All the guinea pigs in these experiments were kept on a diet of hay and
oats and were of large size. The tests were made with different doses
of caffein in order to determine the limits of toxicity when the drug
was administered by mouth.
_Guinea pig 129. White and black male. Weight, 855 grams. Diet,
oats and hay._
June 6: 2.20 p. m., 12 cc of 2 per cent caffein (0.28 gram per kilo)
by mouth; 3 p. m., reflexes increased; 5 p. m., reflexes still more
increased; no other symptoms.
June 7: 9 a. m., found dead; guinea pig passed 75 cc urine, which was
almost colorless. _Autopsy_: Heart and blood vessels injected; lungs
congested; small intestines congested; other organs apparently normal.
_Guinea pig 130. Black and brown male. Weight, 800 grams. Diet, oats
and hay._
June 6: 2.30 p. m., 12 cc of 2 per cent caffein (0.3 gram per kilo)
administered by mouth; 3 p. m., reflexes increased; 5 p. m., increase
of reflexes greater than at 3 p. m.
June 7: 9 a. m., found dead; only a few cubic centimeters of urine
passed since 4 p. m. _Autopsy_: Heart and blood vessels injected; lungs
congested; small intestines congested slightly.
_Guinea pig 181. White and yellow male. Weight, 860 grams. Diet, oats
and hay._
June 6: 2.40 p. m., 12 cc 2 per cent caffein administered by mouth; 3
p. m., reflexes increased; 5 p. m., reflexes still more marked.
June 7: 9 a. m., found dead, pig passed about 5 cc urine since 4 p. m.
of previous day. _Autopsy_: Same as in No. 130.
_Guinea pig 136. White and black male. Weight, 1,000 grams. Diet, oats
and hay._
June 9: 4 p. m., 7.5 cc 2 per cent caffein solution injected
subcutaneously into the back; 4.50 p. m., reflexes increased.
June 10: 9.30 a. m., more sensitive than normal guinea pigs, but
reflexes not quite so marked as at 5 p. m. previous day, about 15
cc urine passed since caffein was injected, reduction of Fehling's
solution considerable, no albumin.
June 13: Alive and in good condition. Appetite good.
(NOTE.--Parallel test with urine from two guinea pigs which
did not receive caffein failed to show reduction of Fehling's solution.)
_Guinea pig 137. White and brown male. Weight, 925 grams. Diet, oats
and hay._
June 9: 4 p. m., 7 cc 2 per cent solution caffein injected
subcutaneously; 4.50 p. m., reflexes increased.
June 10: Reflexes less marked than at 5 p. m. previous day, but is
more sensitive than normal guinea pig, about 10 cc urine passed since
injection of caffein, moderate amount of reduction of Fehling's
solution.
June 13: Guinea pig alive, appetite good, condition good.
June 16: 9 a. m., found dead.
_Guinea pig 135. White and black male. Weight, 955 grams. Diet, hay
and oats._
June 9: 3 p. m., 7.5 cc 2 per cent caffein solution given by mouth
through stomach tube; 4.50 p. m., reflexes increased.
June 10: Reflexes less than on previous day and less marked than in No.
136, a few cubic centimeters dirty brown urine collected but could not
be tested for reduction.
June 13: Condition good, appetite good.
June 16: 9 a. m., found dead.
_Guinea pig 134. White and brown male. Weight, 740 grams. Diet, hay
and oats._
June 9: 2.55 p. m., 6 cc warm 2 per cent caffein solution given by
mouth through stomach tube; 4.50 p. m., reflexes increased.
June 10: 9.30 a. m., reflexes much less than day before, increase
slight, a few cubic centimeters of urine passed since injection of
caffein, looked brown and dirty, could not be tested for reducing
substances.
June 13: Guinea pig alive, appetite good, condition good.
June 14: 9 a. m., found dead.
_Guinea pig 128. White and black male. Weight, 1,075 grams. Diet, hay
and oats._
June 7: 10 a. m., 11 cc 2 per cent caffein by mouth through stomach
tube; 11.10 a. m., no symptoms, no urine passed; 1 p. m., increased
reflexes, about 15 cc (estimated) urine passed; 4 p. m., reflexes
increased, still more urine passed (about 20 cc); 4.50 p. m., tetanus,
frequent attacks, then paralysis and death at 4.58 p. m. _Autopsy_:
Lungs congested; blood vessels of heart injected; intestines slightly
congested; fatty liver.
