Part 34

ADMINISTRATION BY MOUTH.

SERIES A.

The effective dose in these experiments showed considerable variation. One dog (No. 38) died after a dose of 0.12 gram caffein per kilo, while some subjects survived doses of 0.2 and 0.23 gram per kilo. In the 12 experiments given in Table 12, page 62, it will be noticed that from 0.12 to 0.152 gram per kilo proved fatal to three dogs, while three others survived the same amounts in proportion to the body weight. The results were the same with larger doses. It may be observed in this connection that in the case of the five dogs in which vomiting was noticed some time during the 24 hours following the administration of caffein, four survived, No. 38 being the exception. The greater toxicity of caffein in this case is in all probability due to some morbid process, the presence of which was indicated by the high temperature of this subject.

That vomiting may avert a fatal issue after larger doses of caffein is made further probable by experiment on dog No. 48, for which, in the absence of vomiting, a dose of 0.2 gram of caffein per kilo proved fatal. On this supposition the discrepancy in the results obtained in this series may be readily explained. The smallest doses which proved fatal in these experiments were 0.145 and 0.152 gram per kilo. No. 38, which died from a dose of 0.12 gram per kilo, may be considered as an exception, as this subject was not normal. Experiments with caffein on dogs were made at various other times in this laboratory but failed to show that smaller doses of caffein, even when vomiting did not occur after its administration, were fatal, although toxic effects were observed. The conclusion is therefore justified that the minimum fatal dose of caffein for the normal dog is about 0.15 gram per kilo when given by mouth.

SUBCUTANEOUS INJECTION.

SERIES B.

To determine the toxicity of caffein more accurately, especially for comparison with animals of other species, the subcutaneous method of administration was also used. The injections were made with a syringe of 20 cc capacity, the contents of which were introduced into contiguous areas. The results of experiments on six dogs indicate that approximately 150 to 160 mg per kilo is the minimum fatal dose, since such doses proved fatal to two out of the three animals receiving this amount, while three others which received doses of from 143 to 160 mg per kilo survived.

EXPERIMENTS ON PUPPIES.

SERIES C.

In these experiments the resistance of young growing puppies to caffein was studied. Caffein was given by mouth to all the subjects except one, to which it was administered subcutaneously. The protocols, only a few of which are given, and the tabulated data of the experiments (p. 62) show that the age of the animal has a decided influence on the toxicity of caffein.

Dog 11. Weight, 1,260 grams.

August 2: At 10 a. m. given 12.5 cc of 2 per cent of caffein through stomach tube; 2 p. m., had convulsions, diarrhea, salivation, and stiffness of limbs.

August 3: Found dead 9 a. m. Autopsy: Thoracic viscera apparently normal; stomach immensely distended and filled with a white, cheesy mass and some fluid; round worms plentiful in stomach and small intestine; mucosa of entire intestine congested; contents of lower intestine congested; liver pale; spleen flabby; kidney congested.

Dog 10. Weight, 1,650 grams.

July 26: 9.30 a. m., 29 cc of 2 per cent caffein added to 60 cc of milk offered, but refused, and was therefore fed by mouth through stomach tube; 10.25 a. m., no symptoms; 11.30 a. m., restlessness, extremities stiff, post. extremities spread apart, dog shows well-marked symptoms of caffein poisoning; 12.10 p. m., symptoms more severe, extremities extended and spread out, is lying flat on belly so that nose touches floor of the cage; 12.40 p. m., found dead; was alive at 12.10 p. m. Autopsy: Lungs showed hemorrhagic foci in all lobes; heart apparently normal; liver fatty; stomach and intestines filled with round worms; spleen and kidney apparently normal.

Dog 9. Weight, 3,000 grams.

July 25: 350 mg caffein per kilo; 5 p. m., lying down most of the time, occasionally walks about in stall; restlessness present, but not marked; 5.30 p. m., vomit which looked frothy and mucilaginous noticed on the floor of the stall; no meat particles noticed in vomit, though searched for; whines occasionally.

