SERIES A.Number of pig.Weight.Caffein per kiloAppearance of symptoms inGrams.Mg.1298550.28040 minutes130800.30030 minutes131860.28020 minutes135955.1501 hour 50 minutes134740.1603 hours1137925.15050 minutes11361,000.150do.126980.20020 minutes127760.2001 hour1281,075.2003 hoursNumber of pig.Duration of life.Diet.Month.Remarks.129Less than 8 hoursHay and oatsJuneMale.130Less than 18 hoursdo.do.Do.131do.do.do.Do.1356 daysdo.do.Do.1344 daysdo.do.Do.11376 daysdo.do.Do.1136Surviveddo.do.Do.12627 hoursdo.do.Do.12728 hoursdo.do.Do.1287 hoursdo.do.Do.1Subcutaneous injection for comparison.
SERIES A.Number of pig.Weight.Caffein per kiloAppearance of symptoms inGrams.Mg.1298550.28040 minutes130800.30030 minutes131860.28020 minutes135955.1501 hour 50 minutes134740.1603 hours1137925.15050 minutes11361,000.150do.126980.20020 minutes127760.2001 hour1281,075.2003 hoursNumber of pig.Duration of life.Diet.Month.Remarks.129Less than 8 hoursHay and oatsJuneMale.130Less than 18 hoursdo.do.Do.131do.do.do.Do.1356 daysdo.do.Do.1344 daysdo.do.Do.11376 daysdo.do.Do.1136Surviveddo.do.Do.12627 hoursdo.do.Do.12728 hoursdo.do.Do.1287 hoursdo.do.Do.1Subcutaneous injection for comparison.
1Subcutaneous injection for comparison.
SERIES A.Number of pig.Weight.Caffein per kiloAppearance of symptoms inDuration of life.Diet.Month.Remarks.Grams.Mg.1298550.28040 minutesLess than 8 hoursHay and oatsJuneMale.130800.30030 minutesLess than 18 hoursdo.do.Do.131860.28020 minutesdo.do.do.Do.135955.1501 hour 50 minutes6 daysdo.do.Do.134740.1603 hours4 daysdo.do.Do.1137925.15050 minutes6 daysdo.do.Do.11361,000.150do.Surviveddo.do.Do.126980.20020 minutes27 hoursdo.do.Do.127760.2001 hour28 hoursdo.do.Do.1281,075.2003 hours7 hoursdo.do.Do.1Subcutaneous injection for comparison.
SERIES A.Number of pig.Weight.Caffein per kiloAppearance of symptoms inDuration of life.Diet.Month.Remarks.Grams.Mg.1298550.28040 minutesLess than 8 hoursHay and oatsJuneMale.130800.30030 minutesLess than 18 hoursdo.do.Do.131860.28020 minutesdo.do.do.Do.135955.1501 hour 50 minutes6 daysdo.do.Do.134740.1603 hours4 daysdo.do.Do.1137925.15050 minutes6 daysdo.do.Do.11361,000.150do.Surviveddo.do.Do.126980.20020 minutes27 hoursdo.do.Do.127760.2001 hour28 hoursdo.do.Do.1281,075.2003 hours7 hoursdo.do.Do.1Subcutaneous injection for comparison.
1Subcutaneous injection for comparison.
A survey of the results obtained in experiments on guinea pigs shows that the mode of introduction of caffein exerts but little influence on its toxicity. On careful analysis it will be observed that the rate of absorption after the administration of caffein by mouth, subcutaneously, or intraperitoneally is about the same for the time of appearance of symptoms. The persistence of the symptoms of caffein intoxication observed in these experiments for 24 hours after administration points to slow elimination, which may be expected, owing to the fact that the guinea pigs passed but little urine and caffein is not diuretic for these animals. The prolonged presence of caffein in the body probably exerts a harmful influence or after effect, which may accountfor the delayed death of some animals many days after a single dose of caffein was given. Among the factors which undoubtedly influence toxicity, season should be considered, while the presence of a diseased condition undoubtedly tends to decrease the resistance of the guinea pig to caffein. Diet was without any influence on the toxicity of the single dose of caffein.
