However, correlation with another biological effect could be noted. All the substances with hemorrhagiparous effect, also produce a convulsive effect if administered in sufficiently high doses. The convulsive effect of Coramine and thiamine has been known for a long time and we used these substances any time we wanted to induce experimental convulsions. We also have seen that convulsions can be consistently induced in animals through the use of relatively large doses of glycerol or sterols. Convulsions in several human cases have followed the use of these agents. Doses as high as 20 cc. of a 5% solution of the insaponifiable fraction of placenta or of the 2% solution of cholesterol in oil, administered for therapeutic purposes have induced convulsions in patients, with a previous history of convulsive seizures. A convulsive effect in animals has been noted for all the agents mentioned above which also have hemorrhagiparous activity. We were able to induce convulsions in rats, even by injecting 20 cc. of a solution of 10% glucose subcutaneously once a day for a few days. In humans, we also saw convulsions appearing after glucose was administered intravenously in an amount of 100 gm. in a saline preparation to patients treated concomitantly with desoxycorticosterol, although the last substance has no convulsivant effect by itself.

On the other hand, the antihemorrhagic butanol produces a hypnotic effect if administered in high doses. The dose of butanol needed to prevent hemorrhage induced by ficine in mice, for example, was enough to provoke hypnotic activity comparable to that of barbiturates, chloroform and even ether. Very interesting is the fact that these agents also are able to prevent ficine induced hemorrhage if administered in doses sufficiently high to produce hypnotic or narcotic effects. The peculiar correlation between convulsive and hemorrhagiparous effect on the one hand, and hypnotic and hemostatic effect on the other, provides some further understanding of butanol hemostasis, but does not furnish the explanation for the mechanism through which this hemostasis takes place. The most plausible conclusion is that butanol intervenes through several mechanisms, some inducing immediate hemostasis through arterial contraction, while others have a later effect through changes in the blood clotting process, with lack of retraction of the clot and an influence upon fibrinolysis.

Contraction would explain why, with only few exceptions, it is the pathological arterial hemorrhage which responds most favorably to butanol. An immediate influence upon capillary or venous hemorrhage is less manifest and, in a very few cases, absent. The same is true for traumatic hemorrhages where, although there are some good immediate results, in general they are less rapid than for pathological arterial hemorrhage. Because of its immediate effect upon arterial bleeding, butanol became the agent of choice for those pathological hemorrhages which, through their arterial origin, could be fatal in a short time.

One of the big advantages of hemostasis induced by butanol over that obtained through other agents resides in the fact that there is no manifest increase in blood coagulability. Only in concentrations which never can be attained in vivo has butanol been seen to change the coagulability of blood. The inherent danger of thrombosis resulting from high blood coagulability limits the amount of the other agents to be administered. This danger does not exist for butanol and no such limitations are placed upon its use. The fact that normal prothrombin time is uninfluenced by butanol while high prothrombin time is reduced toward normal represents another advantage.

In further studies, we tried to enhance the hemostatic action of butanol without increasing blood coagulability. The addition of calcium salts was of no value but an enhancement was seen with potassium salts.

In a series of experiments, it was noted that, when a solution of butanol is kept for a long time in a stoppered bottle, its activity increases. For long standing preparations, 50% smaller doses were sufficient to protect mice against the action of ficine. The narcotic and toxic effects of these preparations also increased in the same proportion. This led us to add butyric aldehyde, the product of immediate oxidation of butanol, which increased butanol's coagulating effects only very slightly but enhanced its hemostatic effect considerably. The addition of hydrogen peroxide did much the same.

Blood Mixed With Butanol, Used Against Hemorrhages

S. Akad, working in our laboratory, showed that the coagulation time of blood is also increased if butanol, mixed previously with blood, is added. In the clinical application of this observation, we used the patient's own blood extemporaneously mixed with butanol. In a syringe containing, for instance, 10 cc. of the butanol solution, 2-5 cc. of the patient's blood is withdrawn. After mixing them, and without removing the needle from the vein, the contents of the syringe are injected intravenously. A similar mixture can be injected also intramuscularly or subcutaneously. The results have been very good. In some cases in which butanol alone was not able to stop a hemorrhage, the blood butanol mixture did. With this special technique, we have been able, in recent times, to bring most hemorrhages under control within a few minutes.

The fact that agents with positive polar groups, such as sterols, glycerol, coramine, thiamine and others, have hemorrhagiparous activity led us to try to influence hemorrhage with agents considered biologically antagonistic through their negative polar group.

Many years ago, experimenting with chlorine solutions in saline, we observed a manifest effect upon coagulation time. Intravenous injection of such solutions brought coagulation time to values as low as one minute. The addition of these solutions to butanol greatly increase its effect in vitro upon coagulation time but had less effect upon hemostasis in vivo. Similar but somewhat less manifest effects were obtained by adding hydrochloric acid to butanol solution. On the other hand, organic acids such as oxalic, malonic, citric, lactic maleic or citraconic showed a favorable effect. Without changing coagulability of the blood, these acids were seen to increase the hemostatic effect.

Fatty Acids

The same antagonism to sterols and glycerol led us to use fatty acids from cod liver oil. (197) While results in severe large arterial hemorrhages were not impressive, the effect upon oozing capillary, venous and small arterial hemorrhages was very good in a large proportion of cases. For example:

N. V., 57 years old, with multiple pulmonary metastatic lesions from a hypernephroma, had frequent hemoptysis. At times, the bleeding became more accentuated, the patient expectorating clots as well as uncoagulated fresh blood. Intramuscular administration of two doses of 10 cc. of a 6.5% solution of butanol at half hour intervals had little influence upon the bleeding. Intramuscular administration of 1 cc. of a solution of 10% of the mixture of fatty acids obtained from cod liver oil stopped the bleeding in less than 20 minutes, with the effect persisting for more than two months. A new episode of oozing bleeding was again immediately controlled by injection of the fatty acid preparation.

Other cases with hemoptoic sputum, prolonged bleeding from gastric or duodenal ulcers or from rectal or uterine tumors, all corresponding to oozing rather than to acute massive hemorrhage, have responded to administration of this fatty acid preparation. Almost uniformly, these oozing hemorrhages, which had not responded to butanol, were rapidly controlled. We now use butanol mixed with small amounts of hydrogen peroxide and organic acids mentioned above, to control severe arterial hemorrhages while for the oozing type, fatty acids from cod liver oil are used.