were graded on a scale of 0 to 4.

Results: The mean ± SEM gross pleurodesis score in the 70 rabbits that received silver nitrate was 3.34 ± 0.08, which was significantly higher than the score of 2.32 ± 0.09 in the 70 rabbits that received talc. The mean gross pleurodesis score was significantly higher at each of the observation times (p < 0.05), except at 2 months, in the rabbits that received silver nitrate. The pleurodesis was distributed throughout the thorax in the rabbits that received silver nitrate, while it was only in the ventral thorax in the rabbits that received talc slurry. The gross pleurodesis scores showed no tendency to decrease during the 12-month observation period in either treatment group. The persistence of talc in the pleural space did not lead to chronic inflammatory changes because the inflammation scores were similar in both groups at all observation times. The microscopic pleural fibrosis score tended to decrease with time in the silver nitrate group but not in the talc slurry group.

Conclusions: The intrapleural injection of 2 mL of 0.5% silver nitrate produces a better pleurodesis than does the intrapleural injection of 400 mg/kg of talc slurry in rabbits. The pleurodesis induced by silver nitrate persists for at least 1 year. The efficacy of silver nitrate as a sclerosing agent in humans should be evaluated.

Key Words: pleural effusion • pleurodesis • pneumothorax • silver nitrate • talc


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The search for the ideal agent for pleurodesis continues. The agent most commonly used at the beginning of 21st century is talc. Despite the fact that talc has been accepted by many as the agent of choice for creating a pleurodesis in patients with either a pneumothorax or a malignant pleural effusion, it is not ideal. Talc became popular because it is effective in experimental studies1 and is widely available.2 In addition, it appears to be more effective3 and less expensive2 than the tetracycline derivatives or chemotherapeutic agents in humans, and its administration does not interfere with subsequent chemotherapy.4 However, there are serious concerns about its safety. There is evidence that the intrapleural administration of talc induces the ARDS in 0 to 8% of patients, with an overall mortality of approximately 1%.5 6 7

Silver nitrate has been proposed as a possible alternative. Like talc, it is also inexpensive and widely available. It was used in the past with success in patients with pneumothoraces.8 Its use was abandoned in the 1980s for no clear reasons, although the chest pain associated with its administration and the growing popularity of tetracycline were probably responsible.9 The morbidity previously encountered apparently was because of the high concentrations used (1 to 10%). We have previously demonstrated, in our animal model, the effectiveness of lower concentrations of silver nitrate. One month after the intrapleural administration of 0.5% silver nitrate, the pleurodesis obtained was comparable to that produced by tetracycline10 and superior to that produced by talc.11

The purpose of the present study was to compare the effectiveness of the intrapleural injection of 0.5% silver nitrate and 400 mg/kg of talc slurry in producing a pleurodesis in rabbits over a 12-month period. We hypothesized that silver nitrate would be the more effective agent during the first few months after the intrapleural injection, but that the pleurodesis resulting from talc would be better after several months. Talc remains in the pleural space for prolonged periods, and its presence could lead to prolonged inflammation and the continued production of fibrosis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The methods are similar to those we have described previously.10 11 12 New Zealand white rabbits weighing 2.0 to 2.5 kg were lightly anesthetized with ketamine hydrochloride, 35 mg/kg, plus xylazine hydrochloride, 5 mg/kg, intramuscularly. The thorax was prepared for aseptic surgery by shaving the right chest wall and then cleaning it with povidone-iodine solution. A 2-cm skin incision was made midway between the spine and the sternum. The muscles in the seventh or eighth intercostal space were bluntly dissected to allow exposition of the parietal pleura. Under direct vision, a 25-gauge needle was inserted into the pleural space and the sclerosant was injected. In sequence, the muscle and the skin were closed with sutures. After the surgery, the rabbits were closely monitored for clinical evidence of pain (vocalization, tachypnea, and restlessness). Rabbits showing signs of distress were administered buprenorphine hydrochloride, 0.05 mg/kg, subcutaneously. The study was approved by the Ethics Committee of the Heart Institute (InCor), University of São Paulo Medical School, which oversees research involving both animals and humans.

The rabbits were divided into two groups of 70 rabbits. One group received silver nitrate 0.5%, while the other group received sterilized talc slurry, 400 mg/kg, each in a total volume of 2 mL. The sclerosing agents were injected into the right hemithorax. The left hemithorax received no injection and served as a control.

The talc is asbestos free and has a mean particle diameter of 21.5 µm, with the 10th percentile of particle size of 6.4 µm and a 90th percentile of 50.5 µm. The talc is contaminated with minute amounts of dolomite, kaolite, chlorite, and forsterite. The talc slurry was gently shaken immediately before injection. Ten rabbits from each group were sacrificed at 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, and 12 months after the injection, by a lethal injection of pentobarbital into the marginal ear vein. The thorax was removed en bloc. The lung was expanded by the injection of 10% formalin intratracheally. After the tracheal injection, the trachea was ligated and the entire thorax was submerged in a 10% formalin solution for at least 48 h.

