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MEDICINE

The relief from salt

Silver nitrate against the accumulation of liquid between the pulmonary membranes

Every day, our organism produces a quantity equivalent to a tablespoon full of a colorless liquid, released between the pleura, two very tin membranes that cover the thorax internally. Like the oil that lubricates the hinge of a door, this fluid facilitates the sliding of one pleura against the other – one covers the lungs and the other the inside wall of the chest – during breathing. But in some cases this liquid accumulated between the pleura and makes movement of the lungs almost impossible. This is what is observed, for example, with sufferers from lung or breast cancer at an advanced stage. For reasons that are not very clear, in these cases the volume of liquid between the pleura can increase up to 150 times and reach 3 liters, taking up much of the space previously occupied by the lungs. As a consequence, the respiratory capacity diminishes, the oxygenation of the blood falls, and an intense discomfort arises. The sensation, they say, is one of drowning in mid-air.

Called by the doctors “pleural effusion”, this accumulation of liquid between the pleuras affects 1 million persons in the United States, and possibly an equivalent number here. When pleural effusions occurs on repeated occasions, in general, the doctors opt to eliminate the tiny space between the pleuras, which does not usually exceed 10 hundredths of a millimeter. The procedure is simple. After draining the fluid, the doctors inject between these membranes a compound capable of causing an acute inflammation. This inflammation speeds up the production of a fibrous tissue rich in collagen, which makes one pleura stick to the other.

As one pleura joins the other, the possibility of further accumulations of liquid is eliminated, saving the treated from more discomfort. Oddly enough, the extinction of this space does not impair respiration. After almost a decade of searching, the team of the lung doctor Francisco Vargas, from the Heart Institute (Incor), of the University of São Paulo (USP), believes that it can finally offer an alternative that facilitates the carrying out of this procedure, known as pleurodesis, in out-patient departments or in hospitals without sophisticated resources.

Experiments with rabbits, rats and human beings are making it possible for the group led by Vargas to rehabilitate the use in pleurodesis of silver nitrate, a corrosive salt that acts as an antiseptic. This compound used to be used to cause the inflammation that eliminates the space between the pleuras – it was adopted in the first pleurodesis to have reported on, in 1901. But 20 years ago it was found that the nitrate – until then applied in concentrations that varied between 1% and 10% – caused a lot of pain and called for prolonged hospitalization.

In those days, the doctors started to apply the antibiotic tetracycline, regarded as the first option for carrying out pleurodesis until a few years back, when it was taken off the market. Accordingly, one of the few alternatives for carrying out pleurodesis was the use of a mixture of water and talc – the same that used to be used to avoid rashes in babies. Adopted since 1931, talc is currently applied to do pleurodesis in 90% of the cases of recurrence of pleural effusion. But there are problems: up to ten in every one hundred persons who are given an injection of talc to produce pleurodesis may show complications, amongst which the syndrome of acute respiratory discomfort, which causes the closure of the pulmonary alveoli and kills in half the cases. The talc can also build up in the liver and in the brain, generating chronic inflammations. For this reason, even today a compound is being looked for that is as efficient as talc, but with less undesirable effects.

Persistence
Vargas, one of the doctors in the quest for an alternative to the use of talc, did not accept pacifically the discarding of silver nitrate, which is cheap, effective, and easy to handle. “I thought that perhaps nitrate is not improper for carrying out pleurodesis, but that the concentration used was not the most suitable”, he says. His persistence allowed him to arrive at the present results, brought together in the book Derrame pleural (Pleural effusion), published by Vargas, Lisete Teixeira and Evaldo Marchi. Their experiments showed the effectiveness and the safety of the solution of silver nitrate in concentrations of only 0.5%, or 20 times less than was used previously. Today, the team from Incor applies 20 milliliters of a solution of silver nitrate at 0.5% to carry out pleurodesis in patients with malign pleural effusion, arising from advanced cases of cancer. The people treated in this way rarely feel pain, and when they do, it is not intense, according to the researchers. The majority may show a moderate fever, of about 38°C, up to three days after the treatment.

The results of a study from this group published in the Lung magazine at the end of 2003 indicates heartening prospects: the silver nitrate can be efficient in even smaller concentrations, with less side effects. In a test with 120 rabbits, the team from Incor demonstrated that this salt is effective even in a concentration of 0.3%. If it worked in rabbits, it is possible that it works in human beings, with almost null side effects, which could prevent hospitalization during treatment, as is now happening “Over 50 patients treated at Incor completed their pleurodesis in the outpatients’ department”, says Lisete. The doctors’ expectation is that in these cases the people will only go back to hospital to accompany the treatment.

Fractionated doses
The researchers from Incor, who up until now have not found any disadvantage in this new approach, are beginning to understand in detail now the silver nitrate acts in the organism after being injected between the pleuras. In a work published in June in the Chest magazine, Vargas’s team found that both talc and silver nitrate cause an acute inflammation in the first 48 hours after the pleurodesis, which is not restricted to the space between the pleuras. As the area covered by these membranes is large – about 2 square meters -, the particles of talc and the molecules of nitrate pass into the bloodstream after the first six hours of treatment and are distributed throughout the body – a probable explanation for the fever.

“It is possible that the nitrate is eliminated more rapidly from the organism”, says Marchi. If this is true, the inflammation caused by the nitrate ought to disappear more quickly than when it is caused by talc. The preliminary details from a study that is under way suggest that, if the dose of nitrate is fractionated – into three applications in a concentration of 0.1%, instead of a single application at 0.3% -, the inflammation is restricted to the pleural space and is not disseminated through the organism, as happens with talc, even in lower doses.

The Project
Temporal assessment of the extracellular matrix in experimental pleurodesis (nº 97/08764-5); Modality Regular Line of Research Grants; Coordinator Francisco Vargas – Incor (USP); Investment
R$ 136,791.49 (FAPESP)

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