Part 9

Rost stated that caffein is eliminated in the urine unchanged after its introduction into the body and that the amounts found varied with different species of animals. In the rabbit the amount eliminated was about 21 per cent; in the dog about 8 per cent; and in the cat somewhat less than 2.5 per cent. It would appear, therefore, that the cat decomposes caffein more readily than the rabbit or dog; its resistance consequently ought to be greater than that of the other animals. Moderately large doses were accordingly employed in the preliminary experiments (series A), but the results obtained, as shown in the protocols, indicated that caffein is fully as toxic for the cat as for the rabbit or dog. The doses were then decreased and experiments were performed in order to ascertain the smallest toxic as well as the smallest fatal dose.

SERIES A.

Three decigrams of caffein per kilo were administered in these experiments. The results are shown in the following protocols:

_Cat 4. Black and white. Weight, 1,440 grams._

May 26: 10.05 a. m., 22 cc 2 per cent caffein (0.3 gram per kilo) injected subcutaneously; 11.10 a. m., copious salivation, cat irritable, muscular stiffness present, but no tetanus; 11.45 a. m., cat restless, convulsions, attacks of short duration, no paralysis observed after the convulsions, pupils dilated; 4.45 p. m., cat quiet, slight paralysis present.

May 27: Cat exhausted.

May 28: Found dead.

_Cat 5. Black and white male. Weight, 1,396 grams._

June 3: 10 a. m. 21 cc of 2 per cent caffein (0.3 gram per kilo) injected subcutaneously; 12 noon, found dead.

Although there was considerable difference in the duration of life following the injection of the same dose of caffein per kilo, the final outcome was the same, as both cats died from the effects of the drug. One died within 2 hours and the other lived more than 30 hours after its administration. Three decigrams of caffein per kilo is, therefore, surely fatal to these animals. Tests made with smaller doses are shown in the following experiments:

SERIES B.

In these experiments the doses employed ranged between 0.20 and 0.25 gram caffein per kilo.

_Cat 3. Black and white female. Weight, 2,854 grams. Well fed._

June 4: 10.30 a. m., 35 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously; 11 a. m., found dead.

_Cat 6. Black and white. Weight, 1,645 grams._

June 3: 20 cc 2 per cent caffein (0.243 gram per kilo) injected subcutaneously at 3 p. m., cat grew very irritable in a few minutes; about 4. p. m. reflexes decidedly increased; 5 p. m., cat paralyzed.

June 4: Cat found dead.

_Cat 8. Weight, 1,735 grams._

October 7: 4 p. m., 22 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously in the back; 4.30 p. m., cat irritable, salivation profuse, convulsions; died at 5.30 p. m.; no urine passed after caffein was given.

_Cat 9. Weight, 1,960 grams._

October 7: 3.45 p. m., 25 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously in the back; 4.45 p. m., cat very irritable, repeated attacks of convulsions, salivation copious; died at 5.30 p. m.; cat did not urinate after injection of caffein.

_Cat 12. Striped kitten. Weight, 1,185 grams._

October 9: Urine examined, no albumin, no sugar; 1.45 p. m., 12 cc 2 per cent caffein administered; 5 p. m., cat alive, no symptoms except salivation and general irritability.

October 10: 10.30 a. m., found dead. About 15 cc urine collected, but no examination made.

_Cat 14. Black. Weight, 1,855 grams._

October 8: 1.40 p. m., 18.5 cc 2 per cent caffein (0.2 gram per kilo); 3 p. m., cat became restless about 10 minutes after caffein was injected; cried persistently and moved about in cage, no convulsions, cat urinated about 15 cc, cat defecated.

October 9: 9 a. m., cat found dead in cage. Urine gave very heavy reduction of Fehling's solution (much more than was obtained from urine of rabbits); 20 cc urine analyzed contained 4.65 per cent sugar. _Autopsy_: Lungs deeply congested; liver marked fatty infiltration and degeneration; spleen normal; kidneys pale and anemic; intestines normal; stomach normal.

_Cat 15. Striped. Weight, 2,145 grams._

October 8: 2 p. m., 22 cc (0.2 gram per kilo) 2 per cent caffein injected subcutaneously; 2.30 p. m., cat irritable, restless, trying to get out of cage, crying persistently; 2.40, convulsions lasting about two minutes, then cat raised itself and made attempts to get out of cage, no salivation, cat urinated about 10 cc and defecated.

October 9: 9 a. m., cat found dead in cage, about 10 cc of urine contained enormous quantities of sugar. _Autopsy_: Lungs severely congested; liver showed marked fatty degeneration; spleen normal; kidneys slightly pale and anemic; intestines mildly congested; stomach normal.