July 26: 9 a. m., looks well; no signs of the effect of caffein given the day previous.

Dog 8. Yellow female. Weight, 3,100 grams.

July 22: 10.50 a. m., received 1.1 grams of caffein in 10 grams of meat (354 mg caffein per kilo); 3 p. m., vomited mucus; gait clumsy; refused to eat; continually drinking water; very restless; 4 p. m., convulsions set in at 3.55 p. m.; tonic rigidity of the posterior extremities; profuse salivation; convulsions were both tonic and clonic in character, and resembled those seen in rabbits in caffein intoxication; a striking feature was the duration of the spasm, which began at 3.55 p. m. and kept up for more than two hours.

July 23: Found dead at 9 a. m.

The data recorded in the table and in the protocols of the experiments of series C show that four out of the seven animals experimented upon died in less than 24 hours after caffein was fed; three of these received 300 to 354 mg caffein per kilo, and one received 200 mg caffein per kilo. No. 8 vomited four hours after caffein was given. No vomiting was observed in the other three dogs. From 0.300 to 0.350 gram of caffein per kilo may be regarded, therefore, as surely fatal to young growing puppies. That this is in all probability the minimum lethal dose appears from the following experiments: No. 9, which received 350 mg per kilo, vomited one hour after and survived, which indicates that some of it was probably not absorbed. The amount which entered the circulation was therefore less than 350 mg per kilo. Since No. 15, which received 250 mg caffein subcutaneously, likewise survived, the probabilities are that 300 to 350 mg per kilo were the minimum fatal doses for these animals. Moreover, No. 12, which received 200 mg caffein per kilo, survived, no vomiting having been observed. The case of No. 11, in which the same amount of caffein in proportion to body weight proved fatal, may be explained perhaps by the findings of the autopsy.

The results obtained in these experiments justify the conclusion that young growing dogs can stand larger doses of caffein than full-grown and older dogs.

Attention may also be called here to the difference in the symptoms produced by caffein in very young and in adult dogs. It was often noticed in these experiments that the symptoms in older subjects when given toxic doses of caffein set in rather abruptly and ended in instantaneous death. We failed to observe this phenomenon after the administration of large amounts of caffein to very young dogs, in which tonic and clonic convulsions alternating with paresis were observed. These symptoms set in rather gradually and lasted several hours (see experiment No. 8), resembling the rabbit in this regard.

SUMMARY.

The toxicity of caffein for adult dogs is about the same, whether given by mouth or injected subcutaneously. The resistance of puppies to caffein is much greater than that of adults.

TABLE 12.--Administration by mouth; dogs. (Series A.)

----+--------+-------+-----------+------------------------------------ | |Caffein| | No.| Weight.| per | Results. | Remarks. | | kilo. | | ----+--------+-------+-----------+------------------------------------ |Kilos.|Gram.| | 47 | 13.60 | 0.144 |Survived |Vomiting observed. 55 | 12.75 | .200 | do. |Stiffness of muscles; no other | | | | symptoms. 56 | 7.95 | .200 |Found dead | | | | next day | 52 | 13.60 | .147 |Survived | 57 | 6.50 | .230 | do. |Vomited after 1 hour; convulsions | | | | after 1 hour and 45 minutes. 39 | 23.10 | .120 | do. |Increased frequency of respiration, | | | | thirst, loss of appetite, vomited | | | | rest of day when he drank water, | | | | salivation, restlessness, passed | | | | feces frequently. 48 | 11.50 | .174 | do. |Vomiting observed. 48 | 12.00 | .200 |Found dead |No vomiting observed. Second dose | | | next day | was given 8 days after first. 54 | 13.40 | .200 |Survived |Vomiting observed. 49 | 13.15 | .152 |Found dead | | | | next day | 38 | 14.50 | .120 | do. |Symptoms after 1½ hours: Dog had | | | | a temperature of 104° F. before | | | | caffein was given; vomited 3 hours | | | | after caffein was fed. 18 | 10.80 | .145 | do. | ----+--------+-------+-----------+------------------------------------