Part 48

A comparison of the fatal doses of caffein in the experiments on high and low protein diet does not show much difference in the resistance to caffein, since 175 mg per kilo proved fatal to Nos. 30 and 32, while No. 29 died after receiving 150 mg per kilo, and No. 24 received 125 to 185 mg per kilo. Moreover, No. 28, which was changed from low to high protein diet, succumbed when given 125 mg per kilo. Observations made during the experimental period indicate, however, greater toxicity of caffein in the subjects on low protein diet. Dog 30 showed the effects of the drug when the dose was increased to 125 mg of caffein per kilo, while in No. 32, 150 mg per kilo were received without any manifestation of symptoms. Dog 31, which was likewise on a high protein diet, is evidently an exception, and its low resistance to caffein may be accounted for by the condition found at autopsy. In other dogs on low protein diet symptoms of intoxication appeared early in the experiment. In Nos. 29 and 24 it was observed as soon as the amount of caffein was increased to 75 mg per kilo. In dog 28 the first dose of caffein 50 mg per kilo was toxic. The symptoms of gastro-intestinal disturbance were especially marked after caffein on low protein diet. This may seem to contradict the results of experiments on dogs 11 and 20, in which larger doses of caffein failed to induce symptoms of intoxication. But it should be observed that the diet, which consisted almost exclusively of carbohydrates, was given only during the administration of caffein, while in the experiments of series B the subjects received a low protein diet for several weeks before the administration of caffein was begun, and it was continued through the entire caffein period. It will be remarked that the absence of cumulative action in the experiments of the preceding series was also observed in dogs on high as well as on low protein diet. The appearance of symptoms after smaller doses of caffein in the latter experiments might suggest cumulative action, but since these symptoms disappeared on continued administration of the substance cumulation is clearly not indicated. The gastrointestinal lesions observed on post-mortem examination were, it will be recalled, also found in rabbits similarly treated. The explanation suggested probably applies also in the case of dogs.

SERIES C.

As already pointed out in the experiments on acute toxicity of caffein, young growing dogs are probably more resistant to caffein than adults. That this may also hold true in chronic caffein intoxication seemed indicated by the following experiments.

Dog 33. Black female puppy. Weight, 4 kilos. Had been continuously on a meat diet.

December 22: 2.30 p. m., received 0.69 gram of caffein (0.172 gram per kilo); 3.15 p. m., no symptoms except that feces were fetid.

December 23: 11.30 a. m., received 0.79 gram of caffein (0.197 gram per kilo); 1.30 p. m., no symptoms.

December 24: 11 a. m., received 0.87 gram of caffein (0.2009 gram per kilo); 4 p. m., no symptoms.

It will be observed that the only effect produced in dog 33 by feeding caffein was increased intestinal putrefaction, although 2.37 grams of caffein were given in three days. Additional data on the effects of the age of animals on the resistance to caffein seemed desirable. The following experiments were therefore carried out. Six puppies of the same litter were weaned when 7 to 8 weeks old and put on a milk diet. Three of them received this diet throughout the experimental period. Meat was substituted in the other three a few days before the administration of caffein was begun, and was continued until the end of the experiment. Caffein was given by mouth; the initial dose, which was administered for several days and then gradually increased, being 160 to 200 mg for each dog, except one, which received only 100 mg per kilo for several days and then an increased amount.

An intermission of a few days (during which no caffein was given) was allowed. This was done on account of some studies carried on at the same time on the effect of caffein on certain constituents of the urine.

PUP NO. 1.

