A COMPARISON OF THE PROPHYLACTIC EFFECTS OF

ATROPINE AND EPINEPHRINE IN ANAPHYLACTIC

SHOCK AND ANAPHYLACTOID PHENOMENA FROM
VARIOUS COLLOIDS AND ARSPHENAMINE’
PAUL J. HANZLIK AND HOWARD T. KARSNER

From the Laboratories of Pharmacology and of Pathology, School of Medicine,

Western Reserve University, Cleveland
Received for publication, October 31, 1919

CONTENTS
I. Introduction 425
mm. Methods 427
III. Discussion of results 427
1. Prevention by atropine 441
2. Prevention by epinephrine 443
IV. Conclusions 446

I. INTRODUCTION

The results previously reported by us (1) with the intravenous

injection of agar and other non-protein colloids and also the or-
ganic arsenicals, including arsphenamine, into guinea-pigs indi-
cated that these bear no relationship to anaphylaxis or anaphy-
lactic shock. Concerning agar and some other agents further
proof is necessary to establish whether or not an actual stimu-
lation of the bronchi exists in the accompanying pulmonary dis-
tension. This could be obtained in part, at least, by the use of
atropine and epinephrine as bronchodilators in the prophylactic
treatment of the distension.
That is, if the distension is due to active bronchoconstriction,
such as in anaphylactic shock, this should be prevented or relieved
by atropine as originally shown by Auer (2). Atropine also an-
tagonizes the bronchoconstrictor action of peptone in intact
guinea-pigs (Biedl and Kraus (3)), and of both peptone and
histamine in perfused lungs (Baehr and Pick (4)). The dose
‘This investigation was supported in part by a grant from the Therapeutic
Research Committee of the Council on Pharmacy and Chemistry of the American
Medical Association.
425
426 PAUL J. HANZLIK AND HOWARD T. KARSNER

of atropine bears a quantitative relationship to the size of the

intoxicating dose of protein (5).
With epinephrine the effects are more complicated and not so
certain, dependipg in part on the functional state of the bronchi-
olar musculature (Januschke and Pollak (6)) and in part on the
time of administration, since the action is fleeting. Januschke
and Pollak found that epinephrine relaxes the untreated bronchi
somewhat and the greatest bronchodilator action was obtained
when the bronchi were previously constricted by peptone and
muscarine, but not by histamine and ergotoxin. Epinephrine
also relieves the bronchoconstriction by peptone in guinea-pigs
(Biedl and Kraus (3)) and that produced by peptone and hista-
mine in perfused lungs when high concentrations are used
(Baehr and Pick (4)).
It is apparently on the basis of their bronchodilator effects
(perhaps circulatory, in part) that the use of epinephrine is
recommended by Milian (7), Beeson (8) and Hirano (9) and
atropine by Stokes (10) in the treatment of the “ nitritoid crises”
of arsphenamine poisoning, which is regarded by Stokes as a
form of anaphylaxis. Nolf (11) advises the use of epinephrine
in connection with the disturbances accompanying proteose ther-
apy. Whatever the clinical success with the use of these drugs,
experimentally, at least, the basis has not been clearly established.
It does not necessarily follow that whatever beneficial effects
they may have are due to their action on the bronchioles.
We have, therefore, attempted to test out this and also other
features of anaphylactoid reactions. The main objects of the
work may be stated as follows: (1) Prophylactic treatment of
disturbances accompanying the administration of arsphenamine,
peptone and non-protein colloids experimentally in guinea-pigs
by means of atropine and epinephrine; (2) elucidation of the
mechanism of pulmonary distension with agar by means of these
agents; (3) treatment of anaphylactic shock in serum-sensitized
guinea-pigs with epinephrine, for, so far as we know, this has not
been tried. In dogs Pelz and Jackson (12) found epinephrine to
relax the constricted bronchi in anaphylactic shock if injected
early.
 EFFECTS OF ATROPINE AND EPINEPHRINE 427