_Guinea pig 126. White and gray male. Weight, 980 grams. Diet, oats
and hay._
June 7: 9.40 a. m., 9.8 cc 2 per cent caffein given by mouth through
stomach tube; 10 a. m., no symptoms; 11.10 a. m., no urine passed,
reflexes increased; 1 p. m., more sensitive than before; 4 p. m.,
increase of reflexes more marked, no urine passed; 4.45 p. m., about 15
cc urine collected; 5 p. m., no change.
June 8: 9 a. m., reflexes about the same as 5 p. m. previous day, no
urine passed since 4.45 p. m. previous day, considerable reduction
of Fehling's solution, much more than urine of guinea pig No. 127;
11.05 a. m., convulsions; 12 noon, still alive and stretched out on
abdomen; died at 1 p. m. _Autopsy_: Lungs badly congested; heart and
blood vessels injected; blood vessels of kidney and of small intestines
injected; liver engorged with blood; a few necrotic spots in stomach.
_Guinea pig 127. White, black, and brown male. Weight, 760 grams.
Diet, oats and hay._
June 7: 9.50 a. m., 7.6 cc 2 per cent caffein by mouth through stomach
tube; 10 a. m., no symptoms; 11.10 a. m., reflexes increased, no urine
passed; 1 p. m., very sensitive; 4 p. m., sensitiveness increased,
about 20 cc urine passed; 5 p. m., no change.
June 8: 9 a. m., reflexes about the same as 5 p. m. previous day; 9.30
a. m., guinea pig passed 30 cc urine since he received caffein, urine
showed a moderate amount of reduction; 12 noon, convulsions; died at
2.30 p. m. _Autopsy_: Lungs congested; blood vessels of heart and of
intestines injected; numerous necrotic spots in stomach; other organs
apparently normal.
Examination of the protocols shows that the absorption of caffein from
the gastro-intestinal canal was quite rapid, symptoms having been
observed as early as 20 minutes after its introduction. The duration
of life, it will be remarked, varied with the size of the dose. When
approximately 3 decigrams per kilo were fed, all the animals died in
the night. They lived, therefore, less than 18 hours. Two decigrams
per kilo were likewise fatal, but the duration of life was longer.
To decide whether or not this is the smallest fatal dose, smaller
amounts were fed. It seemed at first that about 150 mg per kilo was the
smallest toxic dose, and about 200 mg per kilo the minimum fatal dose.
Macroscopic examination of the organs, however, threw some doubt on
this supposition, for well-marked lesions were noticed in all of the
guinea pigs which received 0.2 gram per kilo. It is quite possible,
therefore, that the minimum fatal dose may be somewhat higher, as we
have reason to believe that, at least in some pathologic conditions,
the susceptibility to caffein is increased. The presence of fatty
changes in the liver of No. 128 and the rapid death in this case
lends especial support to this view. Hence, the minimum fatal dose is
probably greater than 0.2 gram per kilo for the normal guinea pig. The
doses employed for the tests on guinea pigs Nos. 129, 130, and 131 may
be considered therefore the minimum fatal dose for these animals. It
will be also remarked that macroscopical examination of the organs of
these animals failed to reveal the presence of severe lesions. That the
minimum toxic dose is probably much smaller than 0.28 gram per kilo
is indicated by the experiments on guinea pigs Nos. 135 and 134, in
which 0.15 gram caffein per kilo induced mild symptoms in from two to
three hours. Both of these, however, and also No. 137 died four to six
days after the drug was fed. As already pointed out, caffein may be
a factor in the delayed death of guinea pigs which received moderate
doses of it. That this supposition may also be true for guinea pigs
Nos. 134, 135, and 137 is indeed made probable by the observation that
after moderate amounts of caffein symptoms may persist in the guinea
pig for about 24 hours, and also by the fact that the secretion of
urine in these animals was very scanty, as shown in the preceding
record of the experiments; this means slow elimination of caffein and
its products of decomposition. It is conceivable that the presence of
toxic amounts of caffein in the body for a considerable length of time
would induce changes that ultimately lead to the death of the animal or
that morbid processes are set up by the combined action of caffein and
some preexisting poison. Since some guinea pigs, however, survived the
doses indicated, it is more probable that such changes would be brought
about by caffein in the presence of a preexisting poison. The death of
these pigs, and also of No. 137 several days later, is difficult to
account for on any other theory than the one suggested. Were it not
for the fact that controls, that is, animals of the same lot which had
not received caffein survived all of the experimental animals, changed
conditions of environment or accident might be considered the cause of
death in the guinea pigs of the last series.