Oxygen, an agent with a negative anti A character, at the organism level, acts like an anti fatty acid agent at the lower tissular level. For that reason, we will discuss it here.

At the beginning of our work, we were interested in determining the relationship between cellular membrane permeability and the pathogenesis of the two offbalances. If a change in the permeability of cell membrane was the primary mechanism involved, changing the oxygen tension in or around entities where offbalances occur might result in the correction of the abnormal manifestations present.

Clinical studies were made in which oxygen was administered to patients with acid pain pattern. The pain was not relieved as expected. Indeed, its intensity was even increased. These experiments indicate that impaired cell permeability, if it exists, is not the major factor in the pathogenic mechanism involved in the acid pain pattern. Actually, these studies indicated that another pathogenic mechanism was involved since oxygen administration increased this pain. Accordingly, it had an opposite effect on alkaline pain. The intensity of alkaline pain decreased, the pain being often entirely relieved by administration of oxygen. We found that pain produced by traumatic injuries, which was subsequently identified as invariably of the alkaline pattern, could be satisfactorily relieved by oxygen.

Such relief occurred in patients who had suffered all sorts of traumatic injuries, from superficial wounds to severe comminuted fractures.

A curious phenomenon was seen to occur which limited the practical usefulness of oxygen. After first relieving pain, continuation of oxygen administration led to appearance of a new pain. The patient was able to distinguish between original and new pain by its localization, by the different quality of the sensation, and also by the fact that instead of being relieved by oxygen, the new pain tended to increase with the continued administration of oxygen. It disappeared soon after oxygen administration was discontinued. If oxygen were administered again, the new pain returned within a short time. The new pain might become severe and even unbearable with continuation of oxygen administration. On the other hand, when administration of oxygen was stopped, the original pain again appeared within 10-20 minutes.

The appearance of a "new pain" and the resemblance between these changes and those observed with the use of lipids, suggested a change in the pain pattern itself, although the changes induced by oxygen evolved over minutes instead of days. This was confirmed by following the response to acidifying and alkalizing agents, the only adequate means to investigate the pattern in these cases. By this test the new pain was found to be of an acid pattern.

Because of the possibility of inducing a period of calm between the old alkaline and new acid pain, oxygen administration still seemed to be useful. In cases of traumatic pain, always with an alkaline pattern, successful results were obtained. A necessary condition appeared to be the physical and mental ability of the patient to guide the administration of oxygen. He had to recognize if too little or too much was being administered on the basis of the different sensations felt, and consequently, to adjust the administration to the optimum amount. Extreme pain caused by extensive traumatic injuries was controlled very successfully when the patient could be taught to utilize oxygen properly.

In addition to pain relief, an effect upon evolution of the lesion itself was manifest. In a few days with this form of oxygen treatment, guided by the subjective sensations, the healing process itself was observed to be sufficiently advanced to make the pain disappear entirely. Healing of the wounds seemed to be greatly enhanced by oxygen therapy guided by the patient. In several cases of open comminuted fractures in which amputation was considered inevitable on admission, unexpected improvement was noted. Atonic wounds were transformed, becoming rich in granulations, and healing was rapid.

However, the nature of the treatment was such that it could only be successful when properly applied. If dosages were too low, there was no sedative effect; and if doses were too large, new pain was induced. The physical and mental status of the patient thus appeared to be the determining factor for success. The use of an oxygen tent, in which the amount of oxygen can be carefully adjusted, helped in a few cases to maintain proper dosage. But even in this situation, the patient himself must furnish information not so much about intensity of pain, as about changes in the character of pain.

The relationship between the amount of oxygen administered and the clinical results, especially in pain, has suggested that this factor may be significant in other conditions in which oxygen therapy is used. The fact that, despite its general usefulness in the acute stage of myocardial infarction, oxygen does not alleviate the pain in some cases and may even increase it, suggests that the amount administered might not be adequate. In such cases, a decrease in pain intensity following temporary discontinuation of the use of oxygen would indicate that the amount utilized was too high. If the suppression of the oxygen administration is followed immediately by an increase in pain intensity, the amount previously administered has to be considered too low.

