THE LIVER IN ITS RELATION TO ANAPHYLACTIC

SHOCK

CARL VOEGTLIN m B. M. BERNHEIM

Prom the Department of Pharmacology and the Hunterian Laboratory of Experi-

mental Medicine, The Johns Hopkins University

Received for publication, May 30, 1911

In a recent publication, Manwaring’ reported some interesting

experiments on the mechanism of anaphylactic shock in dogs.
He demonstrated the fact that in the absence of some of the
abdominal organs, especially the liver and the intestine, a shock
cannot be produced. Manwaring does not commit himself to a
definite explanation of this observation, although he is inclined
to believe that the liver, after the first injection of the antigen,
contains a specific antibody which, to a smaller extent, is also
fixed in other tissues. The anaphylactic reaction possibly consists
in a protein digestion. The resulting toxin (anaphylatoxin)
possesses the characteristic vasodilating properties, which cause
finally the symptoms of anaphylactic shock in the dog.
On account of the prime importance of this discovery it seemed
to us well worth while to repeat the experiments quoted with a
somewhat improved technic.
The most striking symptom of anaphylactic shock in dogs
consists in an abrupt fall of blood pressure, which is due to a peri-
pheral action of the toxin on the blood vessels, especially those of
the splanchnic area.2 Inourwork we have considered this symp-
tom a criterion of the existence of anaphylactic shock. Special

1 Bull., Johns Hopkins Hosp. 1910, xxi, 275. Zeitschr. f. Immunitat8forsch.,

1910, viii, 1.
2 Biedi and Kraus, Wien. kim. Woch., 1909, xxii, 363. Pearce and Eisenbrey.
Jour. Infect. Die., 1910, vii, 565.
507
508 CARL VOETGLIN AND B. M. BERNHEIM

attention was paid also to the time of blood coagulation and to any
obvious respiratory changes.
The difficulty of excluding the liver from the general circula-
tion was effected by Manwaring by introducing into the portal
vein a cannula which was connected with a second cannula intro-
duced into the external jugular vein, thus allowing the portal
blood to flow directly to the heart; hirudin had been
previously injected to prevent coagulation of the blood. As
stated by Manwaring, hirudin is highly toxic to dogs and it
seemed to us necessary to eliminate this poison in our work. By
making an Eck flstula,3 combined with ligation of the portal vein
near the hilus of the liver and by temporarily clamping the hepatic
artery, it was made possible to test the animals under practically
normal conditions. Some of our dogs were sensitized before,
some after the operation for the Eck fistula. The results of
these experiments are illustrated by the following protocols:

No. 4410. December , 1910. Bull dog. Weight 10 kilo

Ether anaesthesia. Eck fistula cut. Ligation of portal vein near

the hilus of the liver. Prompt recovery. Beef and bone diet.
December 6. Turned out into yard.
December 22. Weight 9.2 kilo. Wound healed. Animal in good
condition.
Subcutaneous injection of 20 cc. normal horse serum.
January 23, 1911. Weight 11 kilo. had been starved for 12 hours.
3-30 p.m. Light ether anaesthesia. Incision along linea alba.
Branch of femoral artery connected with mercury manometer and
kymograph. Femoral vein used for injection of horse serum. Hepatic
artery clamped by means of bull-dog clamp.
Effect of injection of horse serum on blood pressure:
Hepatic artery clamped: 160 mm.
Hepatic artery released: 90 mm.
Ether removed and wound closed at 4.15 p.m.
5-15 p.m. Dog conscious, but unable to walk.
January 24. Found dead.

‘Bernheim, Homans and Voegtlin, The Jour. of Phar. and Exp. Therapeutics,
Vol. 1, No. 5, 1910.
 THE LIVER IN ITS RELATION TO ANAPHYLACTIC SHOCK 509

Autopsy: considerable hemorrhage in peritoneal cavity. Blood dark

color, hemolized to some extent, does not clot. Eck fistula 3 mm. in
length. No collateral circulation of liver.
Caw3e of death: hemorrhage, due to loss of blood from separated
adhesions.

No. 3610. Large male dog. Weight 13.7 kilo.

November 12, 1910. Had been starved for 24 hours.

Ether anaesthesia. Eck fistula made. Portal vein ligated near hilus
of liver.
Deccmber 22. Dog in excellent condition. Weight 14.2 kilo. Sub
cutaneous injection of 30 cc. of normal horse serum.
January 26, 1911. Weight 14.7 kilo. Tested for anaphylactic
reaction. Light ether anaesthesia. Hepatic artery clamped: Branch
of femoral artery connected with kymograph. Horse serum injected
into femoral vein (20 cc.).
Hepatic artery clamped: Blood pressure 120 mm.
Hepatic artery released: Blood pressure 86 mm.
Dog recovers from anaphylactic shock very slowly. Is all right follow-
ing day and is still living at present time (May 28th).

