THE EFFECT OF HIGH TEMPERATURE UPON THE

ACTION AND TOXICITY OF DIGITALIS

ARTHUR D. HIRSCHFELDER, J. BICEK, F. J. KUCERA AND W. HANSON

From the Department of Pharmacology, University of Minnesota

Received for publication May 3, 1920

The use of digitalis in fever has increased so greatly during

the great epidemic of influenza in the past year, and the use of
very large doses recommended by Carey Eggleston has gained
such prominence that it seemed important to determine whether
the action of the drug at high body temperatures is the same as
at normal temperatures, and whether the toxicity of the drug
undergoes any change.
The excellent observations of Trendelenburg, Baker, Haskell
and especially Sollman, Mendenhall and Stingel, have shown
that for the frog’s heart up to 30#{176}
the lethal dose of digitalis,
strophanthus and ouabain diminishes as the temperature is
raised, and the three latter observers demonstrated that for
oceabain the curve diminution follows Van’t Hoff’s law for
the influence of temperature on chemical reaction. However,
these observers did not extend their investigations above 30#{176}C.
or in other words, did not reach the point at which the temper-
ature itself played any marked role as a deleterious factor. It
was therefore of interest to determine the relation of very high
temperatures to this toxicity.
In this series of experiments medium sized frogs (30 to 40
grams) were used and their temperature was regulated by im-
mersing them in a wire cage suspended in a large bath of water
of the required temperature. The rectal temperature of each
frog was then taken and when it had reached the desired point
the required amount of tincture of digitalis was injected into
the anterior lymph sac. In all cases the tincture was prepared
from leaves grown on the campus of the University of Minnesota
427
428 HIRSCHFELDER, BICEK, KUCERA AND HANSON

under the auspices of Prof. E. Newcomb of the College of Phar-

macy; and the amount of drug necessary to cause systolic death
in one hour by the method of Worth Hale was taken as the lethal
dose.
The lethal temperatures for frogs which had not received
digitalis was found to lie between 36#{176}
and 37#{176}C. At temperatures
below 30#{176}
and 36#{176}
the curve follows a fairly uniform curve (ap-
parently parabolic, as supposed by Sollmann, Mendenhall and
Stingel), but as might have been expected the limb of the curve
above 30#{176}
is somewhat steeper than that below it. Ih other
words, there is a definite increase in toxicity between 30#{176}
and
the thermal death point (37#{176}).
As regards the effect of temperature in mammals Gunn has
shown that the excised perfused rabbit’s heart is slowed and
arrested more quickly at higher than at normal body temper-
atures. Jamieson on the other hand, studied the effects of
strophanthin upon the hearts of cats and dogs infected with
acute lobar pneumonia. In these animals when temperatures
ranged from 37#{176}
to 41#{176}he found first that the minimum lethal
dose of the drug was unchanged by the fever or infection and
secondly that the administration of the drug did not alter the
mortality from the infection.
Jamieson’s observations, however, were made upon animals
with comparatively low temperatures. It therefore seemed of
interest to determine what might be the effect of greatly high
temperatures, upon the toxicity of the digitalis in mammals.
In order to determine this the following procedure was adopted:
The cat was anaesthetized with ether, and placed upon a small
metal animal board. A cannula was inserted into carotid artery
and connected with a mercury manometer in the usual manner,
using 5 per cent sodium citrate solution to prevent coagulation.
Another cannula connected with a burette full of 0.9 per cent
NaCl solution was inserted into the femoral vein. The cat was
then placed in a large basin of warm water. at between 43#{176}
and
46#{176}
according to the temperature desired, care being taken that
the manometer with which the carotid artery was connected
should not be placed as high above the basin as to allow the
 ACTION AND TOXICITY OF DIGITALIS 429

