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AN ANALYSIS OF THE NERVOUS CONTROL OF THE
CARDIOVASCULAR CHANGES DURING OCCLU-
SION OF THE HEAD ARTERIES IN CATS

BY

CORA SENNER WINKIN

SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR

THE DEGREE OF DOCTOR OF PHILOSOPHY, IN THE FACULTY

OF PURE SCIENCE, COLUMBIA UNIVERSITY

REPRINTED FROM THE AMERICAN JOURNAL OP PHYSIOLOGY,

Vol. 60, No. 1, p. 1, March, 1922

Baltimore, Maryland

BIOLOGY
LIBRARY

G

Reprinted from THE AMERICAN JOURNAL OF PHYSIOLOGY

Vol. 60, No. 1, March, 1922

AN ANALYSIS OF THE NERVOUS CONTROL OF THE CAR-
DIOVASCULAR CHANGES DURING OCCLUSION
OF THE HEAD ARTERIES IN CATS

CORA SENNER WINKIN

From the Department of Physiology, Columbia University

Received for publication November 4, 1921

STATEMENT OF THE PROBLEM.1 The relations dealt with in this
study are the cardio-vascular relations found in the mammalian or-
ganism under extreme conditions of stress. The procedure of the ex-
periments, occlusion of the head arteries, gives a complete anemia of the
brain, and thus produces a profound change in the internal environment
of the animal. To this the mammal tends to respond by a series of
vigorous reactions. These reactions, moreover, seem to go in a direc-
tion opposite to that of the change in internal conditions of a par-
ticular group of cells. Thus, with an asphyxial accumulation of carbon
dioxide in the medium surrounding the critical medullary cells, there
is released an entire series of reactions which, could they all be carried
to completion, would reduce the tension of this gas in the body fluids
of the cerebral region. Prominent among these reactions is a great and
prolonged rise of blood pressure, involving the extreme resources of the
organism, tending to send a greater volume of blood to the anemic
regions, and hence to decrease the concentration of the carbon dioxide
in the nerve cells of the medulla oblongata. In the cat, this anemic
rise of blood pressure can be well controlled anatomically, and is suscep-

1 A preliminary note has been published in Proc. Soc. Exper. Biol. and Med.,
1921, xviii, 155.

1

THE AMERICAN JOURNAL OP PHYSIOLOGY, VOL. 60, NO. 1

4787 t 6

2 CORA SENNER WINKIN

tible of rather exact registration. Moreover, artificial respiration may
be maintained throughout the reaction, and thus the activity of the
peripheral mechanisms, the heart, blood vessels and internal secretions,
be kept free from the central asphyxial changes. Furthermore, under
artificial respiration, the reaction may be obtained repeatedly in the
same animal. It has therefore offered an opportunity for analyzing
the factors involved in such an emergency reaction to inimical condi-
tions in the central mechanism.

Since the work of Ludwig, Cyon and Bezold in the sixties, the im-
portance of the splanchnic vasomotor fibers for the production of
extensive changes in blood pressure has been recognized. The re-
lated action of the discharge of adrenalin into the blood stream has
recently received considerable emphasis. However, the degree to
which either the splanchnic constrictor fibers or the secretion of the
adrenal glands is involved under such conditions of stress as evoke the
anemic rise, has not been evaluated with sufficient accuracy. This
study has therefore been concerned particularly with the efferent
nervous pathways of the "anemic rise" of pressure: above all, with the
degree to which it involves the splanchnic constrictor fibers. The
extent to which splanchnic involvement has made for adrenal activity
has then been investigated. Finally, the influence of the cardiac
innervation, insofar as this may directly effect changes in the level of
blood pressure during anemia, has also been examined.

Through the restriction of the effect of the arterial occlusion to the
head region alone, the activation of the vascular response by the medulla
oblongata is under close experimental control. Accordingly, the cen-
tral relations of the various nervous levels controlling the efferent
channels could also be investigated. Indeed, the analysis of the
peripheral factors was in large part undertaken in order to establish
more accurately the functional organization of the central nervous
mechanism upon which the vascular response depends, that is, the
extent to which the peripheral agents executing the vascular responses
of the intact animal are activated either by the higher nervous levels,
or by the spinal cord alone.

This analysis was undertaken in connection with the studies on the
central nervous system carried out under Prof. F. H. Pike, which have
dealt particularly with the bearing of its organization on the problem
of "spinal shock." In connection with the problems here opened up
it was necessary to ascertain the exact nature of the peripheral and
central factors controlling the typical vascular response in animals in

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 3

which either no lesions within the central system were undertaken, or
when these were inflicted, no interval for recovery after the operation
was allowed. In comparison with such data, a study of the vascular
responses after recovery from transection of the spinal cord could be
undertaken more intelligently, and the actual changes wrought by the
so-called shock effect evaluated with greater precision.

HISTORY OF THE METHOD. Initiated by the very early work on
abdominal ligation of Stenson (1) and Swammerdam (2), Magendie
and Poiseuille (3) and Sir Astley Cooper (4) in the early nineteenth
century worked out the procedure of cerebral ligation, particularly
the isolation of the four chief arterial channels to the head, and noted
the circulatory changes which followed. Batelli (5) and Hill (6) have
given the earlier history of the procedure in some detail.

The experiments of the eighteen fifties and sixties led to the recogni-
tion of the nervous organs as the chief agents in activating the changes
following arterial ligation: thus the work of Kussmaul and Tenner
(7), Brown Sequard (8), (9) and Vulpian (10) on the head area and of
Schiffer (11) on the spinal cord. The emphasis of the importance of
the medulla for the maintenance of life as given by the work of Le
Gallois and its extension by Flourens (12) was still more increased by
the localization in the same region of the vasoconstrictor center as soon
accomplished by Ludwig (13), Owsjannikow and Dittmar, and soon,
led up to the most complete studies on occlusion of the head arteries
carried out by Sigmund Mayer (14), (15). Mayer not only described
the series of changes following anemia with great detail and accuracy,
but also recognized that the elicitation of the anemic rise was dependent
on conditions of functional conductivity within the brain stem. He
also saw that occlusion of the head arteries was comparable to decapi-
tation with the knife, and that the various functions retained following
cerebral ligation were all to be attributed to the activity of the spinal
cord, notably the residual spinal level of blood pressure of 50 to 60 mm.

Gouty (16) produced circulatory obstruction in the head region by the
injection of lycopodium spores. This work, contemporaneous with
that of Mayer and equally detailed, but carried out under the influence
of the earlier work of Goltz (17), (18) and Vulpian, stressed the residual
spinal functions, maintained following isolation of the medulla. Sub-
sequent work on cerebral anemia was almost exclusively done from
this point of view. Thus the papers of Schlesinger (20), Kowalewsky
and Adamtik (21), Bochefontaine and Vulpian (22), Mayer (23),
attempted to combat this viewpoint by an analysis of the differential

4 CORA SENNER WINKIN

*

effect of compression of the abdominal aorta. Konow and Stenbeck
(24) and Landergren (25) more recently stressed the functional sur-
vival of the cord in the decapitated animal preparation. The residual
spinal blood pressure was analyzed by Pike (26) (1912) who showed
that afferent impulses, presumably from skeletal muscles, were re-
sponsible for it. His observation that a further fall occurs on paralysis
of skeletal muscles by curare has recently been confirmed by Langley,
1919 (27).

A revival of interest in the central relations of the asphyxial picture,
particularly to the higher nervous levels, was in part achieved through
the reexamination of the problems of resuscitation of the organism by
Stewart, (28), (29), (30), (31), (32), (33) Pike and Guthrie. These
observations threw sharply into relief the dependence of resuscitation
on the medullary respiratory and vasoconstrictor mechanisms rather
than on other organs, which, whatever their importance, were found
neither as sensitive nor as susceptible as the medullary and higher
cells. The functional activity of the medulla was abolished 15 minutes
or more, and in its abeyance, no independent existence of the animal
could be reestablished. An analysis of the conditions of so-called
spinal shock was undertaken by Pike (34), (35), (26), who employed
the procedure of cerebral anemia, and the vascular response obtainable
from it, as a means of comparing the various functional levels of the
central nervous system. In this way the central relations, particularly
to the bulbar levels, of the vascular response in anemia were clearly
indicated. A further extension of this problem is found in the study
Of Yates (36), in which the response to anemia was used as a criterion
of the degree of recovery of the vascular system following spinal tran-
section. These studies bring out the importance of the maintenance
of medullary activity as the essential factor in the avoidance of a
shock effect and the relative incompetence of the spinal cord in the
initiation of significant adaptive responses.