Necropsy was performed by one of the investigators (L.R.T.), who was blinded as to the time from injection and whether the animal had received silver nitrate or talc (in some animals, talc was visible in the pleural space). Each pleural cavity was exposed carefully by making bilateral incisions through the diaphragms and all the ribs in approximately the midclavicular line. In this manner, the sternum and the medial portions of the anterior ribs were removed so that the lungs and pleural cavities could be evaluated.

The gross pleurodesis was graded according to the following scheme as we have described previously1 10 11 : 0 = normal; 1 = less than three adhesions; 2 = more than three adhesions, but localized; 3 = generalized scattered adhesions; and 4 = complete obliteration of pleural space by the adhesions.

The presence of hemothorax was graded on a 0 to 4 scale: 0 = no hemothorax; 1 = hemothorax < 15% of the hemithorax; 2 = hemothorax from 15 to 33% of the hemithorax; 3 = hemothorax from 33 to 75% of the hemithorax; and 4 = hemothorax > 75% of the hemithorax. At gross examination, the diagnosis of hemothorax was made if there were blood clots in the pleural space.

Samples of the visceral pleura from each hemithorax were obtained and placed in 10% neutral buffered formalin. These tissue samples were processed routinely and stained with hematoxylin and eosin.11 The degree of microscopic inflammation and fibrosis was graded by L.R.T., who was blinded to the treatment. The inflammation and fibrosis were graded as absent (0), slight (1), mild (2), moderate (3), or severe (4), as described previously.1 10 11

Statistical Analysis
All data are expressed as mean ± SEM. The mean scores for pleurodesis, microscopic fibrosis, and inflammation in the two treatment groups were compared using unpaired t test analysis. When the data failed the normality test, the nonparametric Mann-Whitney rank-sum test was used to compare the values in the two treatment groups. The temporal evolution in both treatment groups was compared using the one-way analysis of variance. Differences were considered significant at p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The intrapleural instillation of silver nitrate resulted in a significantly greater degree of pleurodesis than did talc slurry (Table 1 ). The mean pleurodesis score for all rabbits at all time points after the intrapleural injection of 0.50% silver nitrate (3.34 ± 0.08) was significantly higher (p < 0.001) than that observed after talc, 400 mg/kg (2.32 ± 0.09). The mean macroscopic adhesion score was significantly (p < 0.05) higher at each of the time points in the silver nitrate group, except at 2 months (Fig 1 ). The mean pleurodesis score was at the effective level (> 3) in the group that received silver nitrate, and not effective (< 3) in the rabbits that received talc (Fig 1) . The scores on the left hemithorax were negligible (approximately 0) for all the animals in both groups (Table 1) . The distribution of the pleurodesis differed between silver nitrate and talc; with silver nitrate, the adhesions tended to be throughout the pleural space, while with talc, the adhesions were mostly in the ventral (anterior) part of the pleural space.


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  		Table 1.. Pleural Macroscopic and Microscopic Changes Observed From 1 Month to 1 Year After the Intrapleural Injection of Silver Nitrate or Talc on Both Hemithoraces*

 


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  		Figure 1.. Pleural macroscopic (adhesions) and microscopic (inflammation and fibrosis) changes from 1 month to 1 year after intrapleural injection of silver nitrate (solid line) or talc (dotted line) on the injected hemithorax. *p < 0.05, silver nitrate vs talc.

 
When the pleura was examined microscopically, the mild degree of inflammation (mean score < 2) on the injected side was similar in both groups at all time points in the study (Fig 1) . The intrapleural administration of silver nitrate did result in more fibrosis (Fig 1) . The degree of pleural fibrosis in the first 4 months after the intrapleural injection of the sclerosing agent was significantly (p < 0.05) greater after the administration of 0.50% silver nitrate (mean score > 3) than after talc (mean score < 3). From 6 to 12 months after the intrapleural injection, the pleural fibrosis observed with silver nitrate was similar (p > 0.05) to that obtained with talc (Fig 1) . The fibrosis after the administration of silver nitrate tended to decrease, while that after the administration of talc tended to remain stable.

On the control side 1 month after the injection, rabbits in the silver nitrate group had significantly (p < 0.05) more pleural inflammation and fibrosis than did rabbits in the talc group. However, in only one rabbit did the score exceed 1, and that rabbit had a fibrosis score of 3. If this one rabbit was excluded, the differences would not be statistically significant. After 1 month through 12 months after the injection, the degree of pleural inflammation and fibrosis was similar (p > 0.05) and insignificant (mean score < 1; Table 1 ) in both groups.