II. METHODS
Because of the pulmonary effects, which we were chiefly in-
vestigating, guinea-pigs were chosen as the most suitable animals.
These were injected intravenously in the same way as described
in the previous paper. The various agents used to produce the
respiratory disturbances were prepared in exactly the same way
also. These served as controls for the experiments with atro-
pine and epinephrine reported in this paper. For description of
the results with these, as well as the methods used, the previous
paper (1) should be consulted. It is only necessary to describe
here the method of administering atropine and epinephrine.
Atropine sulphate (0.1 per cent) was always injected intrave-
nously and allowed to act about five minutes before the adniinis-
tration of the agent producing anaphylactoid symptoms and in
the dosage of about 1 mgm. per 100 grams of animal. The usual
effects of increased respiratory rate and hyperexcitability were
observed.
Epinephrine was used intravenously in two ways: (1) Imme-
diately preceding, and (2) together with the agent to be ob-
served. The dosage was that which produces a definite rise of
blood pressure in dogs, namely, 0.5 cc. of 1: 10,000 per kilo or
0.0005 cc. of 1 : 10,000 per gram of guinea-pig. Prompt effects
were produced as indicated by the marked increase in respiratory
and pulse rate. The following agents were studied: arsphena-
mine, agar, dextrin, congo red, peptone, beef serum, typhobac-
ten acacia, pollen extract, starch, althea and serum-sensitized
animals.
HI. DISCUSSION OF RESULTS

The data pertaining to individual experiments with the differ-

ent agents are presented in tables 1 and 2. The descriptions of
the controls, that is, effects of different agents without atropine
and epinephrine as well as normal saline, have been presented in
a previous paper (1) and are omitted in this paper to save space.
Instead, a comparison of all the changes obtained with the dif-
ferent agents in the present series has been made with those of
the controls and the whole is conveniently summarized in table 3.
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THE JOUR. OF PHARM. AND EXPER. THERAP., VOL. XIV. NO. 5

 TABLE 3

Summary of preventive power of atropine and epinephrine against anaphylactoid

. phenomena from various agents injected intravenously as

compared with controls without treatment

COMPLETE4 PARTIAL NONE

Prevention by atropine

Beef serum, whole Agar sol, 0.5 per cent (not fatal, Acacia, 6 per cent (same)
Peptone, 10 per otherwise no change)t Aithea extract, 15 per
cent; small dose Agar sol gel, 1 : 6 (fewer thrombi, cent (about same)
otherwise same, doses larger; Dextrin, 6 per cent
partial prevention to a certain (worse, more disten-
extent) tion)
Arsphenamine, 0.5 per cent Pollen extract, hay fe-
(symptoms less severe, other- ver fall, Mulford
wise same; thrombi present) (about same, perhaps
Beef serum, whole (not fatal) dyspnea less)
Congo red, 1 per cent (symp- Starch (about same)
toms less severe ; no disten-
tion)
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(not fatal, otherwise same)

Serum-sensitization (not fatal;
symptoms and autopsy changes
less severe)
Typhobacterin, Mulford (symp-
toms less severe, otherwise
same)

Prevention by epinephrine

Arsphenamine, 0.5 per cent (less Agar sol, 0.5 per cent
dyspnea, otherwise same) (same; fatal)
Serum-sensitization [not fatal, Agar so! gel, 1 : 6 (same;
more pulmonary hemorrhage, fatal)
otherwise same, epinephrin in- Dextrin, 6 per cent
jected with antigen in one, and (same)
just preceding (less than 2 Peptone, 10 per cent,
minutes) in the other animal] small doses (worse;
thrombi and hemor-
rhages; otherwise
same)
Serum-sensitization (f a-
tal; epinephrine in-
jected after antigen in
one, and 3 minutes be-
fore in another animal)
Starch, 6 per cent (same)

H Means complete recovery as to absence of symptoms and autopsy, and

microscopic changes in lungs, and approaching normal.

t Remarks in parenthesis refer to differences from controls injected with the
same kind of agent and dose without atropine or epinephrine as the case may be.
440
 EFFECTS OF ATROPINE AND EPINEPHRINE 441