_Cat 19. White. Weight, 1,100 grams._

October 20: 13 cc of 2 per cent caffein (0.236 gram per kilo). About 15 minutes later cat became irritable, reflexes increased, persistent crying, stiffness of extremities, diarrhea present; 4.30 p. m., stiffness of muscles, coordination much disturbed, walked with great difficulty; 4.30 p. m., no new symptoms, persistent crying continued.

October 21: Found dead.

_Cat 20. White kitten. Weight, 790 grams._

October 20: 11.35 a. m., 10 cc 2 per cent caffein (0.25 gram per kilo) given subcutaneously; 12 noon, convulsions followed by paralysis; 1.30 p. m., still breathing, apparently in comatose condition, lay on its side, dyspnoea, profuse salivation; 4 p. m., convulsions and death.

The results of the experiments of series B show that a dose of even 0.2 caffein per kilo is very toxic for the cat. Symptoms appeared in one animal 40 minutes after the injection of caffein. Some of them were found dead 18 hours after injection, which means that the duration of life was probably a great deal less since there was evidence that they had been dead for some time. Death occurred quite soon after larger doses were injected. Cat No. 3 died 30 minutes after it received caffein. The amounts employed in these experiments can not be considered therefore as the minimum fatal doses. Smaller doses were then tried, as shown in the experiments of the next series.

SERIES C.

Experiments were performed on five cats which received from 140 to 155 mg per kilo, as follows:

_Cat 24. Striped. Weight, 1,300 grams._

October 25: 10 a. m., 50 cc urine, albumin moderate amount--no sugar; 10 cc caffein injected subcutaneously at 12 noon; 12.30, irritable, cried persistently, no appetite; 4 p. m., no convulsions, but persistent crying.

October 27: Cat was still alive.

_Cat 17. Weight, 2,620 grams._

October 12: 9.30 a. m., 65 cc urine collected; more than a trace of albumin present, no reduction of Fehling's solution; 3 p. m., 20 cc 2 per cent caffein (150 mg per kilo) injected subcutaneously; 3.15 p. m., irritable and restless.

October 13: 9 a. m., about 15 cc urine collected, reduction of Fehling's solution marked; osazone test also positive.

_Cat 23. Black and white. Weight, 1,645 grams._

October 25: 10 a. m., 140 cc urine collected (since October 23), small amount of albumin present, no sugar.

October 27: 9 a. m., no albumin; no sugar in urine; 11.50 a. m., 12.5 cc caffein injected subcutaneously (0.15 gram per kilo); 1 p. m., convulsions and death.

_Cat 7. Striped kitten. Weight, 1,285 grams._

October 11: Urine collected, no albumin, no sugar; 9.50 a. m., 10 cc 2 per cent caffein injected subcutaneously in the back; 10.10, violent convulsions lasting about 30 seconds; 10.20, convulsions of shorter duration; 10.30 convulsions; 10.35, convulsions lasting a few seconds; urine passed about 10.20, contained a moderate amount of albumin, but there was no reduction of Fehling's solution; 10.45, profuse salivation and paralysis; died about 10.50.

_Cat 39. Yellow. Weight, 2,285 grams._

April 13: 2.40 p. m., 16 cc 2 per cent caffein (0.14 gram per kilo) injected subcutaneously in the back; 3.45 p. m., cat died.

Of the five experiments of this series three died after doses of 140, 150, and 155 mg per kilo. The other two showed symptoms of toxicity, but survived a dose of 150 mg per kilo which indicated that the minimum fatal dose was probably reached. To test this supposition smaller doses were administered, as shown in the following experiments.

SERIES D.

Ten cats were used for this series of experiments, and the doses administered varied between 103 and 139 mg per kilo. The results shown in the appended table (p.58) indicate that about 120 to 140 mg of caffein per kilo may induce mild symptoms in some cases. The conclusion may be safely drawn therefore that 150 mg per kilo is approximately the minimum fatal dose for the cat when the drug is given subcutaneously. That smaller doses are, however, by no means to be regarded as always safe is shown in the following experiments.

SERIES E.

_Cat 43. Weight, 3,225 grams._[D]

[D] Cat probably old; had been in the laboratory for several weeks before the experiment. Gained in weight 175 grams.

September 14: 10.20 a. m., 20 cc 2 per cent caffein (0.124 gram per kilo) injected into the back; 11 a. m., tetanus and death. _Autopsy_: Lungs congested; liver congested and showed hemorrhagic spots in capsules and fatty degeneration; kidneys slightly congested; other organs normal.

