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The salt is back

Silver nitrate is reintroduced in the treatment of pleural hemorrhage to reduce the discomfort of terminal patients

Silver nitrate, a corrosive salt with antiseptic powers, is coming to the fore again, in low concentrations, as an alternative to talc powder for the treatment of pleural hemorrhage – a complication common in the advanced stage of some cancers, main those of the lung and breast, and which, just in the United States, affects 250,000 people each year. This disturbance, which characterizes itself by the accumulation of liquid in the pleural cavity – the space delimited by the pleurae, membranes that coat the lungs and the internal walls of the thorax -, diminishing breathing capacity and the oxygenation of the blood, as well as provoking lots of discomfort in the patient.

Responsible for bringing back the use silver nitrate is the pneumologist Francisco Vargas Suso, of the Medical School of the University of São Paulo (FMUSP). Over the last seven years, he has coordinated experiments with rabbits and rats that have demonstrated the efficiency and the safety of the compound. Studies that his team carried out recently on a group of forty five people have confirmed the results.

Besides providing therapy as efficient as talc, the important point is that the silver nitrate can be used in a solution of only 0.5% – while the previous solutions used were of between 1% and 10% – or twenty times more concentrated. If the tests on a greater number of patients confirms this data, the compound will return to be a primordial option for the treatment of pleural hemorrhage and to reduce the discomfort of terminal patients.

Without treatment, the patient dies due insufficient respiration. When the complication relapses (the hemorrhaging comes back) the most common procedure is pleurodesis, which consists of introducing into the cavity a substance that unchains the formation of a fibrous tissue of collagen. Injected into the space between the pleurae, the substance makes one adhere onto the other.

Continuing search
During decades one of the compounds used for this procedure was exactly silver nitrate, applied on the first pleurodesis ever heard of in 1901. However, as studies came forward suggesting that the silver nitrate could cause lots of pain, acute inflammation and prolonged internment, during the 80’s this compounds was no longer used and doctors went on to use the antibiotic tetracycline to produce the pleurodesis. With the removal of the injection form of this antibiotic from the market in the middle of the last decade, only talc – hydrated magnesium silicate – was in use, adopted since 1931 and currently applied in 90% of the cases of re-incidence of pleural hemorrhage.

Though talc is a cheap and effective product, the search for another agent continued. Some researchers with patients submitted to the treatment of pleural hemorrhage with talc indicate that it is associated with the appearance of the Acute Respiratory Distress Syndrome (ARDS), a complication that makes breathing difficult due to the closing of the alveoli, and kills in more than 50% of the cases. Studies related to the occurrence of ARDS in up to 9% of the treated patients. Some experiments even suggest that, after the application, the talc spreads rapidly through the body and accumulates in various organs.

Beginning with these confirmations, Vargas Suso and his fellow workers decided to look for a more efficient compound and with less side effects. Instead of turning their attention to expensive substances, such as the anti-cancer drug bleomycin, or to others in the testing phase such as interleukins – proteins produced by the defense cells of the organism -, they opted to analyze products already applied in pleurodesis and they chose silver nitrate for various reasons: “We had been looking for a cheap product, which could be used in any country of the world. Furthermore, silver nitrate already existed and is of easy manipulation”.

In the middle of the 90s, a partnership formed between the Heart Institute (Incor), the Pneumology of FMUSP and FAPESP created the conditions for the creation of the first pleura laboratory in the country, linked to the Respiratory Illnesses Sector of the institute. Here the group began to research the efficiency of silver nitrate applied to rabbits and rats – experiments that have already produced ten scientific articles, eight of them published in the magazine Chest, one of the most important in the world of clinical pneumology.

One of the first works, published in 1995, compared the action of two different concentrations of a solution of silver nitrate (0.25% and 0.50%) to the action of tetracycline. It was verified that the 0.5% solution had the result very close to that of the antibiotic, and without causing side effects.

What remained to be done was to check if at this dilution the silver nitrate was as effective as a talc salt solution. Ten rabbits were submitted to pleurodesis using 2 ml of 0.5% silver nitrate solution. A further ten went through the same procedure with 2 ml of a solution of talc at the concentration of 400 mg per kilogram. All of them were sacrificed twenty eight days later. Macroscopic and microscopic analysis showed that the nitrate was more efficient, leading to the formation of a fibrous tissue denser than that of the talc. There was only one reaction, it was considered to be insignificant: the nitrate caused inflammation to a slightly higher degree.

To check if the benefits and the undesirable consequences were long lasting, two groups of seventy rabbits each were treated with the two substances and the evolution of the therapy was evaluated for a year. Again the nitrate was found to be better than the talc. On average, the level of pleurodesis was higher in the group that received the nitrate and the fibrous tissue distributed itself more homogeneously through the pleural cavity. The inflammation brought on by the nitrate was greater during the first month, but diminished to levels similar to the one caused by the talc.

The most promising results appeared in recent research with patients suffering from pleural hemorrhage. The greater number of them from patients at the Clinical Hospitals of USP and Pérola Byington, as well as the Cancer Institute of São Paulo, were published during 2000 in the magazine Chest. They included forty nine occurrences of pleurodesis in forty five volunteers. Chosen at random, some were submitted to the procedure with talc. The remainder were treated with 20 ml of a 0.5% solution of silver nitrate. The nitrate proved to be efficient in 96% of the cases as against 84% with the talc. In neither of the groups collateral effects were seen, and the period of interment was almost the same: 3.7 days (nitrate) and 3.4 days (talc).

“The results are very exciting”, Vargas Suso pointed out, but reminds the number of cases analyzed in human beings is still small and that the effectiveness of the nitrate needs to be better proven. Even then, he placed it as an alternative, at least while effectively more safe talcs are not produced, which have particles of a standard size and remain retained in the pleura: “If they are very small, the particles will enter into the orifices of the pleura and spread out through the organism causing harmful effects”.

The project
Temporal Evaluation of the Outer Cellular Matrix in Experimental Pleurodesis (nº 97/08764-5); Modality Regular line of research assistance; Coordinator Francisco Vargas Suso – Medical School of USP; Investment R$ 96,072.23