1 . Prevention by atropine

From the summary in table 3, it is seen that atropine in the

dosage of 0.01 mgm. per gram of animal, equivalent to 600 to
1000 times the average therapeutic dose for man, acts favorably
as a preventive for the effects of beef serum and peptone. Com-
plete prevention as to symptoms, autopsy and microscopic
changes were obtained with beef serum in one animal and some-
what less in another. The usual effects of a small dose of pep-
tone, equivalent to the therapeutic dose recommended by Nolf
(1 1) in the treatment of infectious and febrile conditions, were
completely prevented by atropine. The protection was not so
complete with a dose once as large ; but death, at least, was
prevented.
The partial protection afforded by atropine against the effects
of agar sol, agar sol-gel, arsphenamirie, congo red, serum-sensi-
tization and typhobacterin was concerned principally with dim-
inution in the severity of symptoms. Fatalities from agar sol,
agar sol-gel and the anaphylactic (serum-sensitized) animals were
prevented. So far as autopsy and microscopic changes are con-
cerned there was practically no difference from the controls.
The partial prevention from the effects of beef serum and peptone
have been discussed above.
Concerning agar sol-gel, the interpretation of “partial pre-
vention “ by atropine is perhaps liberal. That is, the controls
received a small dosage, while in the present experiments the
dosage was practically fatal as shown by the results of Novy and
DeKruif (12) and our own experiments with agar sol-gel and epi-
nephrine, in which fatalities occurred with the same dosage.
For this reason, the results with atropine are interpreted as mdi-
cating some protection (as to fatality) , and there is certainly no
doubt about this with agar sol. However, the atropine did not
prevent the general effects of agar sol-gel, namely, symptoms of
respiratory distress, marked pulmonary distention, hemorrhages
and thrombi, although the thrombi were somewhat less conspic-
uous. These experiments, therefore, so far as the mechanism of
agar sol-gel action is concerned, are indecisive as originally hoped
442 PAUL J. HANZLIK AND HOWARD T. KARSNER

for. The comparisons which we hoped to obtain with various

smooth muscle (bronchiolar) stimulants, namely, peptone, beef-
serum and serum-sensitized animals, are too variable to permit
the free use of these, although the tendency is favorable with
beef serum and peptone. That is, complete prevention was ob-
tamed with these augmentors of smooth muscle (bronchiolar,
etc.) in some animals and this was certainly more than was ob-
tamed with agar, indicating that the mechanism of agar action
is different from peptone and similar augmentors of plain muscle.
This would mean that the anaphylactoid effects of agar are not
like or partake of true anaphylactic shock. However, this state-
ment is made reservedly considering the variabifity of results
obtained with the smooth muscle stimulants in this paper.
This is even more true of the results with epinephrine and
agar sol-gel presently to be discussed. Because of this, and a
certain amount of variability in the response of guinea-pigs to
the various agents that have been tried, including agar, it is
manifestly impossible to settle the question of how agar acts
merely by experiments with intact animals. The matter can
finally be settled by perfusion of the lungs. In anticipation of
results along this line to be published later, it can be stated that
agar acts differently from the various smooth muscle stimulants
and, therefore, bears no relation to anaphylactic shock.
A word is necessary as to the mechanism of the partial amelior-
ation obtained with atropine in the majority of our experiments.
The following possibilities exist ; (1) sufficient (moderate or even
less) bronchial relaxation due to the atropine with prevention of
the fatal effects of asphyxia; (2) improvement in or diminished
circulatory disturbances such as cardiac dilatation, from paral-
ysis of the parasympathetic endings by atropine ; (3) respiratory
stimulation by atropine with consequent amelioration of asphyxia;
(4) ineffective central parasympathetic stimulation from as-
phyxia owing to paralysis of vagus endings by atropine. Whether
any particular one or all of these factors are operative we do not
know, and the conditions were not suitable for investigation of
this.
 EFFECTS OF ATROPINE AND EPINEPHRINE 443