_Cat 48. Black female. Weight, 3,050 grams._

September 14: 18 cc 2 per cent caffein (0.118 gram per kilo) injected subcutaneously in the back; 10.30 a. m., violent convulsions and death. _Autopsy_: Lungs congested in spots showing numerous petechia; liver congested; spleen congested; other organs normal.

The diminished resistance to caffein of cats Nos. 43 and 48 might be due to the pathologic changes found on autopsy, for evidence is not wanting that the toxicity of drugs might be greatly altered under pathological conditions. Hunt(40) has shown that resistance to acetonitril is considerably diminished in chronic alcoholism. This seems to be true also of other drugs under abnormal conditions. Smaller doses of atropin(78) are required in lead poisoning than under normal conditions to produce the same results. The following experiment is of interest in this connection, for in this case a much smaller dose than was given in experiments Nos. 43 and 48 produced the typical symptoms of caffein poisoning and proved to be fatal.

_Cat 47, black and white male. Weight, 4,220 grams._

September 15: Received subcutaneously 18 cc 2 per cent caffein (0.084 gram per kilo); no symptoms observed for about six hours.

September 16: No symptoms.

September 17: Weight, 4,250 grams; injected 18 cc 2 per cent caffein (0.084 gram per kilo); tetanus and death after two hours. _Autopsy_: Severe hemorrhagic pneumonia; kidneys pale, other organs normal.

Since two controls survived the same dose in proportion to the body weight of the animal without showing any symptoms, the assumption is justified that the lower resistance to caffein was due to the presence of pneumonia, thus affording additional support to the view that the toxicity of caffein may be increased in disease.

INJECTION INTO THE PERITONEAL CAVITY.

These experiments were carried out on full-grown and on young subjects. As in previous experiments, doses of different sizes were employed. A dose of 0.2 gram per kilo was tried first and then reduced gradually to 0.1 gram per kilo.

_Cat 10. Female. Weight, 2,970 grams._

October 9, 1909: 1.30 p. m., 30 cc 2 per cent caffein (0.2 gram per kilo) injected into the peritoneal cavity; urine examined for albumin and sugar, negative; cat found dead at 2.30 p. m. No urine in the bladder.

_Cat 16. Black female. Weight, 2,420 grams._

October 9, 1910: Urine examined for albumin and sugar, negative; 2.30 p. m., 22 cc 2 per cent caffein (0.183 gram per kilo) injected into the peritoneal cavity; found dead at 3 p. m.

_Cat 99. Well-fed gray female. Weight, 3 kilos._

June 22, 1911: 3.40 p. m., 15 cc 2 per cent caffein injected into peritoneal cavity; salivation and marked irritability within one hour after injection.

June 24: Alive, appetite good.

_Cat 98. Well-fed black male. Weight, 4,100 grams._

June 22: 3.45 p. m., 20.5 cc 2 per cent caffein (0.1 gram per kilo) injected into peritoneal cavity; very irritable a few minutes after injection, no other symptoms.

June 24: No symptoms, appetite good.

_Cat 93. Black and white. Weight, 1,450 grams._

June 22: 3 p. m., 30 cc 2 per cent caffein (0.137 gram per kilo) injected into peritoneal cavity; salivation, no other symptoms; under observation until 6 p. m.

June 23: 9 a. m., no urine, cat showed no symptoms.

June 24: 9 a. m., no symptoms, took nourishment as usual.

_Cat 87. Well-fed white female. Weight, 2,615 grams._

June 23: 2.45 p. m., 19 cc 2 per cent caffein (0.145 gram per kilo) injected into peritoneal cavity; became irritable and restless.

June 24: 9 a. m., no symptoms, took nourishment as usual.

_Cat 97. Gray. Age, 3 months. Weight, 500 grams. Diet, meat._

June 24: 2.25 p. m., 5 cc 2 per cent caffein (0.2 gram per kilo) injected into peritoneal cavity; 4 p. m., no symptoms.

June 29: Died.

_Cat 96. Gray and white. Age, 3 months. Weight, 575 grams. Diet, meat._

June 24: 2.20 p. m., 4 cc 2 per cent caffein (0.139 gram per kilo) injected into peritoneal cavity; 3.55 p. m., no symptoms.

June 30: Died.

_Cat 95. Black. Age, about 3 months. Weight, 860 grams. Diet, meat._

June 24: 10.15 a. m., 8.6 cc 2 per cent caffein injected into peritoneal cavity, salivation immediately after injection; 10.25, convulsions and paralysis; died 10.45 a. m. _Autopsy_: Macroscopical examination of the organs, negative.