---------+---------+--------+-------------+-------------------------- | | | Treatment | Date. | Weight. | Food | (2 per cent | Symptoms. | |(milk). | caffein). | ---------+---------+--------+-------------+-------------------------- | Grams.| cc. | cc. | Apr. 21 | 1,450 | 300 | 10.0 | No symptoms. Apr. 22 | 1,520 | 300 | 10.0 | Do. Apr. 23 | 1,450 | 250 | 10.0 | Do. Apr. 24 | 1,375 | 250 | 10.0 | Do. Apr. 25 | 1,420 | 250 | 10.0 | Do. Apr. 26 | 1,390 | 250 | None. | Apr. 27 | 1,400 | 250 | None. | Apr. 28 | 1,405 | 250 | None. | Apr. 29 | 1,420 | 250 | None. | Passed worms. Apr. 30 | 1,430 | 250 | None. | Do. May 1 | 1,450 | 250 | 10.0 | No symptoms. May 2 | 1,515 | 250 | 15.0 | Do. May 3 | 1,475 | 250 | 15.0 | Do. May 4 | 1,495 | 250 | 15.0 | Do. May 5 | 1,515 | 250 | 22.0 | Seems dull and whines. May 6 | 1,535 | 250 | 20.0 | Whines. May 7 | 1,525 | 250 | 20.0 | No symptoms. May 8 | 1,530 | 250 | 20.0 | Do. May 9 | 1,500 | 250 | 23.0 | Diarrhea; passed worms; | | | | tremor and rigidity of | | | | legs; whines. May 10 | 1,490 | 250 | None. | Completely recovered from | | | | the effects of 9th. May 11 | 1,535 | 250 | 25.0 | Can not balance itself; | | | | continually vomiting. May 12 | 1,460 | 300 | None. | Recovered from effects. May 13 | 1,475 | 350 | None. | In good condition. May 14 | 1,545 | 250 | None. | May 15 | 1,550 | 250 | None. | May 16 | 1,555 | 250 | None. | May 17 | 1,560 | 250 | 25.0 | Salivated in cage; | | | | stiffness of muscles. May 18 | 1,450 | 250 | None. | Weak and stiff; diarrhea. May 19 | 1,500 | 250 | None. | No symptoms. May 20 | 1,565 | 250 | None. | May 21 | 1,545 | 250 | None. | May 22 | (1) | 250 | None. | May 23 | 1,595 | 250 | 27.0 | Tremors; gait clumsy; in- | | | | coordination of movements. May 24 | 1,495 | 250 | 27.0 | Diarrhea; vomited; weak | | | | and stiff; found dead | | | | 9 a. m. 25th. ---------+---------+--------+-------------+--------------------------

(1) Sunday.

Autopsy: Marked pulmonary congestion; liver very pale; heart wall injected; slight inflammation of stomach and intestines.

PUP NO. 2.

---------+---------+---------+------------+--------------------- | | Food | Treatment | Date. | Weight. | (milk). |(2 per cent | Symptoms. | | | caffein). | ---------+---------+---------+------------+--------------------- | Grams. | cc. | cc. | Apr. 21 | 1,350 | 300 | 5.0 | No symptoms. Apr. 22 | 1,240 | 300 | 5.0 | Do. Apr. 23 | 1,250 | 200 | 7.5 | Do. Apr. 24 | 1,205 | 200 | 7.0 | Do. Apr. 25 | 1,220 | 200 | 7.0 | Do. Apr. 26 | 1,210 | 200 | None. | Apr. 27 | 1,210 | 200 | None. | Apr. 28 | 1,205 | 200 | None. | Apr. 29 | 1,200 | 200 | None. | Passed worms. Apr. 30 | 1,210 | 200 | None. | May 1 | 1,220 | 200 | 10.0 | No symptoms. May 2 | 1,220 | 200 | 10.0 | Do. May 3 | 1,235 | 200 | 10.0 | Do. May 4 | 1,235 | 200 | 10.0 | Do. May 5 | 1,235 | 200 | 17.0 | Whines. May 6 | 1,250 | 200 | 17.0 | Do. May 7 | 1,235 | 200 | 15.0 | Diarrhea | | | | and worms. May 8 | 1,250 | 200 | 15.0 | Diarrhea. May 9 | 1,165 | 200 | 18.0 | Little or | | | | no symptoms. May 10 | 1,235 | 200 | None. | No symptoms. May 11 | 1,300 | 200 | 20.0 | Salivated in cage; | | | | refused to eat; | | | | draws up hind legs. May 12 | 1,200 | 200 | None. | Recovered. May 13 | 1,215 | 200 | None. | In good condition. May 14 | 1,280 | 200 | None. | May 15 | 1,300 | 200 | None. | May 16 | 1,310 | 200 | None. | May 17 | 1,310 | 200 | 20.0 | Salivated in cage; | | | | stiff; all symptoms. May 18 | 1,250 | 200 | None. | Weak and stiff. May 19 | 1,245 | 200 | None. | No symptoms. May 20 | 1,310 | 200 | None. | May 21 | 1,325 | 200 | None. | May 22 | 1,325 | 200 | None. | May 23 | 1,325 | 200 | 22.0 | Somewhat stiff. May 24 | 1,315 | 200 | 22.0 | Restless; scratches | | | | eyes; sick. ---------+---------+---------+------------+---------------------

