EDUARDO CESARProduction of ampoules in the pharmacy of the São Paulo Hospital and Clinics: receptacles for the hypertonic solutionEDUARDO CESAR
A simple and 100% Brazilian invention a hypertonic solution, made up with sterilized water with an extremely high concentration of sodium chloride (salt) has become, over the last few years, a safe and efficient alternative to the use of the traditional physiologic salt solution in resuscitating victims of hemorrhagic shock, a situation in which the excessive loss of blood, usually due to a trauma, can kill a person or leave sequelae. Now, new studies in Brazil are raising evidence that a hypertonic solution – known informally in medical circles in Brazil as salgadão (the salty one) – may have even wider effects.
Research indicates that this preparation, normally employed in doses up to ten times smaller than those prescribed for physiologic salt solution, can control cardiac arrhythmia caused by the drop in the bloodstream of a kind of anesthetic, modulate the inflammatory response of the immune system during the shock, and lessen the damages of lesions to the brain and heart resulting from the lack of oxygen produced by the fall in the circulation. Finally, the studies are also throwing some light on the mechanism by which the salgadão works, still not fully explained.
It is not by chance that the research is led by physicians Irineu Velasco and Maurício da Rocha e Silva, the inventors of salgadão, whose discovery was published in 1980, in the American Journal of Physiology. Today working separately, each with teams of their own, each of the scientists is in charge of a FAPESP thematic project that analyzes the use of the hypertonic solution in varied situations and from different angles. “At the first moment, the hypertonic solution seemed like a simple treatment for shock, but we now know that it is a formidable instrument for study, with wide clinical possibilities”, reckons Velasco, a director of the Faculty of Medicine at the University of São Paulo (USP).
It is interesting to note that the hypertonic solution and the physiologic salt solution have, like brothers in the same family, the same essential components, water and salt – but in different concentrations. In the recipe for the physiologic salt solution, 900 milligrams of sodium chloride go into 100 milliliters of water, the same concentration of salt found in the normal cells of the human body. Hence its technical name of isotonic solution. But the hypertonic solution has 7,500 milligrams (7.5 grams) of salt per 100 milliliters of water. That is, the concentration of sodium chloride is eight times greater than in the physiologic salt solution. On account of this difference, the hypertonic solution only freezes at -5º Celsius. Closer to pure water, the physiologic salt solution solidifies at 0º Celsius.
The majority of the new positive effects attributed to salgadão was detected in experiments with mice, rabbits and dogs. This does not mean that there has been no progress in tests with humans. At the Heart Institute (Instituto do Coração – Incor), for example, the preparation of water and a high concentration of salt has achieved success in speeding up the recovery of patients submitted to certain kinds of heart surgery, a situation in which the person undergoes a controlled hemorrhagic shock, since part of his blood is diverted to a machine responsible for keeping the circulation going. “We cannot yet precisely say for what purposes, besides shock, the solution will establish itself as a therapeutic alternative”, says Rocha e Silva, the head of the Cardio-Pneumology Department of the School of Medicine and a director of Incor’s Experimentation Division. “I bet, though, that it is going to be useful in one or two situations, and perhaps heart surgery is one of them”.
Like a good part of the findings in medicine, the discovery of the hypertonic solution was born of chance. At the beginning of the 70’s, when he was working at the Hospital Santa Casa de São Paulo (The Holy House Hospital), Velasco noted, during a session of hemodialysis, that a patient with low blood pressure had his pressure brought back to normal, without any apparent reason. On checking the make-up of the fluid used in the dialysis, the doctor saw that there was too much sodium chloride in it. A nurse had put too much salt into the solution. “The hypertonic solution was born of folly”, says Velasco, jokingly. The episode inspired the doctor to do some research into the use of the solution in patients with hemorrhagic shock, who, due to the great loss of blood, ought to have their blood pressure restored as quickly as possible, in order to save their lives and reduce possible damages.
In his thesis for a doctorate, under the supervision of Rocha e Silva, Velasco sketched the basic mechanisms for the action of the solution, and these afterwards were worked on better in the international article that made the discovery public. “In the light of the first results from the solution, we soon saw that we had something hot in our hands”, Rocha e Silva recalls. From then until now, the salgadão has been the focus of more than 1,300 scientific articles.