The possibility that too much oxygen can induce a proliferation of vessels and connective tissue, as seen in the fibroblastic retinopathy of premature babies kept in an atmosphere too rich in oxygen, fits in with the data mentioned above. We have noted that too much oxygen induced an anoxybiotic process with anabolic character. This explains the abnormal type of offbalance with proliferative tendencies seen in fibroblastic retinopathy. We will return later to a discussion of this important factor in oxygen therapy.

On the basis of findings in traumatic pain, we studied oxygen in cases of painful cancer. Attempts were made to employ it as a diagnostic aid to help determine the acid or alkaline character of pain present on the assumption that oxygen would intensify the first and would relieve the second pain. In a group of subjects, we compared the diagnosis of the existing pattern through concomitant variations in pain intensity and urine pH, the response to acidifying and alkalizing substances, and response to oxygen. In most of these cases, accuracy of the information furnished by the last method was confirmed. However, this method has shown great limitations. Whereas most of the patients were able to recognize an immediate change, they were less precise about a second change when it occurred. At the present stage of this research, it appears that judgment concerning the development of changes could be improved by reducing the concentration of oxygen administered, thus increasing the length of time during which the changes would appear. In general, the results when applied as routine were insufficiently clear to be used as a practical means for the diagnosis of the pattern.

Oxygen also has been tried as a therapeutic agent for controlling alkaline pain pattern in cancer cases. Unfortunately, even in patients who are able to analyze the variations in pain character, the time between the decrease in intensity of the original pain and the appearance and increase in the intensity of the new pain is so variable that it is almost impossible to adjust the dosage of oxygen satisfactorily to obtain a long enough period of calm.

We sought a theoretical explanation for oxygen's effects upon pain. As mentioned above, the reduction of pain of an alkaline pattern and the appearance of a pain of an acid pattern, are in accord with our view of the pathogenesis of these pains through the intervention of the two groups of lipids, fatty acids and anti fatty acids. A tentative explanation can be found in the active role of oxygen upon fatty acids. In the presence of increased oxygen tension, it is possible that oxygen is fixed in greater amounts on abnormal fatty acids, thus reducing their intervention in chloride metabolism. With less chlorides fixed by fatty acids, alkaline compounds would be reduced. This would explain the influence of oxygen upon pain with an alkaline pattern. The appearance of an acid pain pattern produced by increased anoxybiosis seems to be explained by the fact that inactivation of fatty acids, if it goes beyond certain limits, changes the balance toward a predominance of sterols. Besides this mechanism, another also can be considered. Any action upon fatty acids themselves, would reduce their availability as active agents. It seems possible that under higher tension, oxygen is bound to these fatty acids in a way different than the bond which leads to the appearance of activated oxygen. Through it, the role of the unsaturated fatty acid in activating oxygen for the cells would be to decrease intracellular activated oxygen and thus change cell metabolism to the anoxybiotic type. Since the bonds are labile, return of oxygen tension to normal allows the fatty acids to recover their function of activating oxygen. Teleologically, this process can be interpreted as a mechanism to prevent passage of excess oxygen into the cells when the external oxygen tension increases.

Studies of oxygen in normal and abnormal physiology have led us to consider also the possible utilization of various oxygenated compounds as therapeutic agents. A distinction must be made between hydroperoxides, which occur normally in organisms, and peroxides and epoxides. Peroxides result from the binding of molecular oxygen, while the epoxides result from binding of atomic oxygen, both under abnormal conditions. Peroxides were administered as adjunct agents in cases highly refractory to therapy with lipoids having negative polar groups. In preliminary experiments, it could be seen that a certain condition was necessary to influence the desired processes. The peroxide used has to be a lipoid if it is to have influence upon the lipidic system. Some lipoidic peroxides were prepared, and their therapeutic value is still under investigation. The influence of lipoidic epoxides upon the process of carcinogenesis also is under study.