Consideration of the excitatory and depressing effects of the blood
gases has led toward a recognition of their importance in influencing
the behavior of the medullary cells. The literature of the subject is
reviewed by Bethe (37), Hill and Flack (38), Hasselbach (39). Pike,
Coombs and Hastings (40), (41) have pointed out the adaptive nature
of the nervous changes induced by a rapid lowering of CO2 tension in
dyspneic blood, and have suggested that in thus acting in a direction
opposite to environmental change, the organism meets the conditions
by adjustment of physical equilibrium as prescribed by le Chatelier's

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 5

theorem. Mathison (42), (43) has shown the very much greater sensi-
tivity of the medullary over the spinal cells in their response to the
asphyxial agents such as increased CO2 or lactic acid, or decreased
oxygen. Pike and Scott (44) have discussed the regulation of H-ion
concentration in connection with the regulation of mammalian internal
environment.

METHOD. In the present study advantage was taken of the rever-
sibility of the procedure of cerebral anemia. The ability to repeat the
initial stimulating effect of the insult on the medullary cells was ex-
ploited, rather than its abolition of conductivity within them. The
specific problems attacked were dealt with in terms of the intensity and
duration of the anemic rise, under given central and peripheral lesions.
A seemingly significant series of observations on the changes at the
periphery could be obtained by means of the pronounced differences
in the character of the curves recorded.

Mayer (14) had called attention to the fact that the magnitude of
the vasomotor effect under asphyxia could be approached only by the
effect of compression of the thoracic aorta, or injection of strychnine.
From Mathison's work (42), (43), especially from his conception that
all forms of asphyxia are due to definite increase of the acid content
of the blood, cerebral anemia can probably be assumed always to be
acting at a maximum. The procedure followed was essentially that
indicated by Stewart (28). As here used, the emphasis lay especially
on the restriction of the occlusion time to as narrow a limit as possible,
in order to insure more rapid recovery. Accordingly, the shortest
possible occlusion period was uniformly employed and as a routine
procedure the head arteries were released as soon as the spontaneous
fall of pressure at the end of the response set in.

The experiments were all carried out on cats. Ether was the anes-
thetic uniformly employed, and administered by tracheal cannula.
The purpose of the study was essentially to determine the degree of
involvement of the chief factors concerned, rather than their minute
evaluation. This has been left for subsequent study. The extensive
series of Stewart served as a basis of comparison and control.

The head arteries were all secured outside the thoracic wall, the
branches of the left subclavian, separately secured in the axilla, the
right carotid, and right subclavian from within the carotid sheath in
the neck; the left carotid held the blood pressure cannula. All the
arteries were kept under ligatures ready to be occluded by clamps at
the convenience of the experimenter. Since there was no interference

6 CORA SENNER WINKIN

with extra-pulmonic pressure through the operative procedure, artificial
respiration could be dispensed with as long as the medullary cells
remained functional.

Prior to occlusion, ether was reduced until various obvious tests
of the activity of the brain stem could be secured, the return of a vigorous
corneal reflex always being awaited before the circulatory arrest was
made. With the elicitation of the corneal reflex, artificial respiration
was begun, and the clamps on the arteries immediately adjusted. Care
is needed to include all the arterial branches isolated in the clamps.

With the adjustment of the clamps, the entire series of peripheral
effects follows; the eye reflexes are immediately lost, and within about
20 seconds the more marked peripheral effects are released. Deep and
labored breathing sets in, skeletal convulsions appear, and a sharp rise
of blood pressure is recorded which often reaches 200 mm. Hg. or more
(fig. 5a). This frequently outlasts the other functions; the pressure
may not begin to fall until some 10 to 80 seconds after respiratory
failure.

The time from the shutting off of the arteries to the circulatory
failure is then taken as the complete occlusion time. On the average,
this occupied 3 minutes.

Immediately following reestablishment of the circulation there is a
profound depression of all functions. Blood pressure continues falling
markedly when the arteries are released, and finally reaches a level of
about 50 mm. No other medullary responses are elicitable at this time.
Artificial respiration is, of course, maintained throughout the period of
depression, and until such time as the bulbar functions again become
evident.

If no further lesions are inflicted, occlusions of 3 to 4 minutes are
usually followed by a beginning of recovery within 5 to 7 minutes after
release of the arteries. Blood pressure usually starts rising first, and
after a rise of 10 to 15 mm. spontaneous respiratory gasps reappear.
Pressure continues to rise, respiratory movements become more and
more frequent; soon normal pressure is regained and the animal breathes
quietly and regularly. Ten to 15 minutes after release of the arteries,
pressure is usually normal, vibrissae are erect, and the corneal reflex
is again elicitable. At this point, a renewed occlusion of the head
arteries may be done and the entire cycle repeated.

The modification of anatomical conditions was usually carried out
in the interval of depression following a control occlusion. In this
way further etherization was avoided. Except under certain specified

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 7

conditions, the various lesions did not materially change or delay the
picture of the recovery outlined.

THE EXPERIMENTAL RESULTS. 1 . The role of the splanchnic constric-
tor fibers in the rise of pressure during cerebral anemia: Following the
work of Claude Bernard in 1848 who showed that the section of the
cervical cord caused a considerable fall of blood pressure, Bezold, Ludwig
and Cyons (46), (47), (48), (49), (50) measured- the magnitude of these
changes and showed their dependence on the integrity of the splanchnic
system. There was thus demonstrated the relation of the blood pressure
changes to the level which is maintained after the continuity of the cord
with the brain has been interrupted.

Mall (51) showed that frequently 27 per cent of the blood in dogs was
transferred by the splanchnic system, thus explaining the great increase
•of volume in the extremities during rises of systemic pressure (52).
Edwards (53) calculated that 85 cc. of blood in dogs were trans-
located under splanchnic stimulation. In spite of its probable involve-
ment in the powerful vasomotor response of the anemic rise, very little
direct evidence for its participation has been obtained. Hill's (46)
reference to the splanchnic nerves in cerebral anemia is, so far as can
be ascertained, largely by way of implication. For asphyxia itself
both V. Anrep (54) and Cathcart and Clark (55) have argued for con-
siderable splanchnic participation from the dependence on the central
nervous system of the adrenalin release obtained. Finally, some in-
direct evidence for splanchnic nerve involvement has been obtained by
section of the spinal cord in cerebral occlusion. Nawalichin (56)
found that the vasomotor changes following obstruction of the cere-
bral circulation were practically obliterated when the cord had been
sectioned in the cervical region. The same observation was made by
Stewart (28).

In order to obtain any exact, or possibly even quantitative, evalua-
tion of the actual involvement of the splanchnic system, other factors
concerned in the maintenance and change of blood pressure must be
isolated. Three factors in the nervous regulation must above all be
properly controlled. These are (a), the indirect effect of the activity
of the skeletal muscles; (&), the influence of the cardiac innervation; and
(c), the non-splanchnic constrictor (or possibly dilator) fibers in the
vasomotor system.

a. The influence of the skeletal muscles in the anemic rise. The
older authors, Mayer and Gouty, used curarized animals, rabbits and
dogs, for their experiments on cerebral occlusions, and reported anemic

8 CORA SENNER WINKIN

rises as great in magnitude and duration as those recorded by Stewart
(28) or those herein obtained. The relative volume of blood held in
these animals within the splanchnic system, as compared with that
controlled by the somatic innervation is, however, somewhat different
from that in cats. Little experimental attention was here given to
this problem. In one animal, however, curare was injected and a vigor-
ous anemic response was obtained. The occlusion time was normal (3
minutes) ; the anemic increment, however, was below the average, being
only 80 mm. In another cat, both sciatics and the brachial plexuses
on both sides were divided. Pressure did not fall after the lesions.
Both stellate ganglia were then removed. The animal gave an anemic
increment of 100 mm. Hg.

It seems accordingly that the muscular factor is of no primary signifi-
cance in either the initiation or the maintenance of the anemic rise.
The fact that no great depression of the level of blood pressure results
in spite of extensive elimination of muscular innervation is interesting
in comparison with subsequent results, and effectively contrasts the
influence of skeletal innervation and visceral innervation on blood pres-
sure.

b. The influence of the cardiac innervation on the anemic rise. The
influence of the cardiac nerves on the anemic rise may be exerted in
either of two ways. The change in rate and amplitude of the heart
beat may affect the output per minute as emphasized by Tigerstedt, (57)
or afferent impulses aroused within the heart may affect reflexly the
efferent cardio-vascular innervation as discussed by Hill (59). It is
conceivable that in either of these ways, or both, the heart may influence
significantly the level of blood pressure.