For the time being, the only approved use for the hypertonic solution is as an alternative to the use of physiologic salt solution to treat hemorrhagic shock. What, by the way, characterizes this clinical situation? When there is an important loss of blood (one liter or more, in a 70-kilo adult), circulation collapses: blood pressure falls so much that the heart cannot pump blood any longer – rich in oxygen and nutrients – to the tissues of the body. The result: with their supply cut off, the organs start to collapse. The victim of hemorrhagic shock starts a cold sweat and get pale. His pupils dilate. His mouth goes dry. Breathing becomes irregular. The flow of urine diminishes. The pace of the heartbeats shoots up, and, at the same time, their signals become weaker. Unless the blood pressure is brought back to normal, death is imminent.
In theory, when someone finds himself in the situation described above, the ideal treatment would be to replace the volume of blood that has come out of the body with the same liquid, as quickly as possible. In practice, for several reasons, such as the impossibility of having to hand a varied stock of blood free of infectious diseases, no doctor does this at the moment that he is attending to a patient with hemorrhagic shock. He resorts to large quantities of physiologic salt solution or small volumes of the hypertonic solution.
Why does he do this? Still in the 80’s, Velasco and Rocha e Silva showed that a few milliliters of the hypertonic solution had a beneficial effect on the victim of a shock, on three fronts: they brought about a vasodilatation of the arteries, they improved the performance of the myocardium (the heart), and they reallocated fluids that were stocked in parts of the organism to the inside of the veins. This triple help would be fundamental for the patient to overcome the loss of blood, in a process similar, but more complex, to the one carried out by the administration of physiologic salt solution.
Since then, there have been advances in the direction of trying to understand the mechanism of the action of the salt-rich preparation. More recent research credits the effects of the salty solution to two factors: to its greater osmotic pressure, compared with the tissues of the body, and to the existence in animals and human beings of a neural component, a sort of sensor of the levels of sodium chloride, which promptly recognizes this difference in pressure. What does this mean in lay terms?
Let us take it in parts. For being more concentrated (having more solutes in its make-up) than blood, the hypertonic solution shows greater osmotic pressure. That is, it has greater capacity to attract solvents (fluids) from solutions with a lower osmotic pressure. As the concentration of solutes inside bodily tissues is lower than it is in the solution, the latter ends up taking fluids out of the inside of the cells and transporting these liquids to the insides of the blood vessels and the interstices (the tiny spaces that exist between tissues or between parts of the body). “The volume of fluid in the circulatory system increases, which helps to restore the blood pressure of the patient in a hemorrhagic shock”, comments Heraldo Possolo de Souza, the coordinator of the Clinical Emergency Laboratory of the School of Medicine, where the research is done on Velasco’s thematic project.
As, up until now, only one kind of extremely concentrated solution has managed to produce these effects (the hypertonic solution), the researchers know that the difference in osmotic pressure cannot explain the whole mechanism for the action of salgadão. There must therefore be a specific action of salt on the organism. So the hypothesis arises that human beings must have a kind of neural sensor of the concentration of sodium chloride, which is activated when there are changes of pressure. “In evolutionary terms, this could be a vestige of the ancestral times when life arose in the sea (an environment rich in salt)”, explains Velasco.
For the proponents of this idea, this sensor is located in the region of the lungs, since the solution needs to pass through this part of the organism for its effects to begin. Experiments carried out at the Faculty of Medicine suggest that the vagus, a cranial nerve that supplies sensorial fibers for the heart and the organs of the thorax, bears some relation with this sensor. However, the theory that there is such a neural sensor is not a consensus amongst the inventors of the solution. “There is not sufficient evidence that this phenomenon occurs”, explains Rocha e Silva. “Actually, there are strong indications that it does not occur”.