These experiments were performed on well-fed animals which were kept under observation for several days before the tests with caffein were made. The diet consisted of meat exclusively. In some cases the urine was examined for albumin and sugar before caffein was given. No tests with caffein were made if large amounts of albumin were found. It may be remarked that sugar was never found in cats before the administration of caffein, but that considerable amounts of it were found in some cases after it was given. Studies by various modes of administration were made, by subcutaneous injection, intraperitoneally, or by mouth. Attention was also directed to the resistance to caffein in young cats, several experiments on kittens being made with this object in view.
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, dyspnœa, 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]
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 toxicityof drugs might be greatly altered under pathological conditions. Hunt40has 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 atropin78are 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.
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.
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, dyspnœa 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 per kiloSymptoms.Duration of life.Grams.Gram.41,4400.3065 minutesOver 29 hours.51,396.30About 2 hours.SERIES B.32,8540.2530 minutes.61,645.243Few minutes1 hour 30 minutes.81,735.2530 minutes.1 hour.91,960.251 hour1 hour 45 minutes.121,185.203 hoursLess than 18 hours.141,855.201 hour 20 minutesDo.152,145.2040 minutes.Do.191,100.23615 minutesDo.20790.254 hours 30 minutes.SERIES C.241,3000.1531 hourSurvived.172,620.1515 minutesDo.231,645.151 hour 10 minutes.71,285.15520 minutes1 hour.92,285.1465 minutes.SERIES D.137300.139Restlessness211,165.138None25965.103do.261,605.125do.271,625.125do.282,335.128do.Received 2 doses: survived.402,710.129do.Do.411,785.123do.Do.422,315.112do.Do.382,325.120MildDied after second dose.SERIES E.433,2250.12440 minutes.483,050.118Died soon after.474,220.084Survived.2474,250.0842 hours.1Pathological conditions.2Two days after first injection.
1Pathological conditions.2Two days after first injection.
Table 10.—Injections into peritoneal cavity; cats.
SERIES A.Number.Weight.Caffein per kiloSymptoms.Duration of life.Grams.Gram.993,0000.100MildSurvived.984,100.100do.1Do.931,450.137Very mildDo.872,615.145do.Do.97505.200None5 days.96575.139do.6 days.95860.20015 minutes30 minutes.94790.200DiarrheaSurvived.102,970.2001 hour.162,420.18330 minutes.1In few minutes.
1In few minutes.
Table11.—Administration of caffein by mouth; cats.
SERIES A.Number.Weight.Caffein per kiloSymptoms.Duration of life.Grams.Gram.913,0500.151 hour 40 minutes2 hours.883,260.151 hour 40 minutes.921,750.1625 minutesSurvived.872,620.153 hoursDo.902,685.201 hour 15 minutesLess than 18 hours.892,860.2075 minutes.822,450.15Less than 24 hours.1002,740.1241 hour 40 minutesSurvived.931,640.125Do.
The toxicity of caffein in cats is shown to be the same when given by mouth as when injected subcutaneously, the minimum fatal doses in both cases being 0.15 gram per kilo. When introduced by the intraperitoneal route, caffein is, on the contrary, distinctly less toxic. After the administration of 0.137 and 0.145 gramcaffein per kilo (Nos. 93 and 87) salivation in one cat (No. 93) and irritability and muscular stiffness in the other were the only effects noticed. These symptoms were no longer observed the next day and the cats appeared to be perfectly normal. Experiments with larger doses indicate that the minimum fatal dose by this method of administration is about 0.2 gram per kilo.
The experiments were carried out on well-fed adult dogs and on puppies, kept under observation for some time before the drug was administered. Only those manifesting no signs of abnormality were used for these tests. Caffein was given by mouth mixed with 10 to 20 grams of meat, or subcutaneously in 2 per cent aqueous solution. The young animals received caffein dissolved in milk. The determination of the minimum toxic or fatal doses when the drug was fed presented considerable difficulty, as in many instances the ingestion of the drug was closely followed by vomiting.
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.
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.
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 experimentsthat 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.
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.)