Frank (57), mathematically, and Erlanger (58) by sphygmomano-
metric measurements, have attempted to show that the output of the
heart remained a constant, or in other words that pulse pressure times
pulse rate remains a constant. Wickwire (60) has shown that the
usual compensatory changes in heart rate to a change in the systemic
blood pressure may be absent in deep anesthesia or in cases of restric-
tion of the volume of blood flow to the brain. Under normal circum-
stances, Erlanger's statement probably holds true, but may not
necessarily apply under critical conditions.

1. Effect of the vagus. Mosso (61), Gouty- and Stewart found that
following the first short rise in blood pressure (which in the intact ani-
mal is never very great) there is a considerable slowing of the pulse.
As long as this slowing of the pulse persists, pressure ceases to rise, and

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 9

is indeed often lowered. After about half a minute of this effect, the
heart seems to break away from this retardation, and the beat is, if
anything, accelerated and pressure immediately rises to the maximum
level which is maintained until its final fall. The slowing of the heart
rate and the depression of blood pressure gives the anemic rise its
typical double crest. Both Gouty (16) and Stewart (26) saw this
double crest disappear on section of the vagi, leaving a smooth curve,
which attains its maximum height somewhat more rapidly, but is not
otherwise greatly altered in time or intensity.

Bilateral vagotomy has been done only incidentally to other lesions.
The results confirm the earlier findings.

2. Excision of the stellate ganglia. Section of the accelerators as the
only lesion was undertaken in five cats, all except one dissection being
made in the open thorax under artificial respiration. In all cases the
entire stellate ganglion was removed. The mass of nervous tissue was
secured by a hemostat and this then cut away from all the connections
by which it was held, until the hemostat could be removed without
tearing. All the records therefore give a picture of the effects obtained
by excision of the entire ganglion including, of course, those additional
accelerator fibers recorded by Ranson, Spadolini and Wickwire (60),
which reach the stellate ganglion by way of the superior cervical
ganglion.

Hunt (62) recorded a loss of pressure on section of the stellate ganglia.
Wickwire found a considerable loss (60 mm.) on their section, when this
was undertaken without a previous vagotomy. In two cats, 1 and 3,
a similar depression was noted. In cat 2, however, the fall was only
20 mm. In cat 7, in which pressure was already very low, no change
at all was noted.

Section of the accelerators on both sides seems, like double vagotomy,
to have a typical effect on the contour of the curve. It also tends to
obliterate the double nature of the curve, which then more closely
approaches a single peak. Characteristically, section of the accelera-
tors imparts to the anemic rise a marked plateau effect. After a
relatively restricted latent period, pressure rises sharply to its maximum
level (fig. 1, occlusion 2), near which it is maintained until just prior
to its final fall, when it may again strike the greatest height. The
anemic increment of pressure for the five cats examined lay between
120 and 160 mm. Hg. Such a vagus effect as made itself felt, curiously
enough, appeared somewhat later than when the accelerators were
intact, and the slowing was recorded at the crest of the wave at a very

10 CORA SENNER WINKIN

high level of blood pressure. Occasionally a sharp depressor effect
may be recorded, which is rapidly compensated for; this effect gives an
M-shaped appearance to the curve. On the whole, with the stellate
ganglia excised, pressor responses are more promptly executed and
longer maintained. In six additional cats, section of the accelerators
was complicated by other lesions. In the two cases in which it was
preceded by low section of the sympathetic chain, an anemic increment
of 80 mm. was obtained in each.

Fig. 1. Cat 4; Occlusion 1. Cerebral anemia, anomalous contour of curve.
In this, great fall of pressure replaces the rise ordinarily obtained. The levels of
blood pressure before anemia, after anemia and after recovery of bulbar function
are shown. Head arteries were released immediately after the rise of pressure,
in which the pre-occlusion level was partially recovered. Pressure fell sub-
sequently as low as the lowest point obtained during anemia, but regained 90 mm.
above this level with the return of bulbar function.

Occlusion 2: Cerebral anemia; record following excision of both stellate gan-
glia. When anemia is induced, pressure is 50 mm. lower than after recovery of
bulbar function, prior to section of the stellates; M-shaped curve, showing sharp
immediate rise of pressure, almost to its maximal height; vagus effect appears at
crest of wave. Temporary recovery on release of head arteries, followed by fall
to lowest level of pressure (55 mm. Hg. above base line) . This low level was three
times reached in this animal. Final rise of pressure on renewed return of res-
piration and other medullary activities.

Each occlusion occupied 3 minutes.

CAKDIO-VASCTJLAR CHANGES DURING CEREBRAL ANEMIA 11

3. Excision of the entire cardiac innervation. In three cats the sec-
t'on of both vagi and accelerators was undertaken without any previous
lesion. In two of them, section of the vagi was undertaken first, and
in both cases a rise of 20 mm. obtained. Subsequent section of the
stellates did not appreciably lower (by more than 5 mm.) the original
level. The order in which the section of the cardiac nerves is carried
out is, therefore, significant for the general level of pressure, and is
again in agreement with Miss Wickwire's findings. Several successive
curves were obtained from cat 5. The anemic increment was in these
cases somewhat reduced, increments of 80 to 100 mm. being obtained
after elimination of all the extrinsic cardiac nerves. When all cardiac
nerves were sectioned, the curve tended to be smooth, the initial acute
rise not being at all delayed. No change in the occlusion time was
noted.

Recovery from occlusion after excision of one or both sets of the
extrinsic cardiac nerves was uniformly o.btained. The time interval
of recovery was in no way different from that in normal animals.

In additional cats to be mentioned later, excision of the extrinsic
innervation was preceded by a low section in the sympathetic chain.
One animal gave an even higher anemic increment (125 mm. Hg.)
than is usually obtained after section of the cardiac nerves alone.

In all the curves of reaction to anemia from animals with denervated
hearts, pressure was not uniformly maintained at the maximal level.
In two cases the pressure dropped immediately; in the rest (4 cases)
a plateau was maintained.

4- Effect of the cardiac innervation on the anemic rise. Neither lesion
of the cardiac innervation, as a whole, nor of the vagi, nor of the stellate
ganglia separately, greatly affects the blood pressure response. Its
duration seems to be fairly constant for the given individual tested.
Excision of the entire cardiac innervation may reduce the anemic merer
ment in some cases, but the reduction when it occurs does not seem to
be considerable.

However, the cardiac nerves seem to have considerable influence on
the level of blood pressure in the more detailed relations of the anemic
rise, especially in the early part of the reaction. From the results
of the section of the accelerators, particularly the abruptness with which
an intense rise appears immediately on occlusion of the head arteries,
it seems that the conception of the action of the accelerators must be
extended. Marey asserted in 1881 that with the vagus intact no very
great rise of pressure can be obtained. Indeed, as long as the vagi are

12 CORA SENNER WINKIN

functional the maximal anemic increment is not immediately obtained,
and cannot be reached in tlie early part of the occlusion unless the
vagi be sectioned. The same seems to follow also for the accelerators
since, when they are removed, the vagus cannot prevent the immediate
and considerable augmentation of pressure. In the earlier part of the
anemic response, the combined action of the entire cardiac innervation
seems to effect a considerable check on the rapid rise of blood pressure.
This may be due to afferent or efferent impulses, but the accelerators
seem to be involved as well as the vagi.

The relations of the cardiac innervation to the second rise of pressure
are not so clear. Stewart (28) attributed this in part to accelerator
fibers in the stellate ganglion, and possibly in the vagus, but recently
Stewart and Rogofif (63) have demonstrated the possibility of producing

Fig. 2. Cat 23; cerebral anemia. Splanchnic nerves sectioned at their entry
to coeliac ganglia. Occlusion time 3 minutes. Skeletal convulsions and res-
piratory spasms evident. The only factors in the vascular reaction recognizable
in the tracing are the changes in heart rate. This is accompanied by a very slight
•change in level as the heart is breaking away at the usual time from its slow rate.
Two respiratory gasps are later imposed on the tracing.

cardiac acceleration by sciatic stimulation even after the heart is com-
pletely denervated. In this series of experiments the rise appears very
definitely in cats with accelerators removed and vagus intact. It must,
therefore, be referable to vasomotor or endocrine effects under these
conditions. Ordinarily, there is no break in the curve after double
vagotomy, the fall due to vagus slowing being absent. In two cats,
however, such a second rise has also been seen when the heart was com-
pletely denervated. It seems that the cessation of the vagus effect,
while undoubtedly significant, is only one of the factors involved.

In the absence of the influence of tne cardiac nerves on the initiation
and maintenance of the reaction to cerebral anemia, it seems that we
must look to the vasomotor mechanism itself.