The instigating fact is that, amid the disagreements and the efforts to understand the action of the hypertonic solution, other effects of the salt-rich solution have been discovered. One of these benefits is the decrease in the extension of lesions to the brain (and to the heart) in patients who have survived hemorrhagic shock. These lesions, called ischemia, are the result of an insufficient flow of oxygen and nutrients in this region. When the shock occurs and the brain ceases to receive the normal quantity of blood, part of the neurons dies. The problem is that when the flow of fluids (with oxygen) to the region affected by the lesion is reestablished, in a process that is technically called reperfusion, a second damage to the cell takes place, labeled delayed neuronal death. “It is a paradox”, says Souza. “We need to reperfuse the patient, but the return of oxygen to the injured area causes more cell destruction”.
Now the good news: in mice with ischemia, the researchers from USP found that the use of the hypertonic solution makes the reperfusion less aggressive to the area that has already been damaged. In another line of work, salgadão has given an indication that can be an ally in the control of overdoses with drugs. In experiments on hearts of rabbits and dogs, physician Augusto Scalabrini Neto and colleagues from the Clinical Emergencies Laboratory managed to revert, using only the hypertonic solution, a case of cardiac arrhythmia caused by intoxication from bupivacaine, a drug used as a local anesthetic.
When it falls accidentally into the bloodstream, this substance blocks the heart’s sodium channels, making the heartbeats fail. If it is not controlled, the problem can be fatal. In the tests, with the help of a sophisticated apparatus called a patch clamp, the administration of salgadão to the cardiac cells in these animals opened up the sodium channels, paving the way for the electrical stimulus to reach the heart and to make the muscle work. The results heartened the researchers, who are now going to see if salgadão can also diminish cardiac arrhythmia caused by another drug – cocaine.
Another surprising effect of the solution has to do with its apparent activity in the immune system in the course of hemorrhagic shock. Studies with rats found evidence that salgadão increases the production of an important enzyme for the inflammatory response, called cyclooxygenase 2 (COX2). “We saw that the solution is capable of altering the expression of a gene that codifies this enzyme”, Souza explains. What is important about this? Without the COX2, the organism does not synthesize prostaglandin, a family of substances similar to a hormone, some of which are produced when there is cell trauma.
That means that, without the prostaglandin, there is no inflammation, which, in the first instance, is nothing less than a natural and necessary response by the immune system faced by an aggression. In a second stage, it is usually necessary to control this inflammation, which causes the patient pain and discomfort, but, straight after the aggression, this reaction is indispensable.This line of research is showing, therefore, that salgadão can be a modulator of a lesser or greater presence of COX2 in the organism. “It may be that the improvement in the inflammatory response may help to prevent infections”, Souza comments.
For some time now, scientists from here and abroad have been finding promising indications about the repercussions of the hypertonic solution on the immune system. At the end of the last decade, a group of researchers from the University of California discovered that the hypertonic solution, despite being eliminated by the urine about six hours after being administered, manages to conserve for roughly one day the defense mechanisms in the victims of hemorrhagic shock treated with the hypertonic solution. Amongst other problems, the loss of large volumes of blood depresses the immune system, a situation that leaves the door open for viruses and bacteria to attack the already debilitated victim of hemorrhagic shock. To investigate the possible long term effects of the solution on the defending cells, an interesting study with mice was carried out at Incor.
First, the animals suffered from hemorrhage. Next, they were split into two groups: one part of the animals was given the preparation rich in salt, and the other, physiologic salt solution. Finally, 24 hours after the beginning of the treatment, a severe infection was set off in all the animals, and the mortality in each group was analyzed. The results: 70% of the mice that had been given physiologic salt solution succumbed to the infection, against 20% of those given the hypertonic solution.
Over the last two decades, at least a dozen small and medium studies have been carried out in various parts of the world, comparing the possible benefits of using the hypertonic solution and a placebo (an innocuous preparation) in patients with hemorrhagic shock who had reached the hospital alive. According to Rocha e Silva, about 1,600 persons took part in these experiments, without knowing, obviously, if they were receiving salgadão or a placebo; they also received, of course, the clinical treatment needed, in accordance with the seriousness of the situation. If the data from all these studies is gathered together in one large experiment, the results in favor of the use of the hypertonic solution are not to be disdained.
Amongst the casualties who received the innocuous preparation, 30% died, against 20% of those who were given the salty solution. This reduction in mortality is recognized in Europe, where the majority of countries has approved the use of the hypertonic solution for hemorrhagic shock. “But the FDA (the organ in the United States that regulates the sale of medicines) does not recognize this kind of analysis, that joins up data from several research studies”, explains Rocha e Silva.