No. 3410. Black female dog. Weight 11 kilo.

November 5, 1910. Subcutaneous injection of 25 cc. normal horse

serum.
November 6. Ether anaesthesia. Eck fistula made. Recovers soon
after operation. Fed on beef, bread and bones.
November 9. Turned out into yard.
December 17. Animal in excellent condition. Had been starved for
18 hours. Weight 11.2 kilo. Light ether anaesthesia. Hepatic artery
dissected out and clamped by means of bull-dog clamp. Branch of
femoral artery connected with kymograph. Femoral vein used for
injection of horse serum (10 cc.).
Hepatic artery clamped: Blood pressure 170 mm.
Hepatic artery released: Blood pressure 90 mm.
Dog dies after ten minutes with symptoms of asphyxia ad great fall
of blood pressure.
Autopsy: Liver dark red, congested. Blood clots very slowly and
forms only small coagulum. Lungs collapsed.
510 CARL VOEGTLIN AND B. M. BERNHEIM

These experiments conclusively demonstrate the fact that the

liver is essential for the development of anaphylactic shock. We
have never observed the slightest fall in blood pressure at the time
of the second injection of the horse serum when the liver was
excluded from the general circulation. We, therefore, cannot
confirm the statement of Manwaring, that an atypical shock may
develop independently of the liver. Whether this difference is
due to the fact that Manwaring used hirudin in his experi-
ments we are not able to state, as the number of our successful
experiments (six) is too small for such an assertion. It may be
interesting to note that in three of the dogs which were sensitized
alter the operation for the Eck fistula, no shock developed at the
time of the second injection of the horse serum. One might think
that in these cases the anti-anaphylactic mechanism described by
several investigators had rendered the horse serum phylactically
inacti’ e before it had a chance to reach the liver and give rise to
an antibody. This consideration is, as may be strongly empha-
sized, of a hypothetical nature. Still it may have some value as
a working hypothesis in devising further experiments.
The question now arises, What is the mechanism by means of
which the liver develops the anaphylactic shock? One might
think of two possibilities. First, the vasodilating substance is
produced outside of the liver and acts secondarily on the liver
capillaries, causing a dilation in this area which is sufficient to
account for the tremendous fall in arterial pressure. This explan-
ation is not very plausible for the following reason: In sensitized
dogs in which the liver is excluded from the general circulation, no
shock develops after the second injection of the antigen if a cer-
tain period (5 to 10 minutes) has elapsed between the time of
injection and the releasing of the liver ligatures. Had the ana-
phylactic toxin been produced outside of the liver (in any consider-
able amount) it certainly should act after it gets access to the liver
capillaries, unless it is inactivated in some way or another. One
might also expect from the work of Schultz,4 that some symptoms
(peristalsis, defecation, urination) would arise, as this investiga-

‘This Journal, vol. I, p. 549, 1909-10, and vol. II, p. 221, 1910.
 THE LIVER IN ITS RELATION TO ANAPHYLACTIC SHOCK 511

tor had shown that isolated smooth muscles of sensitized animals

(guinea pigs) gives a contraction on being brought into contact
with the antigen used for the sensitization. As a matter of fact,
none of those symptoms can be observed. It is, therefore, very
doubtful that the liver plays only a secondary role in anaphylactic
shock in the sense that the anaphylatoxin is produced mainly in
the circulating blood and fixed tissues (other than the liver) and
that it acts, after its production in specifically dilating the liver
capillaries.
In this investigation we have tested another possibility. Man-
Waring mentioned among other explanations, that anaphylactic
shock might be due to a liberation of some substances normally
present in the cells of the liver and intestine, or appearing in these
tissues only after the sensitization with protein.
The liver of dogs, killed under light ether anaesthesia by bleed-
ing from the carotid artery, was freed from all traces of blood by
perfusion from the portal vein with a 0.8 per cent NaCl solution,
kept at a temperature of 37#{176}
C. Saline extracts (5 cc.) of such
organs injected into normal dogs caused a temporary, but con-
siderable, fall of blood pressure (60 mm.). There seemed to be
no qualitatiye difference in the action of liver extracts of normal
and sensitized animals.
In some of the animals which were injected without the use of
an anaesthetic, defecation and urination followed the injection of
the extract, besides the appearance of muscular weakness and
nervous depression, symptoms found in anaphylactic shock.
The activity of the liver extract is lost by boiling. The filtrate
from the coagulum is lacking in all the characteristic properties.
From this we may conclude that in all probability the active
substance is either of protein or enzymatic nature. Further
experimental work along these lines, which is in progress, is neces-
sary to decide whether or not anaphylactic shock really depends
on the liberation of a definite substance by the liver.