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 13

It is interesting to note, however, that when the animal is no longer
intact, and the peripheral resistance has been markedly lowered by a
high transection of the cord, these relations are changed. Yates (36)
has observed that cats which showed a considerable anemic rise after
recovery from such a section, completely lost their ability to react to
cerebral anemia following a subsequent excision of the stellate ganglia.
However important for all practical purposes the vasomotor control
may be, the considerable involvement of cardiac factors in the inte-
grated response, particularly in the event of injury to the vasomotor
nerves, must not be overlooked.

c. Influence of the splanchnic nerves on the anemic rise. The wide
distribution of the splanchnics, gives a possibility for various lesions
within the system. Section of the splanchnics was therefore undertaken
1, in the base of the sympathetic chain before leaving the thorax; 2, in
the abdomen, just prior to their entrance into the coeliac ganglion;
3, in various levels of the spinal cord in the thoracic region.

The anatomical relations of the splanchnic outflow in the cat have
been described by Langley (64), who concludes that the fibers destined
to enter the splanchnic nerves leave the cord in large part below the
level of the sixth thoracic, though occasionally fibers can be traced at
the level of the fifth and even fourth thoracic. Langley's statement
appears based only in part on his own observations, and is largely
founded on the work of other investigators embodied in the papers
quoted. Several authors included higher levels for the effects studied
based on experimental rather than anatomical evidence though all
have stated that the effect elicitable is relatively slight. Bayliss and
Starling gave 3rd thoracic as supplying the portal circulation, Bradford,
the 3rd thoracic as supplying the kidney; and Schafer and Moore,
3rd thoracic as supplying the spleen.

In a more recent study on cats Ranson (65) has re-investigated the
problem. He confirms Langley's findings and considers the 4th thor-
acic the highest limit of the splanchnic outflow. Ranson's material,
however, was in part restricted to animals in which only the levels
below the 6th thoracic were examined. Ranson has investigated fur-
ther the level at which the splanchnic nerve leaves the sympathetic
chain. In far the greater number of cases (13 out of 17) the nerve was
given off between the 1st lumbar and 13th thoracic ganglion, in the
remaining four cases, the nerve left between the 1st and 2nd lumbar
ganglia. The relation of this branching to the diaphragm was not
stated.

14 CORA SENNER WINKIN

1. Lesions within the splanchnic outflow: Section of the sympathetic
chain; thoracic section of the splanchnics. In 12 animals the splanchnic
outflow was interrupted in the lower thorax. Under artificial respira-
tion, a low midventral incision was extended bilaterally on either side
of the diaphragm, and the lungs held back while the sympathetic chain
was isolated and sectioned.

Section of the sympathetic chain below the level of the 8th or 9th
thoracic vertebrae usually gives a very marked fall of pressure.
When the splanchnic branch from the sympathetic chain itself is cut,
this depression amounts at least to 80 mm. Hg. In spite of this low
level of pressure, spontaneous respiration is not usually lost, and wrhen
ether is reduced, eye reflexes and other skeletal responses are readily
elicitable. The condition of the animal, however, is precarious, and
prolonged operative manipulations with too great a depth of anes-
thesia will readily cause complete loss of the bulbar responses. This
precarious .condition is in fact met with in all extended lesions within
the splanchnic system, and offers some difficulty in the further manip-
ulation of the animals.

Occlusion of the head arteries in this series generally gave a relatively
vigorous response. The intensity of the response varied, the degree
of variation from the normal being dependent apparently on the nature
of the lesion.

Group I. In these animals section of the sympathetic chain was
undertaken in its lower levels, post-mortem examination showing no
lesion above the level of the 8th thoracic. In two of these animals
autopsy showed the lesion incomplete on one side, thus amounting
largely to a unilateral injury. The anemic response obtained in four
of these animals was very considerable, the values being 100, 120, 140,
150 mm. Hg., respectively. The contour of the curves was typical of
the normal anemic responses, and the rise of pressure easily over-reached
the original control level of blood pressure. All these cats showed a
normal recovery from the occlusion. In nos. 12 and 15, excision of the
stellate ganglia was done subsequent to recovery and a third occlusion
obtained. Cat 15 that had shown an unusually vigorous response in
its first occlusion gave an increment of 125 mm. Hg. after excision of
both vagi and both stellates. The thoracic chain was sectioned at the
level of the 8th and 9th thoracic on one side, between the 10th and llth
on the other. Cat 11 was slightly different. The original depression
of blood pressure after section of the chain was 80 mm. Hg.; the anemic
increment was somewhat reduced, amounting only to 70 mm. so that

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 15

the anemic rise fell short of reaching the original level. The cat
recovered, however, and subsequently made up the 10 mm. difference
in an anemic rise obtained after the stellate ganglia had been excised.
The greater splanchnics may have been involved in this case.

Group II. This comprised the remaining 7 cats of the series. In
all these animals a complete bilateral section of the splanchnic nerves
was done in the thorax between their branching from the sympathetic
chain and before their entry into the diaphragm. On cutting the
splanchnic nerves the initial, fall of pressure was great, averaging 80
mm. In four cats the effect of occlusion was well marked, the curves
differing from the normal only in a slight reduction of the anemic
increment of blood pressure, this being 70 mm. in three cases.
In these cases also pressure did not reach the level held prior to section.

In the three remaining cats of the series a still greater depression
of the anemic response was obtained. Cat 20 gave a most complete
picture. The anemic rise reduplicated all the characteristics of the
normal response on a smaller scale. A vagus effect appeared promi-
nently. The maximum anemic increment of pressure in these experi-
ments was 40 mm. When pressure fell spontaneously after occlusion
it reached the identical level maintained after section of the splanchnics
prior to occlusion. Low section of the spinal cord at this time induced
a further fall of only 10 mm. Hg. In cat 22 the acclerators were also
removed, and an even greater depression of the anemic response was
obtained, the entire change of level on occlusion amounting to only
5 mm.

Cat 21 was slightly anomalous but yet highly instructive. The
animal showed a great resistance to anemia, and it took some 15 minutes
before the respiratory and vasomotor responses fully faded out. At
first the Record clearly approximated that of cat 20, an initial rise of
30 mm. being shown. With the parsistence of the bulbar functions,
however, there was reproduced on a different scale, the wide oscilla-
tions procurable in all animals difficult to asphyxiate. At first the
vasomotor oscillations were slight and rather irregular, but they grad-
ually developed into large and rapid waves in which the greatest ex-
cursion of blood pressure was developed, amounting to a fluctuation of
60 mm. at the height of the response. The level of blood pressure
from which these oscillations developed was not raised, the whole
response being simply recorded within this maximum variation of
60 mm. This offers a striking contrast to the analogous records of
incomplete occlusion periods of similar length obtained in intact ani-

16 CORA SENNER WINK1N

mals. In such animals the level of pressure shows similar oscillations,
but these vary within a much greater range, usually approaching 200
mm. difference in level. No recovery of bulbar functions was elicited
from any of these animals. That this was not the necessary conse-
q/uence of a lesion at this level, but merely an indication of the precarious
conditions of animals exposed to this double lesion, is shown in the
following experiments.

Section of the sympathetic chain; abdominal section of the splanchnics.
Although the blood pressure response is. seriously reduced by section
of the splanchnic nerves above the diaphragm, a slight degree of re-
sponse still seems elicitable. It seems possible, however, completely
to eliminate all rise of blood pressure as the result of bulbar anemia,
while maintaining all other evidence of medullary activity, by section of
the greater splanchnic nerves in the abdomen.

Dissection for the splanchnics in the abdomen was made 'by the
method indicated in Sherrington's Mammalian Physiology (66). The
incisions were made from the back, through the latissimus dorsi mus-
cles, and the nerves were cut just before their entry into the coeliac
ganglion. The identity of the nerves was first tested by electrical
stimulation with shielded electrodes.

A striking example of the result of this section was obtained in cat
23. In this animal (fig. 2) the greatest excursion of blood pressure
amounted to 10 mm., yet all other effects of occlusion were noted. An
asphyxial effect on the vagi appeared in the pressure curve followed by
a very slight improvement in the level. From this point on, however,
pressure fell very gradually, until, at the end of 3 minutes, it remained
constant. In this very gradual fall, pressure reached a level some
20 mm. below that of the original pressure before occlusion. After
digital compression of the abdominal aorta, spontaneous respiration
returned in this animal. When respiration had become completely
reestablished and a corneal reflex again obtained, the trachea was
clamped. No asphyxial rise of pressure to speak of was obtained, the
entire subsequent variation of pressure being well within 20 mm. Hg.
Respiratory waves and some vagus effect were recorded; failure of the
heart soon followed.

