The Effects of Intravenous Injections
In this procedure a glass cannula was fastened in one of the external jugular veins and filled with the same solution as that to be injected. A short rubber tube was attached and tightly clamped close to the glass. Later, for the injection, the syringe needle was inserted through the rubber and into the fluid in the cannula, the clip on the vein was removed, and the injection made.
The solutions employed intravenously were adrenin 1:10,000, 1:50,000, and 1:100,000, in distilled water.
The smallest amount which produced any change in clotting time was 0.1 cubic centimeter of a dilution of 1:100,000 in a cat weighing two kilos, a dose of 0.0005 milligram per kilo. Four tests previous to the injection averaged 5 minutes, and none was shorter than 4 minutes. Immediately after the injection the time was 2 minutes, but at the next test the effect had disappeared. Doubling the dose in the same cat—i. e., giving 0.2 cubic centimeter (0.001 milligram per kilo)—shortened the coagulation time for about 40 minutes:
| Dec. 23. | 10.30 | 4 | minutes |
| .35 | 4 | “ | |
| .41 | 4 | “ | |
| .46 | Adrenin, 0.001 milligram per kilo. | ||
| .47 | 2.5 | minutes | |
| .50 | 3 | “ | |
| .53 | 3.5 | “ | |
| 11.00 | 1.5 | “ | |
| .05 | 1.5 | “ | |
| .10 | 3 | “ | |
| .15 | 2 | “ | |
| .20 | 4 | “ | |
| .26 | 4.5 | “ | |
| .31 | 5 | “ | |
From 10.47, immediately after the second injection, till 11.20 the average time for clotting was 2.5 minutes, whereas both before and after this period the time was 4 minutes or longer. At 11.00 o’clock and 11.05, when the end point was reached in 1.5 minutes (a reduction of 63 per cent), a thick jelly was found on examining the cannula. The changes in clotting time in this case are represented graphically in [Fig. 26].
Figure 26.—Shortening of coagulation time after injection of adrenin, 0.2 cubic centimeter, 1:100,000, (0.001 milligram per kilo), at 10:46. In this and following Figures a scale for coagulation time is given in minutes at the left.
In another case a dose of 0.0005 milligram per kilo failed to produce any change, but 0.001 milligram per kilo (0.28 cubic centimeter of adrenin, 1:100,000, given a cat weighing 2.8 kilos) brought a sharp decline in the record, as follows:
| Jan. 9. | 11.32 | 6 | minutes |
| .40 | 6 | “ | |
| .47 | Adrenin, 0.001 milligram per kilo. | ||
| .48 | 5.5 | minutes | |
| .55 | 4 | “ | |
| 12.00 | 5.5 | “ | |
| .06 | 7 | “ | |
In these instances the animals were decerebrated. For decerebrate cats, the least amount of adrenin, intravenously, needed to produce shortening of coagulation time is approximately 0.001 milligram per kilo.
In the above cases rapid clotting was manifest directly after minute doses. Larger doses, however, may produce primarily not faster clotting but slower, and that may be followed in turn by a much shorter coagulation time. The figures below present such an instance:
| Nov. 25. | 2.36 | 3 | minutes |
| .40 | 3 | “ | |
| .43 | Adrenin, 0.5 cubic centimeter, 1:10,000. | ||
| .44 | 4 | minutes | |
| .49 | 3.5 | “ | |
| .53 | 1.5 | “ | |
| .55 | 1.5 | “ | |
| .58 | 2 | “ | |
| 3.00 | 2.5 | “ | |
| .03 | 1.5 | “ | |
| .05 | 1.5 | “ | |
| .07 | 2.5 | “ | |
| .10 | 1.5 | “ | |
| .14 | 1.5 | “ | |
| .16 | 2.5 | “ | |
| .19 | 3 | “ | |
| .23 | 3 | “ | |
| .30 | 3 | “ | |
This unexpected primary increase of coagulation time, lasting at least six minutes, is in striking contrast to the later remarkable shortening of the process from 3 to an average of 1.7 minutes for more than 20 minutes (see [Fig. 27], A).
Figure 27.—A, Primary lengthening followed by shortening of the coagulation time when adrenin, 0.5 cubic centimeter 1:10,000 (0.05 milligram), was injected slowly at 2:43. B, Lengthening of the coagulation time without shortening when the same dose was injected rapidly at 10:08.
If a strong solution, i. e., 1:10,000, is injected rapidly, the process may be prolonged as above, but not followed as above by shortening, thus:
| Nov. 28. | 9.59 | 3 | minutes |
| 10.03 | 3 | “ | |
| .08 | Adrenin, 0.5 cubic centimeter, 1:10,000. | ||
| .10 | 3 | minutes | |
| .14 | 3.5 | “ | |
| .18 | 3.5 | “ | |
| .22 | 3.5 | “ | |
| .26 | 3 | “ | |
| .29 | 3 | “ | |
| .33 | 3 | “ | |
There was in this case no decrease in coagulation time at any test for a half-hour after the injection, but instead a lengthening (see [Fig. 27], B). Howell[9] has reported the interesting observation that repeated massive doses of adrenin given to dogs may so greatly retard coagulation that the animals may be said to be hemophilic. These two instances show that on coagulation large doses have the contrary effect to small, just as Hoskins[10] showed was true for intestinal and Lyman and I[11] showed was true for arterial smooth muscle.
In a few experiments the brain and the cord to midthorax were destroyed through the orbit. Artificial respiration then maintained the animal in uniform condition. Under these circumstances, adrenin intravenously had more lasting effects than when given to the usual decerebrate animals with intact cord. [Fig. 28] illustrates such a case. For thirty minutes before injection the clotting time averaged 5.4 minutes. Then, about ten minutes after one cubic centimeter of adrenin, 1:50,000, had been slowly injected, clotting began to quicken; during the next twenty minutes the average was 3.4 minutes, and during the following forty-five minutes the average was 1.9 minutes—only 35 per cent as long as it had been before the injection.
Figure 28.—Persistent shortening of the coagulation time after injecting (in an animal with brain and upper cord pithed) adrenin, 1 cubic centimeter, 1:50,000 (0.02 milligram), at 11:01–02. The dash lines represent averages.
In another case in which the brain and upper cord were similarly destroyed, the clotting time, which for a half-hour had averaged 3.9 minutes, was reduced by one cubic centimeter of adrenin, 1:100,000, to an average for the next hour and forty minutes of 2.3 minutes, with 1.5 and 3 minutes as extremes. During the first forty minutes of this period of one hour and forty minutes of rapid clotting all of eight tests except two showed a coagulation time of 2 minutes or less. The explanation of this persistent rapid clotting in animals with spinal cord pithed is not yet clear.
As indicated in Figs. 26, 27 and 28, the records of coagulation show oscillations. Some of these ups and downs are, of course, within the limits of error of the method, but in our experience they have occurred so characteristically after injection of adrenin, and so often have appeared in a rough rhythm, that they have given the impression of being real accompaniments of faster clotting. It may be that two factors are operating, one tending to hasten, the other to retard the process, and that the equilibrium disturbed by adrenin is recovered only after interaction to and fro between the two factors.
The oscillations in coagulation time after the injections suggest that clotting might vary with changes in blood pressure, for that also commonly oscillates after a dose of adrenin (see, e. g., [Fig. 23]). Simultaneous recording of blood pressure and determining of coagulation time have revealed that each may vary without corresponding variation in the other. Within ordinary limits, therefore, changes of blood pressure do not change the rate of clotting.