However, it is quite patent that mere bronchial relaxation

from atropine need not be assumed as responsible for the bene-
ficial effects of relief that it may give, particularly with such a
drug as arsphenamine, and probably also of congo red. If this
is true, the further assumption that the arsphenamine reactions
are a form of anaphylactic shock is certainly unjustified. This is
believed to be the case. The results reported in our previous
paper fortify this conclusion, since arsphenamine did not at all
produce effects resembling those of anaphylaxis or anaphylactic
shock. On the contrary, the disturbances were regarded to be
of circulatory origin and, therefore, any amelioration that atro-
pine may give is to be attributed to an improvement in the cir-
culation rather than the supposed bronchiolar effects, at least in
guinea-pigs. There is no good reason to believe that human
individuals behave differently.
Atropine was found to give no demonstrable relief from the
symptoms and disturbances produced by acacia, althea, dextrin,
pollen extract and starch. Because of this and the reasons pre-
sented in our previous paper it is reasonable to conclude that
the effects of these agents bear no relationship to anaphylaxis or
anaphylactic shock.
Conclusions. The intravenous injection of atropine in guinea-
pigs in the dosage of 0.01 mgm. per gram of body weight can
completely prevent the toxic effects produced by the intravenous
injection of beef serum, and peptone in doses corresponding to
those used in the proteose therapy of Nolf. Partial protection
was obtained against the effects (principally symptoms of re-
spiratory distress) of agar sol, agar sol-gel, arsphenamine, congo
red, peptone (large doses), serum-sensitization (anaphylactic
shock) and typhobacterin. No protection was obtained against
the effects of acacia, althea, dextrin, pollen extract and starch.

2. Prevention by epinephrine

As indicated by the summary in table 3, protection with epi-

nephrine against the anaphylactoid symptoms produced by va-
rious agents is even less than with atropine. Epinephrine itself
444 PAUL J. HANZLIK AND HOWARD T. KARSNER

(in the dosage used) produces rather profound effects such as in-
creased respiration and pulmonary hemorrhages. Therefore, the
experiments were limited to a number of the more important
agents, namely, agar so!, agar sol-gel, dextrin, peptone, serum
sensitization, starch and arsphenamine.
Partial protection was obtained only against 2 of these, namely
arsphenamine and in serum-sensitization (anaphylactic shock).
In the arsphenamine animals there was merely some amelioration
of symptoms, the remaining effects being present as in the con-
trols. This amelioration is probably mainly concerned with the
circulation resulting in relief from the asphyxia due in turn to the
depressant action of arsenic as in untreated animals. The effects
of epinephrine on previously untreated (unconstricted) bronchi-
oles being indeed doubtful, and this taken together with the pos-
sibilities indicated above with atropin, and the fact that the ef-
fects of arsphenamine in control animals do not resemble those
of true anaphylactic shock, confirms the conviction that what-
ever beneficial effects epinephrine may have in the disturbances
from arsphenamine are concerned with improvement in the cir-
culation. The burden of proof rests on those who attribute the
benefits to bronchiolar relaxation, and consequently amelioration
of anaphylactic shock or anaphylaxis.
It is seen that the protective powers of epinephrine in true
anaphylactic shock vary with the time of administration of the
drug (see tables 2 and 3). In two animals death was prevented
when the epinephrine was injected together with and just pre-
ceding the injection of the antigen (horse-serum). On the other
hand, when a greater interval elapsed between the injection of
epinephrine and antigen, the two animals injected died of ana-
phylactic shock in the usual way. In one animal the epinephrine
was injected three minutes before and in the other some time
after the antigen when the conditions for eliciting the symptoms
of anaphylactic shock were under mobilization and leading to a
fatal issue from the bronchiolar spasm. These results agree per-
fectly with the well known pharmacological actions of epinephrine
on the bronchi. That is, epinephrine is effective as a dilator
only on constricted bronchioles, when it is present in effective
 EFFECTS OF ATROPINE AND EPINEPHRINE 445