Section of the thoracic spinal cord. Section of the spinal cord was
undertaken in 16 cats. The laminectomy was carried out immediately
following tracheotomy, the wipund temporarily closed by hemostats
and the head arteries then prepared for ligation. Finally the cord
was sectioned, and blood pressure allowed to reach a constant level

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA

17

before inflicting any further lesions. Several successive sections of the
cord were frequently carried out in the same animal before occlusion
was produced.

Section of the thoracic cord was carried out at various levels. The
effect of section varied considerably with the level of the lesion, and to
some extent also with the individual animal. Certain results, however,
are patent. Lesion in the lowest levels of the thorax elicited only a
slight permanent fall of pressure, and did not seriously affect the anemic
response. Lesions in the midthoracic, at the level of the 8th thoracic
and 9th thoracic vertebrae were more apt to elicit a profound fall of
pressure, and seriously to reduce the anemic increment. Lesions in
the upper thorax also elicited a great fall on section and often completely

Fig. 3. Cat 30: cerebral anemia. Spinal cord sectioned at the level of the 5th
thoractic verterbra. This reaction shows the features of the typical blood vas-
cular response to anemia in every respect, but the level to which the maximal
rise of pressure (second rise) attains. The anemic increment here is only 50 mm.
Hg. Cardiac effects of slowing and acceleration recorded as usual.

abolished the rise of pressure. There were, however, certain individuals
in which even a high thoracic lesion did not evoke a maximum fall of
pressure, and in which a relatively vigorous response was obtained even
after a high dorsal section. Accordingly the experimental material
can be roughly classified into three groups:

Group I. Lesions in the lower thoracic region. Very vigorous responses
to cerebral anemia can still be obtained from animals with a lesion at
the level of the 10th to 12th thoracic vertebrae. Cat 25 with section
at T 10-11 showed an anemic increment of 125 mm. Hg. In cat
24 an anemic response lasting over 5 minutes was obtained, in which
the variation of pressure extended over 75 mm. Hg. The contour of

CORA SENNER WINKIN

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CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 23

this curve will be discussed below in connection with similar anomalous
curves obtained from control records in other animals. In these cats
a fall of pressure replaces the usual rise; the variation of level being
of the same order of magnitude. In cat 24, despite the great drop of
pressure, the original level was regained toward the end of the anemic
response at the time usually occupied by the second rise of pressure.

Measurements of loss of pressure after section in the lowest levels
of the thorax show a maximal total loss of 50 mm. Hg. Frequently
only a few millimeters are lost. In cat 30 the 10 mm. lost after section
at the 10th thoracic were completely recovered within 10 minutes,
pressure rising even above the level recorded prior to transection.

Group II. Abolition of the anemic response. Lesions of the cord
in the region of the 8th thoracic usually entail a rather severe effect;
the loss of pressure following this section may amount to 80 mm. Hg.
If the fall is as great as this, the anemic response is apt to be seriously
diminished. Cat 25, which gave a very vigorous response after section
at T 10, showed a further loss of 80 mm. when the cord was sectioned
at T 8, the level falling 100 mm. below that held when the animal was
intact. The anemic increment after section at T 8 was only 30 mm.
Hg. The reduction of the anemic increment to a variation of pressure
of only 30 to 40 mm. was seen in five other experiments, (cats 24, 30,
38, 40, and 42) in which section in the region of the 8th to 10th thoracic
gave a considerable depression of the level of blood pressure and in
which anemia of the bulb failed to evoke an increment of pressure
greater than 40 mm. That the vagus is partially responsible for this
effect is indicated by cat 42, in which an initial response after section
in the 8th thoracic gave an increment of only 20 mm. This increment,
however, rose slightly above 40 mm. in a subsequent occlusion after
the vagi had been sectioned.

Section of the cord above the 8th thoracic in three animals, cats 35,
39 and 44, gave a very marked fall of pressure in all these cases and no
anemic response greater than 30 mm. was obtainable in any one of
them. In cat 44, only one section was made at T 6, and no anemic
increment at all was obtainable after occlusion. In the other two ani-
mals several successive sections were undertaken before occlusion was
tested. In cat 39, the first section was carried out at T 7; this was
followed by a fall of 55 mm.; 40 mm. more were lost in successive sec-
tions ascending to the level of T 4. In cat 35, 80 mm. were lost by
section at T 8, and only 20 mm. more by successive sections to T 6.
The level of pressure above base line from which only a minimal sub-

24 CORA SENNER WINKIN

sequent fall occurs under further manipulations, lies between 35 to 50
mm., the residual pressure maintained by the spinal cord alone.

Group III. Retention of an anemic effect. The midthoracic region
is apparently not critical for vasomotor responses in all animals. In
cat 34 section at the 8th thoracic gave a loss of only 30 mm. Hg. and
an anemic increment of 68 mm. Hg. was obtained. The relatively
slight loss of pressure following section at T 7 in cat 39 above mentioned
also shows that in some animals the higher levels of the cord are of
great importance.

However, the most significant indication of participation of the upper
levels of the cord in conveying fibers significant for the vasomotor
response was obtained in four additional animals. A strikingly com-
plete anemic rise was obtained from cat 30, in which the cord had been
sectioned as high as T 5 (fig. 3) . The anemic increment here was 54
mm. In cat 38 a well-maintained response of 44 mm. was obtained on
occlusion after section at T 6. In cat 31 a rise of the same magnitude
(40 mm.) was obtained after section at T 2. The level maintained
after section at T 2 prior to occlusion was 65 mm. Hg. above base
line and did not reach the level of 50 mm. until after occlusion. An
interesting record of the potency of the higher levels in certain indi-
viduals for both the maintenance of blood pressure and its variation is
best given in the following protocol — cat 40.

Condensed protocol, cat 40 (pressure here given in level above base line) April 22, 1918

Tracheotomy, blood pressure, cannula, laminectomy, head arteries prepared

for ligation.

2:30 Control blood pressure — 130 mm. Hg.

2:35 Section of cord at T 8

2:40 Level of blood pressure — 118 mm. Hg.

2:45 Section of cord at T 6

2:47 Level of blood pressure — 90 mm. Hg., total depression of pressure — 40 mm.

2:48 Corneal reflex

Occlusion. Sharp rise of pressure to 114 mm. drop to 90 mm. Hg., great
vagus effect, rise again to 130 mm.: anemic increment — 40 mm.

2:51 Pressure released before spontaneous fall began, gasps immediately return,
fall to 80 mm.

2:57 Respiration reestablished, section of cord at T 5

2:58 Level of blood pressure — 70 mm. Hg., total depression of pressure — 60 mm.

2:59 Corneal reflex, occlusion: — -incomplete

3:01 Further manipulation of clamps, immediate rise of pressure to 114 mm.,
anemic increment — 44 mm.

3:04 Released before spontaneous fall, pressure drops to 50 mm. Hg., but imme-
diately begins again to recover

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 25

3:05 Gasps return, pressure continues rising

3:10 Pressure reaches 90 mm. Hg. again, regular waves in blood pressure curve,
respiration reestablished

3 : 17 Section of cord at T 4, pressure drops to 70 mm.

Corneal reflex, Occlusion: sharp rise of pressure to 100 mm. fall to 60 mm.
during vagus slowing, subsequent rise to 112 mm.; anemic increment —
42 mm.

3:23 Pressure released before spontaneous fail, drops sharply to 44 mm. but
immediately begins to rise again

3:25 Gasps return

3:33 Pressure at 84 mm. again, respiration reestablished

3:39 Section of cord at T 2, pressure falls to 46 mm. Hg. total depression of pres-
sure, 84 mm.

3:40 Corneal reflex, Occlusion: initial rise to 64 mm. Hg. fall to 30 mm, during
vagus slowing, second rise to 74 mm. Hg. anemic increment — 28 mm.

3:42 30 Head arteries released before spontaneous fall, pressure immediately
falls to 20 mm. but again regains level

3:45 Pressure has reached 54 mm., gasps return, further rise to 60 mm. respira-
tion reestablished
Thorax opened, artificial respiration administered

4:05 Sympathetic chain cut in midthoracic, pressure fall to 40 mm. total depres-
sion of pressure — 90 mm.

4:07 Corneal reflex: occlusion, rise to 52 mm. slight fall, rise to 48 mm. anemic
increment — 12 mm.

4:11 Release of head arteries, pressure drops to 30 mm.

4:14 Gasps return, pressure rises to 40 mm. respiration reestablished

4:55 Splanchnics cut in psoas muscles, no effect on blood pressure, no recovery
of level or return of respiration

5:10 Artificial respiration intermitted, pressure drops to base line.