_Cat 94. Black and white. Weight, 790 grams. Age, about 3 months. Diet, meat._

June 24: 10 a. m., 8 cc 2 per cent caffein injected into peritoneal cavity; 4 p. m. under continual observation since injection, cat very irritable, respiration more rapid than normal, diarrhea present.

Examination of the above protocols show that a dose of 2 decigrams per kilo was fatal within one hour to one cat and that a somewhat smaller dose killed another individual in 30 minutes. Amounts under 0.15 gram per kilo were just sufficient to induce mild symptoms, such as increased irritability and salivation, which disappeared within a few hours. In no case were the effects noticeable on the following day. The experiments on young kittens are especially interesting, as they proved, contrary to expectation, to be distinctly more resistant than full grown individuals. The death of Nos. 97 and 96 within five and six days, respectively, can not be ascribed to caffein, since some of the controls also died. Moreover, it will be remarked in this connection that no symptoms appeared in three of the four young kittens after the administration of a dose which was rapidly fatal to adult cats. The rapid death of No. 95 after the same dose forms an exception which can not be accounted for, as macroscopical examination at autopsy proved negative.

ADMINISTRATION BY MOUTH.

Two decigrams per kilo were given at first, but it was found that this amount was surely fatal. The dose was therefore reduced to 0.125 gram per kilo. In all of these experiments caffein was given by means of a soft rubber catheter slipped over the stem of a funnel which served as a stomach tube. A 2 per cent aqueous solution was used throughout these tests except in one case in which caffein was given mixed with the food.

_Cat 92. Black and white female. Weight, 1,750 grams._

June 10: 12.05 p. m., 14 cc 2 per cent caffein (0.16 gram per kilo) given by mouth; cat was quiet when tied on holder, struggled only a little when tube was put into stomach; 12.30 p. m., cat vomited, no other symptoms.

June 13: Condition good, appetite good.

_Cat 87. White female. Weight, 2,620 grams. Diet, meat._

June 5: 2.15 p. m., 20 cc 2 per cent caffein (0.15 gram per kilo) solution administered by mouth through stomach tube; 2.30 p. m., cat irritable, but no other symptoms; 5 p. m., condition about the same, except that it was more irritable and showed some stiffness of the extremities.

June 13: Alive and in good condition, appetite good, not irritable.

_Cat 91. White female. Weight, 3,050 grams._

June 10: 12 noon, 23 cc (0.15 gram per kilo) of 2 per cent caffein administered by mouth, cat struggled violently; 1.30, salivation; 1.40 p. m., convulsions; died at 2 p. m. _Autopsy_: Congestion of lungs, liver, and spleen; heart vessels injected; other organs normal.

_Cat 88. Black and white female. Weight, 3,260 grams. Diet, meat._

June 5: 2.20 p. m., 25 cc of 2 per cent caffein (0.15 gram per kilo) given by mouth; 2.45 p. m., cat irritable, no other symptoms (cat did not vomit after the administration of caffein); 4 p. m., cat found dead. _Autopsy_: Liver very much congested; heart contracted; body was still warm at the time of autopsy.

_Cat 90. White and yellow female. Weight, 2,685 grams. Diet, meat._

June 5: 3.15 p. m., 27 cc of 2 per cent caffein (0.2 gram per kilo) given by mouth through stomach tube, about half an hour later cat became irritable and began to salivate; at 4.30 p. m. salivation became more marked, dyspnoea was well developed, and the cat was quite restless and had tremors; 5 p. m., short spasms of posterior extremities, but lay quietly in the cage most of the time; 5.20 p. m., convulsions of short duration and death, muscular relaxation followed immediately after convulsions, no vomiting, diarrhea observed after administration of caffein, and cat passed about 10 cc of urine.

June 6: 9 a. m., found dead.

_Cat 89. White and black female. Weight, 2,860 grams. Diet, meat._

June 5: 3.15 p. m., 28.6 cc (0.2 gram per kilo) of 2 per cent caffein given by mouth through stomach tube, no vomiting observed, nor any other symptoms; 3.30, found dead. _Autopsy_: Organs normal; liver congested.

_Cat 82. Gray female. March 3, weight 2,450 grams; June 6, weight 2,750 grams. Diet, 150 grams of meat daily._

June 7: Given 0.4125 gram of caffein in 150 grams of meat, did not eat.

June 8: Given 0.4125 gram of caffein in 150 grams of meat, refused to eat.

June 9: Given 150 grams of meat without caffein, ate all of it.

June 10: No food given.