concentration , which must be at the time constriction is occurring

or just preceding it. After the bronchiolar constriction has oc-
curred, as it does rather violently and with remarkable rapidity
in anaphylactic shock, epinephrine is no longer active because a
fatal issue has practically supervened. Larger doses might per-
haps still be effective, but these were practically precluded in
our experiments with guinea-pigs because of the extensive pul-
monary hemorrhages produced by epinephrine itself and the con-
sequent complications. As indicated by the results obtained,
epinephrine is effective as a prophylactic in anaphylactic shock
of guinea-pigs when injected together with the antigen or imme-
diately preceding it.
These results with epinephrine in anaphylactic shock, throw
some light on the mechanism of agar action and similar colloids.
We have seen how epinephrine acts as a prophylactic in anaphy-
lactic shock ?hen injected under proper conditions, and this is
due, no doubt, to an alleviation of the bronchoconstriction as
indicated by the diminished pulmonary distention at autopsy,
and other effects. Epinephrine was injected in the same way
in the experiments with agar, but practically no protection what-
soever was obtained. In fact, certain effects (pulmonary hemor-
rhages) were accentuated. The fatalities were greater. This is
so because the mechanism through which epinephrine exerts its
beneficial effects is absent in agar action, namely, active broncho-
constriction. Therefore, the pulmonary distention from agar
and similarly acting agents cannot be due to the same cause as in
anaphylaxis or anaphylactic shock.
Besides being inefficient against agar, epinephrine furnished
no protection against the effects of dextrin, and small doses of
peptone and starch. On the contrary, the incidence of pulmonary
hemorrhages was increased. Experimentally at least, the pro-
tective power of epinephrine in the proteose therapy of Noif
has not been confirmed.
Conclusions. When injected together with the antigen or im-
mediately preceding it, epinephrine in the dosage of 0.0005 cc.
of 1: 10,000 per gram of body weight intravenously prevents
death from true anaphylactic shock in guinea-pigs. The partial
446 PAUL J. HANZLIK AND HOWARD T. KARSNER

protection afforded by epinephrine intravenously against the

symptoms from arsphenamine disturbances is attributed to cir-
culatory improvement. Epinephrine exerts no protection against
the effects of agar sol, agar sol-gel, dextrin, peptone (small
doses) , starch, and when injected after or too long before the
antigen in serum sensitized animals.
On the basis of the results obtained with atrOpin and epi-
nephrine, the mechanism of action of agar and similar agents bears
no relationship to true anaphylaxis or anaphylactic shock.

Iv. CONCLUSIONS

1 The. intravenous injection of atropine in guinea-pigs in the

dosage of 0.01 mgm. per gram of body weight can completely
prevent the toxic effects produced by the intravenous injection
of beef serum ; and peptone in doses corresponding to those used
in the proteose therapy of Nolf. Partial protection was obtained
against the effects (principally symptoms of respiratory distress)
of agar so!, agar sol-gel, arsphenamine, congo red; peptone (lar-
ger doses), serum-sensitization (death in anaphylactic shock) and
typhobacterin. No protection was obtained against the effects
of acacia, aithea, dextrin, pollen extract and starch. -

2. When injected together with the antigen or immediately

preceding it, epinephrine in the dosage of 0.0005 cc. of 1 : 10,000
per gram of body weight intravenously prevents death from true
anaphylactic shock in guinea-pigs. The partial protection af-
forded by epinephrine (intravenously) against the symptoms of
arsphenamine disturbances is attributed to circulatory improve-
ment. Epinephrine exerts no protection against the effects of
agar so!, agar sol-gel, dextrin, peptone (small doses), starch and
when injected after or too long before the antigen in serum-
sensitized animals.
On the basis of the results obtained with atropine and epi-
nephrine, the mechanism of action of agar and similar agents
bears no relationship to true anaphylaxis or anaphylactic shock.
 EFFECTS OF ATROPINE AND EPINEPHRINE 447

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