Effect of the splanchnic constrictor fibers on the anemic rise. The bur-
den of the anemic response seems to lie in the vasomotor apparatus,
and, if the evidence of these experiments is adequate, almost exclusively
on the splanchnic constrictor fibers. Peripheral section of the splanch-
nic nerves, with its great depression of blood pressure, and the sub-
sequent inability to obtain any anemic increment whatever, speaks
strongly, almost unequivocally, for such an interpretation. Additional
evidence for the importance of the splanchnic pathway for the vaso-
motor changes during anemia is the relation of the level of blood pressure
after section within the splanchnic outflow to the anemic increment
elicitable on occlusion. The data show quite clearly that the greater
the initial depression, the less powerful the response.

This very definite grading of the blood pressure level to the magni-
tude of the anemic rise gives a further insight into the anatomical
relations of the splanchnic outflow. In the cats examined the greatest

26

CORA SENNER WINKIN

Fig. 4. Cat. 45. Repeated cerebral anemia; double vagotomy; 10th successive
occlusion; dissociation of reaction curve into two distinctly separated peaks is
shown fully established. Second peak in this occlusion is still considerably
greater than the first. Pressure falls very low at the end of the response (30 mm.
Hg. above base line). Each curve occupies approximately half the period of the
reaction.

Seventeenth successive occlusion: Dissociated curves show little difference
in time relations compared with those obtained 2 hours earlier. Difference in
contour found in the greater emphasis of the first as compared with the second
peak of pressure. The rise in level prior to occlusion represents the recovery of
blood pressure after the preceding occlusion following the return of respiratory
gasps.

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 27

average ouflow from the cord to the sympathetic chain is apparently
in the region of the 6th to 8th thoracic. Yet the outflow is not restricted
to the lower thoracic region, for fibers in the higher thoracic region even
as high as the 1st or 2nd, have in these experiments been found of some
importance both for the maintenance of the level and the changes
of blood pressure. Such a curve as that obtained from cat 30 (fig. 3)
shows convincingly that in some animals a good proportion of fibers
leave the spinal cord to enter the sympathetic chain above the level of
the 5th thoracic vertebra.

While therefore the anatomical findings of Langley and Ranson for
the average level of outflow have in the main been verified, the involve-
ment of higher levels already indicated by the various physiological
researches quoted by Langley has received a rather striking con-
firmation.

In such an instance, the physiological evidence may well have pre-
cedence over the anatomical, for whereas a small bundle of fibers is
most difficult to stain and trace microscopically, a weak physiological
effect, when definitely isolated, is quite unmistakable. The involvement
of these fibers from the higher levels within the splanchnic system, be-
comes of particular importance when the entire burden of the splanch-
nic function is restricted to these levels. Since the very high out-
flow presumably goes by way of the stellate ganglion, it is necessary to
differentiate between the effect of the splanchnic fibers proper and the
accelerators. However, in these cats in which an abdominal or high
spinal section completely abolished the rise, the cardiac nerves seemed
completely impotent against the lowered peripheral resistance.

Accordingly, the vasomotor impulses that travel through the splanch-
nic nerves to the coeliac ganglion may leave the cord as high as the
first or second thoracic. They may, however, stay in the cord through-
out the thoracic region and leave it even below the diaphragm. Ran-
son 's results on the very low level at which the splanchnic nerve leaves
the chain in cats, is in close agreement with these findings.

There thus appears to be a double pathway for the splanchnic out-
flow in the thorax, one within the cord, the other outside of it. The
outflow of the splanchnic fibers from the cord to the sympathetic chain
seems distributed over the entire thoracic region, the relative distribu-
tion varying from one individual to another.

In this light the impossibility of abolishing the anemic rise by a sec-
tion which implicates only part of the splanchnic system is explicable.
The wide distribution of the splanchnic fibers would make it difficult

28 CORA SENNER WINKIN

to compromise the response by a definitive lesion. Such a lesion could,
it seems, be secured only when the section falls sufficiently far out in
the periphery or sufficiently high up in the cord, definitely to interrupt
the conduction pathways from medulla to coeliac ganglion. Unless this
interruption is accomplished, the fibers that are left in continuity with
the medulla and the periphery are able to initiate an anemic rise which,
even if considerably diminished in intensity, repeats all other char-
acteristics of the usual vasomotor response.

To the splanchnic innervation, therefore, the most significant fac-
tors in the blood vascular reaction to cerebral anemia can be attrib-
uted: the initiation of the rise and the level which this reaches. Since
these factors can be controlled by differential lesions within the splanch-
nic system, the influence of the non-splanchinc vasomotors may be
neglected for the purposes of the present survey.

On the influence of the splanchnic system on the maintenance of the
normal level of blood pressure: The splanchnic fibers seem involved when
the level of pressure is above 50 to 60 mm. for unless a complete interrup-
tion of the conduction path from medulla to coeliac ganglion has been
demonstrated, pressure returns to a higher level the height depending
apparently on the number of fibers in the splanchnic system remaining
functional. The level of 50 to 60 mm. is that shown by Mayer, Gouty
and later workers to be that maintained by the spinal cord alone. Yates
also finds this level to be approximately that reached by blood pressure
after recovery (2 to 32 days) from high transection of the spinal cord
at 8th cervical to 5th thoracic. Her average level of pressure lay some-
what lower than this, between 40 to 50 mm. From Pike's and Langley's
studies this residual spinal level appears rather as a skeletal or somatic,
than as a vascular or sympathetic phenomenon.

The difference between the residual spinal level and the normal one —
a difference of 80 to 100 mm. — would therefore appear as accounted
for largely by the action of the sympathetic neurones within the splanch-
nic system. When the range of variation during anemia is examined,
this is seen to be three to four times as great in the animal with splanch-
nics intact as in the animal which is largely dependent on its skeletal
musculature. The variation of pressure in cats with low thoracic
section of the sympathetic chain is greatly restricted where the animal
was highly resistant to anemia and a period as long as 15 minutes elapsed
before the processes activated by the higher levels ceased. Further-
more, as long as the splanchnic system is functional, pressure does not
drop below the level of 50 to 60 mm. Hg., however great the variation

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 29

of pressure and no matter how exigent the inimical conditions. This is
well illustrated by the variation of pressure noted in figure 3. The pro-
tocol of cat 40 where pressure in maintained in excess of 60 mm. until
after a section of the spinal cord at the level of the 4th thoracic, also
emphasizes the relation of this level to splanchnic activity.

On some anomalous curves. In a relatively large number of cats
(8 in 60) a depression of blood pressure was obtained on occlusion in-
stead of the usual anemic increment. This depression of the level of
blood pressure was great, approaching the order of magnitude of the
usual positive effect. In six of these cats, pressure fell 100 mm. and
more below the original level of blood pressure. Most of these curves
represented control occlusions, one example of which has been figured
(fig. 1, occlusion 1) in which no previous lesion had been inflicted the
vagi being intact in 'all cases. In one case, cat 24, also mentioned,
this depression appeared after low section of the spinal cord. In these
cats on occlusion there followed no initial increment, or only a very
slight increase in the level (5 mm.). Pressure then continued constant
foi some 20 seconds. Following this a great and very rapid fall of
blood pressure set in from which recovery occurred at about the time
ordinarily occupied by the second rise of blood pressure. In this recov-
ery from the low level of blood pressure, however, pressure approached
but never completely attained the original level observed before
occlusion.

The magnitude of the effect might argue for the involvement of the
splanchnic system. As such, it might be aroused by an afferent excita-
tion of the depressor fibers in the vagus. The relation of the depressor
to the splanchnic system and also to the discharge of adrenalin (which
would of course be involved in all splanchnic excitation) has been dis-
cussed by Ludwig and Cyon (48) and Oliver and Schafer. Bayliss
(67) has dealt with the antagonism of asphyxia and depressor
stimulation.

On the other hand, the depression of blood pressure, instead of being
due to the cardiac innervation set into action through an afferent chan-
nel, might be affected directly through a change in the minute volume
of the heart, especially under changed conditions within the vagus sys-
tem. Wickjvire (60) has particularly noticed that different degrees
of the depth of anesthesia gravely influence the changes in the level of
blood pressure due to the vagus system.