June 11: No food given.

June 12: Given 0.4125 gram caffein in 150 grams of meat (150 mg per kilo), ate all of it.

June 13: Found dead. _Autopsy_: Lungs congested, liver congested; other organs apparently normal.

_Cat 100. Gray female. Weight, 2,740 grams. Diet, meat._

July 17: 3 p. m., 17 cc of 2 per cent caffein (124 mg per kilo) given by mouth through stomach tube at 3.20 p. m.; 5 p. m., very irritable, but no other symptoms.

July 18: Under observation all day, no symptoms.

_Cat 93. Black and white female. Weight, 1,640 grams._

July 17: 3.30 p. m., 10 cc (0.125 gram per kilo) of 2 per cent caffein given by mouth through stomach tube.

July 18: Under observation all day, no symptoms.

From the results of the experiments of this series it appears that 0.15 gram caffein per kilo may be fatal within a few hours after its administration, even if the drug is mixed with a moderate amount of meat. Experiments 87 and 92 show, however, that this amount may be borne by some individuals without any serious consequences, as the cats were under observation for some time after they received caffein, and no untoward symptoms were noticed in either of them during this time. It may be remarked that cat No. 92 vomited shortly after it received caffein. It is practically certain, therefore, that this amount of caffein in proportion to the weight of the animal will in the great majority of cases prove fatal, and perhaps in a smaller percentage of individuals it is surely toxic if it does not escape absorption. Smaller doses may cause irritability in some individuals, but symptoms referable to nervous symptoms of muscles were absent, as in experiments Nos. 93 and 100. The minimum fatal dose of caffein for the cat when given by mouth is, therefore, 0.15 gram per kilo.

TABLE 9.--_Subcutaneous injection; cats._

SERIES A.

+--------+---------+-----------------------+------------------- Number.| Weight.| Caffein | Symptoms. | Duration of life. | |per kilo.| | -------+--------+---------+-----------------------+------------------- |_Grams._| _Gram._ | | 4 | 1,440 | 0.30 | 65 minutes | Over 29 hours. 5 | 1,396 | .30 | | About 2 hours. -------+--------+---------+-----------------------+-------------------

SERIES B.

+--------+---------+-----------------------+------------------- 3 | 2,854 | 0.25 | | 30 minutes. 6 | 1,645 | .243 | Few minutes | 1 hour 30 minutes. 8 | 1,735 | .25 | 30 minutes. | 1 hour. 9 | 1,960 | .25 | 1 hour | 1 hour 45 minutes. 12 | 1,185 | .20 | 3 hours | Less than 18 hours. 14 | 1,855 | .20 | 1 hour 20 minutes | Do. 15 | 2,145 | .20 | 40 minutes. | Do. 19 | 1,100 | .236 | 15 minutes | Do. 20 | 790 | .25 | | 4 hours 30 minutes. -------+--------+---------+-----------------------+--------------------

SERIES C.

+--------+---------+-----------------------+------------------- 24 | 1,300 | 0.153 | 1 hour | Survived. 17 | 2,620 | .15 | 15 minutes | Do. 23 | 1,645 | .15 | | 1 hour 10 minutes. 7 | 1,285 | .155 | 20 minutes | 1 hour. 9 | 2,285 | .14 | | 65 minutes. -------+--------+---------+-----------------------+-------------------

SERIES D.

+--------+---------+-----------------------+------------------- Number.|Weight. | Caffein | Symptoms. | Duration of life. | |per kilo.| | -------+--------+---------+-----------------------+------------------- |_Grams._| _Gram._ | | 13 | 730 | 0.139 | Restlessness | 21 | 1,165 | .138 | None | 25 | 965 | .103 | do. | 26 | 1,605 | .125 | do. | 27 | 1,625 | .125 | do. | 28 | 2,335 | .128 | do. | Received 2 doses: | | | | survived. 40 | 2,710 | .129 | do. | Do. 41 | 1,785 | .123 | do. | Do. 42 | 2,315 | .112 | do. | Do. 38 | 2,325 | .120 | Mild | Died after second | | | | dose. -------+--------+---------+-----------------------+-------------------

SERIES E.(1)

+--------+---------+-----------------------+------------------- 43 | 3,225 | 0.124 | | 40 minutes. 48 | 3,050 | .118 | | Died soon after. 47 | 4,220 | .084 | | Survived. (2)47 | 4,250 | .084 | | 2 hours. -------+--------+---------+-----------------------+-------------------

(1) Pathological conditions.

(2) Two days after first injection.

TABLE 10.--_Injections into peritoneal cavity; cats._