Part 14

December 23: 11.30 a. m., received 1.375 grams caffein (0.125 gram per kilo) had vomited food of the day before, but could notice no caffein or capsules in vomit; 4.30 p. m., no symptoms, seemed in good spirits, appetite good, had no meat to feed with, so was given low nitrogen feed, of which he ate about one-fourth.

December 24: 9 a. m., found dead, stiff, and cold. The most striking effect of caffein in this dog is the increased intestinal putrefaction. The feces were still fetid 10 days after the administration of caffein was stopped.

_Autopsy, dog 28_: Stomach partially filled with an undigested food mass; mucosa showed severe inflammation; small intestines presented a hemorrhagic enteritis along whole extent; large intestine also exhibited mild inflammation; liver was engorged; spleen appeared normal; kidneys slightly congested in cortical portion; other organs appeared normal.

_Dog 24. White and tan male_: Was put on low protein diet six weeks before experiments with caffein were begun. The initial dose of 50 mg per kilo was then administered on eight consecutive days. The only symptoms observed during this period of caffein administration were those of intestinal putrefaction. Fetid feces were noticed already after the first dose of caffein was injected. When the second dose of 75 mg of caffein was repeated, mild symptoms appeared, but none have been observed even with increased amounts of caffein.

One-third nitrogen diet. Received daily 0.269 gram nitrogen per kilo (88.269 calories per kilo).

October 26: Weight 11.15 kilos. Food consisted of 5 grams cracker meal per kilo; meat, 3 grams per kilo; lard, 2 grams per kilo; tapioca, 10.69 grams per kilo. Kept in a cold, damp room with poor ventilation until November 20.

November 3: Weight, 11 kilos.

November 10: Weight, 10.75 kilos.

November 20: Weight, 10.55 kilos; changed to a warm room, with bedding and good ventilation.

November 29: Weight, 10.85 kilos.

December 1: Put into a cage.

December 6: Weight, 10.90 kilos; 11.25 a. m., received 28 cc 2 per cent caffein subcutaneously in side, below the shoulders, area washed with alcohol and ether, approximately 50 mg per kilo administered, no symptoms.

December 7: 10.15 a. m., received 28 cc 2 per cent caffein injected subcutaneously; feces soft and very fetid; 1 p. m., depressed in spirit, eyes dull.

December 9: 10.45 a. m., received 25 cc 2 per cent caffein solution subcutaneously, feces still fetid, site of injection inflamed and swollen, no other symptoms.

December 10: Inflammation of area of injection more pronounced; 2 p. m., given 0.5449 gram caffein and 30 grams of meat; 4 p. m., fed, no symptoms, feces fetid.

December 11: 12 a. m., given 0.5459 gram caffein and 30 grams of meat, no symptoms, feces fetid.

December 12, 13: Given 0.5459 gram caffein daily, without noticing any symptoms.

December 14: 12 a. m., received 0.817 gram caffein (75 mg per kilo); 2.30 p. m., restless and uncomfortable, no other symptoms.

December 15: 11.30 a. m., received 0.8175 gram caffein by mouth; 2 p. m., depressed in spirit, acted as though sick, no other symptoms.

December 16: Weight, 11 kilos; 11 a. m., received 0.100 gram caffein per kilo (1.100 grams) by mouth, no symptoms.

December 17: Rested.

December 18: 2.30 p. m., received 1.100 grams caffein by mouth; 4 p. m., no symptoms.

December 19: 12 noon, received 1.100 grams caffein by mouth; 4.15 p. m., no symptoms.

December 20: 2.45 p. m., given 1.375 grams caffein (0.125 gram per kilo); 3.45 p. m., vomited--one of the capsules being found intact, the other broken open; 4 p. m., given regular diet, containing 1.3757 grams caffein in capsules, ate most of this during the night, whined at intervals, coordination disturbed, appeared very sick, but exhibited no other symptoms.

December 21: 9 a. m., found dead, stiff, and cold.

The total amount of caffein received by dog 24 was between 10.109 and 11.484 grams. As one of the capsules vomited was intact and the other broken open, the amount was probably about 10.75 grams. The fatal dose in this case was undoubtedly less than 185 mg per kilo--somewhere between 125 and 185 mg. Autopsy showed heart in diastole; posterior lobe of right lung deeply congested; liver engorged; gall cyst filled; spleen appeared normal; stomach well filled with semifluid mass; pyloric portion of stomach exhibited a severe inflammation of mucosa; mucosa of duodenum greatly inflamed and showed hemorrhagic areas and catarrhal exudate; remainder of small intestine also exhibited mild inflammation; kidneys deeply engorged, mesentery injected.

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.