II. RELATION OF THE ADRENAL GLANDS TO THE RISE OF PRESSURE
DURING CEREBRAL ANEMIA. The extensive involvement of the splanch-

30 CORA SENNER WINKIN

nic system in the anemic response makes the activity, or some pro-
duct of the activity, of the adrenal glands of considerable significance
for the problem of its control. Following the discovery by Oliver and
Schafer (68) of the pressor action of injected extract of adrenal tissue,
workers have tended to emphasize the close physiological relation of
the glands and their pressor activity to the splanchnic system. The
literature is extensive (69), (70), (71), (72), (73), (74), (75), but it will
not be reviewed at this time. Nor will the literature on the liberation
of adrenalin (75 to 90) be considered here. The evidence for the parti-
cipation of adrenalin in the response to asphyxia and other conditions
of stress is also extensive (91 to 98), but its consideration will be left
for a later paper. The relation of the contour of the typical curve
obtained on electrical stimulation of the splanchnic nerves to the ad-
renals, and also to the cardiac mechanism, has been dealt with by
several authors (104), (105), (106), (107). A further analysis of this
contour is also postponed.

Effect of repeated occlusion cm intact cats. Elliott's assumption (75)
that adrenalin is consumed under conditions of stress makes it con-
ceivable that the rapid repetition of so radical a procedure as arterial
occlusion could influence the amount of circulating adrenalin. Since
the relation of adrenalin to the myo-neural junction has been experi-
mentally demonstrated, Professor Pike has suggested that, physiolo-
gically, it may be associated with the process of conduction from sym-
pathetic nerve fiber to smooth muscle, and directly or indirectly with
the processes of excitation in smooth muscle. The work of Keith Lucas
would suggest such a possibility (108). Accordingly, such an increase
of activity of sympathetic nerve and smooth muscle as accompanies
cerebral anemia should lead to a more rapid consumption of adrenalin.
This conclusion follows from Elliott's hypothesis of the consumption
of adrenalin. The procedure of repeated occlusion has accordingly
been attempted first in intact animals in order to reach a control condi-
tion of maximal exhaustion of circulating adrenalin, and then in animals
in which the adrenal glands had been permanently ligated.

The great resistance of the animals to repeated occlusion has been
frequently demonstrated in the experimental material already given.
Numerous other evidences of the relative indefatigability of vasomotor
responses are found in the literature. Notable here are the analogous
experimental conditions in the work of Gushing (99), who found that
the process of raising the blood pressure by increasing the intracranial
tension, and thus also inducing a partial anemia, could be repeated

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 31

indefinitely. The difficulty of inducing fatigue of the central vasomotor
cells under normal conditions has been discussed in various connections
by W. T. Porter (100), (101).

The experiments already described in this series on repetition of
occlusion have been complicated by the infliction of lesions in the
splanchnic system so that the actual ability of the animals to with-
stand repeated occlusions, and the effect of this procedure on the anemic
response, was not clear. Furthermore, not more than six or eight suc-
cessive occlusions at most were obtained. Accordingly, in five cats
the effects of repeated occlusion were tested. Occlusion was done and
when the final spontaneous fall of pressure occurred, the clamps were
promptly released and recovery awaited. The corneal reflex was used
as before as an index of returned bulbar activity. With its elicitation
clamps were again adjusted on the head arteries, and this process
repeated several times.

If the occlusion period was not too long maintained in any one clos-
ure, it was possible to repeat the procedure practically indefinitely.
In the three most striking experiments, cats 45, 46 and 48, the experi-
ments had to be halted arbitrarily because of extraneous reasons, the
time consumed being too long. Cat 45 yielded 18 successive occlu-
sions (fig. 4); cat 46, 13 successive occlusions; cat 49, 11 successive
occlusions. These experiments lasted over 3 hours in addition to the
time necessary for the preliminary operative manipulations which
always consumed over half an hour. Cat 46 was intact, cat 45 had
suffered double vagotomy, and in cat 48, (fig. 5A) both stellate ganglia
had been removed. No marked difference in the behavior of these
cats under the test could be noted. In fact, the cats showed a remark-
able constancy in behavior. The characteristic occlusion time — 2
to 4 minutes — in each individual was retained with considerable uni-
formity throughout each series. Furthermore, the time needed for
recovery of the bulbar functions after release of the arteries was almost
uniform for each cat examined. The recovery time which, on the whole,
may be said to vary directly with the occlusion time, did not in all
cases follow this relation. Cat 46, which gave a constant occlusion
time of 2 minutes usually showed a recovery of a corneal reflex
within 7 . minutes subsequently. Cat 45, however, (vagotomized)
invariably showed a 20-minute interval between occlusions. In this
interval a well-marked recovery of blood pressure was noticeable and,
with the return of respiration, blood pressure rose at least from 60 to
80 mm. above the level after occlusion, before a corneal reflex was

32 CORA SENNER WINKIN

obtained. The average level between occlusions was relatively high,
pressure seldom falling below 60 mm. Hg.

The first four or five occlusions obtained differed in no very striking
detail from control occlusions. The main change from the type of
these earlier occlusions appeared gradually. This was a slight delay
in the appearance of the first rise in pressure and a gradual increase in
the magnitude of this first effect. The fall of pressure from this first
level also became more pronounced; pressure dropped to increasingly
lower levels at this time on successive occlusions. By the time of the
seventh or ninth occlusion the emphasis on this first part of the curve
became so well marked that the entire response appeared more as two
separate curves rather than one, the two summits in the tracing being
very symmetrically distributed both in time and space. The fall of
pressure following the initial rise was so great in some of the animals
as to approach the base line very closely, dropping to a level of only
10 to 20 mm. Hg.

The characteristic new contour of the rise, once established, is re-
tained in all subsequent tracings in the same animal with great uni-
formity (fig. 5B). The latter part of the series of occlusion records
accordingly shows this new type of anemic rise. The marked drop in
the double curve is quite different from the dip due to vagus action
seen in the ordinary control pressure curve of anemia. It comes much
later (fig. 4); it is also decidedly more abrupt and greater. In fact,
it seems much more like an actual collapse of blood pressure. It appears
uncomplicated by slowing of the heart. The very definite time rela-
tions established in these dissociated curves are striking. Indeed, the
supplementary rise, once it has become separated from the initial rise
by the marked temporary collapse of blood pressure, is recorded at
exactly the same point in all later occlusions obtained in a given animal.
This time closely approximates half of the occlusion time of the animal
in which it appears, namely, at 1 minute in cats of 2-minute occlusions,
and so forth. A decrease of the anemic increment was obtained in the
course of the repetitions. Rises of 80 to 100 mm. gradually replaced
the original increment of 120 to 140 mm.

One further observation on these cats is worth noting. Post-mor-
tem examination showed that the blood of these animals failed to clot
readily. It frequently flowed freely from the carotid artery when the
cannula was removed. In a prolonged dissection in one animal, the
blood flowed freely from every rupture of a large vessel, even as late
as one hour after death.

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA

33

Effect of repeated occlusions in cats deprived of adrenal glands. The
procedure of repeated occlusion in the same animal was undertaken in
a final series (six cats) in which both adrenal glands were ligated. In
each of these animals one control occlusion was made, then by means
of dissection through the latissimus dorsi (double incision from the
back) the adrenals were isolated and secured by ligatures. No signifi-
cant fall of pressure was obtained immediately on ligation of the ad-
renals, thus confirming the observation of Hoskins and McClure (102)
and Young and Lehman (103). Following this, the procedure was

Fig. 5 A: Control curve of 3 minute occlusion. Ligation of the head arteries
in the intact and fresh animal. Initial rise is followed by a depression level
coming cogether with a slowing of the heart. High level of pressure maintained
throughout the response.

B. Cat 48: Repeated cerebral anemia; stellate ganglia excised; 14th successive
occlusion. Dissociation of two peaks very well marked. Level of pressure
between occlusions extremely low (20 mm. Hg. above base line).

C. Cat 53: Repeated cerebral anemia; adrenal glands ligated; 7th successive
occlusion, obtained just before collapse. Drum revolving at same rate as above.
Time of this reaction, 2 minutes. Control reaction in this animal, when fresh
and intact had occupied 3| minutes. Abruptness of initial rise and final fall
characteristic of records after ligation of the adrenals.