PUP NO. 3.

---------+---------+---------+------------+------------------------ Apr. 21 | 1,215 | 300 | None. | Apr. 22 | 1,220 | 300 | None. | Apr. 23 | 1,220 | 200 | None. | Apr. 24 | 1,200 | 200 | None. | Apr. 25 | 1,205 | 200 | None. | Apr. 26 | 1,195 | 200 | None. | Apr. 27 | 1,200 | 200 | (1) | Apr. 28 | 1,215 | 200 | None. | Apr. 29 | 1,220 | 200 | None. | Apr. 30 | 1,200 | 200 | None. | May 1 | 1,225 | 200 | 10.0 | No symptoms. May 2 | 1,230 | 200 | 10.0 | Do. May 3 | 1,235 | 200 | 10.0 | Coughs and whines. May 4 | 1,245 | 200 | 10.0 | Passed worms. May 5 | 1,270 | 200 | 17.0 | Eyes appear dim | | | | and is continually | | | | scratching them. May 6 | 1,260 | 200 | 17.0 | Appears restless and | | | | draws up hind legs | | | | when walking. May 7 | 1,240 | 200 | 15.0 | Eyes dim; passed | | | | worms; diarrhea. May 8 | 1,265 | 200 | 15.0 | Coughing continually; | | | | very restless. May 9 | 1,240 | 200 | 18.0 | 12 noon; salivated in | | | | cage; passed worms; | | | | diarrhea; foaming at | | | | mouth; can not balance | | | | himself; rigidity and | | | | tremor of hind legs. | | | | 2.15, found dead. ---------+---------+---------+------------+------------------------

(1) Urine squeezed from bladder.

Autopsy: Severe pulmonary congestion; catarrhal gastritis; mild enteritis with small hemorrhagic areas on mucosa.

PUP NO. 4.

---------+--------+----------+-----------+---------------------------- | | |Treatment | Date. | Weight.| Food. |(2 per cent| Symptoms. | | | caffein). | ---------+--------+----------+-----------+---------------------------- |Grams.| Milk | cc. | | | (cc). | | Apr. 28 | 1,670 | 300 | | Apr. 29 | 1,670 | 300 | | Apr. 30 | 1,670 | 300 | | May 1 | 1,690 | 300 | | May 2 | 1,690 | 300 | | May 3 | | 300 | | May 4 | 1,720 | 300 | | May 5 | 1,735 | 300 | | | | | | | |Meat | | | |(grams).| | May 6 | 1,760 | 60 | | May 7 | 1,745 | 80 | | May 8 | 1,710 | 180 | | May 9 | 1,750 | 180 | | May 10 | 1,750 | 180 | | May 11 | 1,755 | 180 | 10.0 |No symptoms. May 12 | 1,730 | 180 | None. | May 13 | 1,785 | 180 | None. | May 14 | 1,835 | 115 | 10.0 | Do. May 15 | 1,820 | 115 | 10.0 | Do. May 16 | 1,835 | 115 | 10.0 |Passed worms. May 17 | 1,860 | 115 | 10.0 |Feces soft and black. May 18 | 1,855 | 115 | 15.0 |Stiff; loss of appetite. May 19 | 1,770 | 115 | 15.0 |Loss of appetite. May 20 | 1,755 | 115 | 15.0 | Do. May 21 | 1,780 | 115 | 17.0 |Restless. May 22 | | 115 | 17.0 |Feces soft and black. May 23 | 1,785 | 115 | 17.0 |Loss of appetite. May 24 | 1,795 | 115 | |Loss of appetite; threw up | | | | worms. May 25 | 1,630 | 115 | 20.0 |Loss of appetite; worms; | | | | cough; diarrhea. May 26 | 1,600 | 115 | 23.0 |Weak; no appetite; diarrhea; | | | | cough. May 27 | | | |Found dead, 9 a. m. ---------+--------+----------+-----------+----------------------------