To allow the use of the preparation with a salt concentration in their country, the Americans require a major clinical study to be carried out – and not the sum of small research studies. It is an enterprise that would consume about US$ 5 million. “But the United States armed forces are thinking about financing a study like this”, says Rocha e Silva. But if it is not the military, there will hardly be any pharmaceutical industry interested in carrying out such a study, since there is no prospect of any financial profit from the hypertonic solution. The Brazilians did not take out a patent in the 80’s, and even if they had, the protection of intellectual property would have expired today.
Ironically, not even an American researcher who modified the solution by adding a macromolecule called dextran that prolongsthe effects of pure salgadão and got a patent for this new product in his own country managed to make any money. As the United States has not yet approved the use of the hypertonic solution and the patent is not valid in Europe, where the solution with dextran is in use, the scientist has not fattened his bank account with his invention.
What is the need for researching the use of the hypertonic solution, if physiologic salt solution has been saving lives since the First World War, when it became the standard treatment for hemorrhagic shock? This solution is a fabulous treatment, but, for it to take effect, it has to be administered in large quantities, in a process that can take hours. “Normally, for each liter of blood lost, we inject three of isotonic solution”, says Souza. That is why it is normal and expected for the patient in these cases to have an excess of liquid in his organism for two or three days. As salgadão is applied much more rapidly and in a much smaller dose, there is no excessive injection of fluids.
“In hemorrhage victims with neurological lesions, we have already seen that the use of the hypertonic solution “dries out” the brain and improves the swelling in the region”, comments Rocha e Silva. Ironically, when his team from Incor tried to reproduce this clinical observation in a controlled experiment, with dogs submitted to hemorrhage and brain damage similar to those of people after an accident, this positive result did not appear. It is another mystery involving the hypertonic solution, which will yet give scientists a lot of work.
The impact of a trauma
In the big cities, just like what usually happens in war zones, victims of hemorrhagic shock are a constant in ambulances and the public first aid posts. If, on the battlefield, this clinical condition is usually a consequence of wounds caused by bullets or bombs, in the urban environment, except for gunshot victims, traffic accidents are probably responsible for the majority of cases of hemorrhagic shock, usually because of the strong mechanical traumas arising from car crashes. Hemorrhagic shock is therefore almost always connected with some situation of violence, whether voluntary or otherwise.
Data from the World Health Organization (WHO) shows that over 5 million persons, above all males, die every year as a result of some kind of trauma (with hemorrhagic shock ensuing), over 90% of them from poor or developing countries. This is without adding those who suffer from countless sequelae, a blow to their quality of life and to their productivity at work. “The economic loss that hemorrhagic shock causes society is incalculable”, says Heraldo Possolo de Souza, the coordinator of the Clinical Emergencies Laboratory of the Faculty of Medicine, at the University of São Paulo (USP).
The statistics show that half of the trauma victims lose their lives immediately, at the place of the accident. Amongst the survivors of the accident/aggression, there are another two peaks of mortality: the first happens minutes or hours after the trauma; and the second, weeks later, as a result of important failings in the functioning of multiple organs and systems. The fate of the other half of the survivors of accidents/aggression is going to depend on a number of factors, such as the seriousness of the hemorrhagic shock, the time taken to rescue, and, logically, the kind of treatment used when aided. For these trauma patients who are still fighting for their lives, one of the first actions taken by nurses or doctors, as soon as they have access to the victim, is to physiologic salt solution – or the hypertonic solution – into the vein of the casualty, so as to combat the hemorrhagic shock.
The projects
1. General Mechanisms of Ischemia and Reperfusion, their Repercussions on Various Organs and their Mediation (96/10377-7); Modality: Thematic project; Coordinator: Irineu Velasco – Faculty of Medicine/USP; Investments: RS$ 798,488.11 and US$ 121,583.00.
2. Initial Treatment of Shock (98/15658-0); Modality: Thematic project; Coordinator: Maurício da Rocha e Silva – Incor; Investments: R$ 189,858.33 and US$ 541,103.31.