The intrapleural administration of either silver nitrate or talc slurry did not cause distress in any of the animals. The rabbits rapidly regained a normal feeding pattern and resumed normal activities after the injection. None of the rabbits required any medication for vocalization, tachypnea, or restlessness. No animal died prematurely.

Only three rabbits developed a hemothorax, and all were in the silver nitrate group (4.3%). Two hemothoraces (one grade 2 and one grade 3) were observed at 1 month after the intrapleural injection, and one hemothorax (grade 1) was observed at 6 months.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrates that in this rabbit model, silver nitrate at a concentration of 0.5% is more effective than talc, 400 mg/kg, in inducing pleurodesis. It also demonstrates that the pleurodesis obtained with silver nitrate is considerably better from the first month after the intrapleural injection and during the entire 1-year follow-up. The study also suggests that the maintenance of talc particles in the pleural space for prolonged periods does not result in any more chronic inflammation than does the single injection of silver nitrate.

The mechanisms responsible for the pleurodesis that follow the intrapleural administration of a sclerosing agent are not completely understood. It is accepted that the first events between the intrapleural injection and the fusion of the visceral and parietal pleura are the injury manifested by the denudation of the mesothelial cells13 and the development of an exudative pleural effusion.14 The reparation is complex and involves several processes, including the acute inflammatory reaction to the injury, the regeneration of the damaged cells, the migration of connective tissue cells, the synthesis of extracellular matrix proteins, and the collagenization with acquisition of wound strength.15

Several factors should be considered regarding the process occurring from the instillation of the sclerosing agent to the tissue repair or the development of a pleurodesis. These include the degree of injury (proportional to the probability of developing a pleurodesis),10 the capacity of the mesothelial cells and fibroblasts to secrete collagen, enzymes (as metalloproteinases) that degrade collagen, and inhibitors of these enzymes.16 It has been suggested that the duration, extent, and intensity of the inflammation may influence the end result. This proposition is based on the fact that in rabbits, talc pleurodesis is inhibited by systemic corticosteroids17 and by the intrapleural administration of tumor necrosis factor-blocking antibodies.18 However, in the present study, the degree of pleural inflammation was mild (score < 2), with no significant changes during the 12 month of follow-up and was similar for both agents.

Silver nitrate shows promise as an agent for pleurodesis. It is inexpensive and widely available. The present study confirms our previous observations10 11 that the intrapleural injection of 2 mL of 0.5% silver nitrate is effective in producing a pleurodesis. It also confirms that silver nitrate is significantly better than talc, 400 mg/kg. Moreover, the pleurodesis induced by silver nitrate is still present 1 year after the intrapleural injection. It should be noted that in the past, the intrapleural injection of higher concentrations of silver nitrate in humans produced severe pain.9 Although the rabbits in the present study did not experience obvious distress, the amount of pain that will result from the intrapleural injection of this lower concentration of silver nitrate in humans remains to be determined.

One might question why talc did not produce continued inflammation because it was present in the pleural space. Although we cannot answer this question definitively, we believe that the lack of continued inflammation with talc is because of the fact that it becomes encased in fibrous tissue in the ventral part of the chest. This limited distribution also explains our observation that the pleurodesis resulting from talc is predominantly located in the gravity-dependent portion of the chest.

There are limited studies regarding the persistence of pleurodesis after the intrapleural injection of pleural sclerosants in either humans or animals. Sassoon and coworkers19 studied rabbits serially for up to 6 months after the intrapleural injection of minocycline, 10 mg/kg. They reported that there was a nonsignificant decrease in the pleurodesis score over the 6 months of observation. Interestingly, using the same scoring system as used in the present article, the mean pleurodesis score at 6 months was only 2.0,19 which can be compared with a mean pleurodesis score > 3 with silver nitrate at 6 months, 8 months, 10 months, and 12 months in the present study. Previously, we tried to study the pleurodesis up to 120 days after intrapleural mitoxantrone injection.20 Although the pleurodesis score tended to increase with time and the mean score at 60 days (3.7) was higher than at 15 days or 30 days, attempts to study these animals at 120 days were unsuccessful because of a mortality > 80%.20 No rabbit died after either silver nitrate or talc administration in the present study.

In conclusion, the present study demonstrates that the intrapleural injection of 2 mL of 0.5% silver nitrate produces a more effective pleurodesis than does the intrapleural injection of talc slurry, 400 mg/kg, in rabbits. The pleurodesis resulting from silver nitrate is better distributed throughout the pleural space than that resulting from talc slurry. The pleurodesis induced by the silver nitrate persisted throughout the 12-month follow-up period. Silver nitrate should be re-evaluated as a pleural sclerosant in humans.


   Footnotes
 
This study was supported by the Foundation to Support Research from the State of São Paulo and National Board of Scientific and Technologic Development of Brazil.

Received for publication July 10, 2000. Accepted for publication October 3, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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