Litrate solution to flow back into the cannula. The temperature

of the animal was taken per rectum from time to time and after
about for.ty-five minutes it was found to have risen to the desired
level of 43#{176}C. After a short sojourn of fifteen minutes at this
level a preliminary blood pressure tracing was taken and then
a dose of 0.5 mil. of the tincture of digitalis was injected by means
of a syringe needle inserted obliquely through the wall of the
rubber tube leading to the cannula in the femoral vein, and the
whole amount of the drug then washed into the blood strain
with a couple of mils. of salt solution from the burette. This
injection of 0.5 mil. was repeated at definite intervals of 1.25 to
to 1.5 minutes, in another series at five-minute intervals until
death ensued. Since the former was somewhat too rapid to
allow the effect of each dose to become complete, the lethal
doses obtained in this are somewhat too high, but nevertheless
the results obtained with the normal and with the febrile animals
by this method are comparable with one another, and show the
same general relations as those obtained by the slower injections.
The results obtained with injections of 0.5 thil. at five-minute
intervals are more trustworthy and show for the normal animals
a lethal dose similar to that found by the very similar methods
of Hatcher and of Rowntree and Macht.
In both these series it was found that the lethal dose of digitalis
for cats whose temperatures was elevated to 43#{176}
is much smaller
than the lethal dose at normal temperatures.
In the febrile animals the digitalis was found to cause the
typical slowing of the pulse rate and increase in the blood pres-
sure, as well as ventricular extrasystoles and inversion of the
T wave on the electrocardiogram. The blood pressure in the
febrile animals was usually depressed below the normal level
and the drug usually caused it to rise to above the normal level,
somewhat above the latter, thereby inducing a greater rise than
was usually obtained in normal animals.
The electrocardiograph showed inversion of the T wave is
induced at 43#{176}exactly as it is in animals at the normal temper-
atures.
430 HIRSCHFELDER, BICEK, KUCERA AND HANSON

Intervals between injections, 5 minutes

NORMALANIMALS , AVERAGELETIIAL
LETHAL DOSE PER KiLO’ COEFFICIENT
(TEMPERATURE) DOSE

37#{176}
to 39#{176} 0.80, 0.70, 1.4 0.94
41#{176} 0.73, 0.79, 0.80, 0.80, 0.76, 0.70 0.78
42#{176} 0.73, 0.54, 0.51 0.59
43#{176} 0.24, 0.25, 0.5, 0.5 0.375

Intervals between injections, 1 to 14 minutes

Normal 2.2, 2.8, 1.45, 1.9 1.90

43#{176} 0.76, 0.6, 0.6 0.63
* Each figure represents the result obtained on one cat.

The results of these experiments show that although the heart

muscle in these cases was free from injury due to the prolonged
fever or toxaemia, the factor of high temperature alone was
sufficient to render it much more susceptible to the effects of
digitalis than is the normal heart muscle.
Great care must therefore be exercised in using digitalis in
large doses for patients with high fever. Indeed, for animals
at a temperature of 43#{176},
the dosage recommended by Eggleston
in the treatment of clinical cases of myocardial insufficiency
(0.14 cat units per pound of patient = 2.2 X 0.14 = 0.308 cat
unit per kilo of patient) would represent about the average
lethal dose per kilo and would be more than the lethal dose for
several of the animals of our series. The results of these experi-
ments is borne out by the clinical experience of T. Stuart Hart
reported in a paper on the effects of digitalis in influenzal bron-
chopneumonia published since our work was finished. Hart
reports that in four cases of his series of influenzal broncho-
pneumonia cases, heart block resulted from the administration
of 3 drachms of tincture of digitalis, which is about half the
dose at which similar effects might be expected in afebrile heart
cases.
For patients with fever, therefore, the larger doses of digitalis
must be avoided, and the effects of the drug must be watched.
with the greatest care during treatment.
 ACTION AND TOXICITY OF DIGITALIS 431

REFERENCES

BAKER, W. F.: Lilly Sci. Bull., Indianapolis, 1913, i, 77.

EGGLESTON, C.: Arch. Int. Med., 1915, xvi, 1; Jour. Am. Med. Assoc., 1917, lxix,
951.
GUNN, J. W. C.: Jour. Pharm. and Exper. Therap., 1914-15, vi, 39.
HART, T. S.: Am. Jour. Med. Sci., 1919, clviii, 649.
HASKELL, C. C.: Lilly Sci. Bull., Indianapolis, 1914, Ser. I, 199.
JAMIESON: Jour. Exper. Med., 1915, xxii, 629.
SOLLMANN, T., MENDENHALL, W. L., AND STINGEL, J. L.: Jour. Pharm., 1914-
1915, vi, 533.
TRENDELENBURG, P.: Arch. f. exper. Path. u. Pharmakol., 1909, lxi, 256.

TH JOUR. OF PUARM. AND EXPER. THERAP., VOL. XV, NO. 5