Autopsy.--Lung uniformly congested; liver deeply congested; heart muscle pale with hemorrhagic areas; kidneys pale with hemorrhagic spots on surface and in cortex; slight catarrhal inflammation of stomach and the small intestines.

PUP NO. 5.

---------+--------+----------+-----------+---------------------------- | | |Treatment | Date. | Weight.| Food. |(2 per cent| Symptoms. | | | caffein). | ---------+--------+----------+-----------+---------------------------- |Grams.| Milk | cc. | | | (cc). | | Apr. 28 | 1,745 | 300 | | Apr. 29 | 1,745 | 300 | | Apr. 30 | 1,750 | 300 | | May 1 | 1,765 | 300 | | May 2 | 1,765 | 300 | | May 3 | | 300 | | May 4 | 1,490 | 300 | | May 5 | 1,805 | 300 | | | |Meat | | | |(grams).| | | | | | May 6 | 1,815 | 60 | | May 7 | 1,825 | 80 | | May 8 | 1,770 | 180 | | May 9 | 1,795 | 180 | | May 10 | 1,805 | 180 | | May 11 | 1,800 | 180 | 10.0 |No symptoms. May 12 | 1,720 | 180 | None. | May 13 | 1,815 | 180 | None. | May 14 | 1,845 | 115 | 10.0 | Do. May 15 | 1,830 | 115 | 10.0 | Do. May 16 | 1,815 | 115 | 10.0 |Loss of weight; no other | | | | symptoms. May 17 | 1,830 | 115 | 15.0 |No symptoms. May 18 | 1,835 | 115 | 15.0 |Stiffness. May 19 | 1,825 | 115 | 15.0 |No symptoms. May 20 | 1,850 | 115 | 15.0 |A little stiff. May 21 | 1,835 | 115 | 17.0 |No symptoms. May 22 | | 115 | 17.0 | May 23 | 1,820 | 115 | 17.0 | Do. May 24 | 1,835 | 115 | 20.0 | Do. May 25 | 1,840 | 115 | 20.0 |Feces soft and black. May 26 | 1,820 | 115 | 23.0 | May 27 | 1,840 | 115 | 25.0 |A little stiff. May 28 | 1,830 | 115 | 25.0 | May 29 | | 115 | None. | May 30 | | 115 | None. | May 31 | 1,770 | 115 | None. | June 1 | 1,765 | 115 | 25.0 |Diarrhea; stiff in hind | | | | legs. June 2 | 1,750 | 115 | 27.5 |Diarrhea and worms. June 3 | 1,635 | | 27.5 |Paralyzed; vomited; | | | | died at 3 p. m. ---------+--------+----------+-----------+----------------------------

PUP NO. 6.

---------+--------+----------+-----------+---------------------------- | | |Treatment | Date. | Weight.| Food. |(2 per cent| Symptoms. | | | caffein). | ---------+--------+----------+-----------+---------------------------- |Grams.| Milk | cc. | | | (cc). | | Apr. 28 | | 300 | | Apr. 29 | 1,280 | 300 | | Apr. 30 | 1,290 | 300 | | May 1 | 1,315 | 300 | | May 2 | 1,330 | 300 | | May 3 | | 300 | | May 4 | 1,360 | 300 | | May 5 | 1,365 | 300 | | | |Meat | | | |(grams).| | | | | | May 6 | 1,395 | 60 | | May 7 | 1,365 | 80 | | May 8 | 1,340 | 180 | | May 9 | 1,380 | 180 | | May 10 | 1,400 | 180 | | May 11 | 1,425 | 180 | 14.5 |No symptoms. May 12 | 1,470 | 180 | None. | May 13 | 1,485 | 180 | None. | May 14 | 1,510 | 115 | 14.5 | Do. May 15 | 1,500 | 115 | 14.5 | Do. May 16 | 1,485 | 115 | 14.5 |Passed worms. May 17 | 1,480 | 115 | 14.5 | May 18 | 1,485 | 115 | 19.5 |Feces soft and black; | | | | almost diarrhea. May 19 | 1,495 | 115 | 19.5 | May 20 | 1,500 | 115 | 19.5 |Scratches her eyes and | | | | chases her tail. May 21 | 1,500 | 115 | 17.0 | May 22 | | 115 | 17.0 | May 23 | 1,470 | 115 | 17.0 | May 24 | 1,465 | 115 | 20.0 | May 25 | 1,450 | 115 | 20.0 |Feces soft and black. May 26 | 1,450 | 115 | 23.0 |Diarrhea and worms. May 27 | 1,355 | 115 | 23.0 |Refused to eat all food. May 28 | 1,270 | 115 | 23.0 |Threw up worms, stiff, and | | | | has skin over both eyes. May 29 | | | |Found dead. ---------+--------+----------+-----------+----------------------------

Highest amount of caffein given, 362 mg per kilo. No autopsy.

Examination of the results obtained in the experiments of series C shows that young and growing dogs tolerate large amounts of caffein. In four subjects of this series, Nos. 1, 2, 3, and 6, no effect was observed when moderately large amounts (160 to 200 mg per kilo of caffein) were fed. Symptoms were noticed only when these amounts of caffein were increased from 50 to 60 per cent. The other two dogs, Nos. 4 and 5, of this series were less resistant, however, to caffein, as 0.16 gram of the drug per kilo induced well-marked symptoms. Since these were fed meat, while Nos. 1, 2, and 3 received milk, the difference in toxicity may be due to the diet employed, but No. 6, which likewise received a meat diet, failed to show the effects of caffein when 200 mg per kilo were fed. On the other hand, it should be noticed that No. 1 died after receiving 360 mg per kilo, No. 2 survived a dose of 334 mg, while No. 3 died after a dose of 322 mg per kilo of caffein. The fatal doses for Nos. 4, 5, and 6 were 287, 335, and 300 mg per kilo, respectively. Although the differences are too small to justify any definite conclusion regarding the effect of a milk diet or of a meat diet on the toxicity of caffein, the results nevertheless suggest a reasonable possibility that caffein is more toxic to young dogs when on an exclusively meat diet than when fed milk. It is perfectly evident, however, that the resistance to caffein in either case is very great, almost twice that of adult subjects. As shown in series A and B, 125 to 175 mg per kilo proved fatal to all but two animals in these experiments, while symptoms of toxicity appeared after much smaller doses. In other respects the behavior of young dogs toward caffein was the same as that of the adult. In neither case was cumulation nor tolerance observed under the conditions of these experiments. The findings at autopsy were likewise similar, as gastro-enteritis was the chief lesion observed on macroscopic examination. It might be mentioned, however, in this connection, that the symptoms of caffein intoxication in young dogs often presented marked differences from those observed in those of more advanced age. The resemblance of the effects of caffein in young puppies and in rabbits was very striking. In both, the tonic with clonic convulsions were observed after a sufficient quantity of caffein was administered. In the dogs which were fully grown a large dose of caffein was usually followed by tonic convulsions and almost instantaneous death.