THE AMERICAN JOURNAL OF PHYSIOLOGY, VOL. 60, NO. 1

34 CORA SENNER WINKIN

identical to that in intact animals: ether was reduced, a corneal reflex
elicited, and successive occlusion of the arteries done as soon as recovery
from the last preceding occlusion had occurred. The cats differed
somewhat in the rapidity with which the effect of the ligation of the
adrenals appeared in the anemic blood pressure curve. In two
cats, 52 and 56, the first occlusion following ligation showed little
difference, and certainly no curtailment when compared with the
control curve. In cat 52 the level of maximal pressure was maintained
2 full minutes longer than in the control. However, in the other four
cats, the curves obtained following ligation of the glands immediately
presented a marked contrast as compared with the normal occlusion
and with the records obtained under repeated occlusion in the control
series of intact animals. The characteristic feature of this change
appeared at once and was retained until failure of the animal. This
was an absolute halving of the occlusion time, and the retention, either
of a reduced double curve, or of a single vigorous rise. In the two cats,
52 and 56 already referred to, this same reduction appeared somewhat
later in the record. The occlusion time was not halved in cat 52 until
the fifth occlusion following ligation of the glands; in cat 56, not until
the fourth occlusion. In both these cats there also remained a dis-
tinct double rise in the pressure curve, which was not observable in
the curves from the other animals. Autopsy showed no difference
in the completeness of the ligation in these two animals.

In the cats in which the adrenals had been ligated the complete in-
ability to restore the bulbar functions had to be faced in all cases before
nine successive occlusions had been made. There were no exceptions
to this early complete collapse in any of the cats observed. Two cats,
54 and 52 already mentioned, gave eight successive occlusions after
ligation of the glands. Cat 53 gave seven; (fig. 5 C) cat 57, five; cat
56, otherwise so resistant to a change in its long occlusion periods and
retention of normal contour, succumbed after only four occlusions.
Only one occlusion was obtained from cat 55. Figured in hours of
survival under this procedure, this meant a maximal survival of 2^
hours, a minimal survival of 15 minutes. However, only two cats of
the series failed within an hour of the ligation of the glands under suc-
cessive occlusions. The average survival time was 1| hours.

Very few indications of the approaching collapse appeared in the
record, the only index being perhaps the very low level of blood pres-
sure between any two successive occlusions. This low level was estab-
lished in all cases immediately after the spontaneous fall of pressure

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 35

closing the first occlusion that followed ligation of the adrenals. At
this time pressure fell to 30 or 40 mm. Hg. — a level 20 to 30 mm. lower
than in the intact animals at a corresponding time. In spite of the
subsequent return of respiration and other bulbar activities, the pres-
sure remained uniformly low. A return of the corneal reflex was ob-
tained even at this reduced level. The level of blood pressure main-
tained between successive occlusions varied somewhat. On comparing
the amount of recovery of blood pressure in a given animal after occlu-
sion, and the number of occlusions obtainable, it was found that, at
least in the extreme cases, a direct variation could be noted. The two
very vigorous animals which gave eight reactions after ligation of the
glands, cats 52 and 54, showed a recovery of pressure of 40 to 50 mm.
during the period following release of the head arteries; whereas cats
55 (one occlusion) and 57 (five occlusions) never regained more than
10 mm. at the time of the return of respiration. Cats 53 (seven occlu-
sions) and 56 (four occlusions) occupied a rather intermediate position,
never showing an increase of more than 20 mm. pressure during
recovery of bulbar function.

No change in the time needed for the return of medullary activity, as
determined by the return of respiration and ocular reflexes, was noted
in these animals. As in the control series of repeated occlusion in
intact animals, this was not different after ligation of the adrenals from
that obtained in the fresh animal. Periods of recovery of from 10 to
20 minutes were recorded, being fairly constant for the given individual.

No significant decrease in the anemic increment was observed, in
cats 53 (seven occlusions) and 57 (five occlusions) where increments of
120 to 140 mm. were obtained just prior to failure. These were oddly
enough the smooth curves recorded under early collapse. A much
more pronounced decrease in the anemic increment was shown in the
other animals in which more occlusions were obtained; in cat 52,
(eight occlusions) the last occlusion recorded showed an increment of
only 65 mm.

The contour of the curves obtained is of considerable interest. Cats
53 and 56 immediately showed a single rise occupying about half the
original occlusion time (fig. 6), and this was a smooth unbroken curve.
Though the reduction in time was just as manifest in all the other cats,
the obliteration of the double nature of the curve was not so clearly
marked. In these cats the characteristic contour of the anemic rise
as seen in the fresh animal, merged gradually into the smooth curtailed
curve following adrenal ligation. The changes most evident were the

36 CORA SENNER WINKIN

greater abruptness of the initial rise while the depression of level due
to vagus activity was apt to be increasingly delayed and tended to
appear on the crest^of the wave, somewhat similar to the effect described
after section of the accelerators. The precipitous fall which occurs in
these animals with ligated adrenals just about half as late as in intact
cats then appears as soon as the point of maximal pressure is gained,
namely, immediately after cessation of the vagus depression.

Fig. 6. Cerebral anemia following ligation of the adrenals. Cat. 53. Arterial
occlusion immediately following tying off of the glands. Occlusion time, 1|
minutes. Time of control occlusion obtained from this animal, 3 minutes.

Effect of the adrenal glands on the anemic rise. The marked shorten-
ing of the anemic response eventually obtained in all the animals in
which the adrenal glands had been ligated seems to isolate a further
factor concerned in the production of the anemic rise. Apparently the
great influence which the splanchnic system is able to exert on the level
of blood pressure under the critical conditions of anemia, is due in part
to the adjuvant activity of the adrenal glands. These experiments,
therefore, bear on the discussion of the emergency relation of the glands,
since apparently some involvement of the glands or some product of
their activity must be conceded under the extreme condition of cere-
bral anemia. Furthermore, some clue as to the nature of the activity
of the adrenals is given by inspection of the curves obtained.

Loss of pressure. There has been noted a close parallelism between
the later curves obtained from all animals suffering repeated occlusion,
whether intact or deprived of adrenals. A failure of blood pressure

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 37

(temporary or permanent) is recorded under both conditions within
half the time normally occupied by the blood vascular response. When
the animal is intact, this drop of pressure occurs in the seventh or
eighth occlusion and in all subsequent curves of a given series. When
the adrenals are ligated, it may be established immediately, although
this is not necessarily the case. Under these conditions the halving
of the response is recorded before four successive occlusions have been
inflicted and is found in all occlusions which follow in these animals.
This precocious loss of level in blood pressure can therefore be obtained
either when the animal has been exposed to rapidly repeated cerebral
anemia, or when the activity of the adrenal glands is completely abol-
ished. Accordingly, the main factor in the production of this early
failure of pressure seems concerned in all cases with the availability
in the blood stream of some product of adrenal activity.

Restoration of level of blood pressure. An examination of the supple-
mentary rise of blood pressure in the repeatedly occluded but intact
cats in comparison with the permanent failure of pressure at half the
normal occlusion time when the adrenals are ligated, leads to a consid-
eration of the theories of emergency function of the adrenals. This
secondary rise is most probably related to the presence of functional
adrenals.

The secondary rise was interpreted in a preliminary report of these
experiments as an indication of an increased liberation of adrenalin
from the glands, and the constant interval prior to its appearance, as a
latent period, relatively long, of adrenal secretion. The argument was
advanced that these experiments offered evidence confirming Cannon's
position on the increased secretion of adrenalin under emergency condi-
tions. However, in view of the presumable consumption of the pro-
ducts of adrenal activity during cerebral anemia already discussed, the
conception of the emergency liberation of adrenalin must be somewhat
modified. The further discussion of any of the current hypotheses of
the liberation of adrenalin must be deferred until further experimental
evidence has been accumulated. Two definite statements, however,
appear justified by the facts. In the first place, since curves of per-
fectly normal contour were obtainable in two animals after ligation of
the adrenals, an increased liberation or secretion of adrenalin, one or
both, is not necessary for the carrying out of the typical blood vascular
response to anemia in the fresh animal.

That these results were due to experimental error can hardly be pos-
sible since there was seen in these animals a gradual and relatively slow

38 CORA SENNEB WINKIN

transition of the normal curve into the abbreviated response typical
for animals with ligated adrenals. Such a gradual transition is also
found in the intact repeatedly occluded animals. In the second place,
from the premature failure of the vascular response, after the ligation
of the adrenals, particularly in contrast to the secondary rise that is
seen in the intact repeatedly occluded animals, the conclusion may be
drawn that some product of adrenal activity must be available to make
possible the continued action of sympathetic nerve on smooth muscle
for any length of time.

Survival after adrenal ligation. In all the work reported on excision
of the adrenal glands, sudden death has never been noted. However,
when all adrenal tissue is excised, collapse and death follow, the inter-
val of life varying in different animals. The earlier work on cats has
been reviewed by Hultgren and Anderson (109), who particularly
described the prelethal stage. Elliott (73) recorded the failure of blood
pressure in addition to the loss of the pressor reaction in the moribund
cat, and in a later paper he has summarized a series of tests given in
these conditions, demonstrating a complete collapse of vascular tone.
Gautrelet and Thomas, (110) later Hoskins, (111) have confirmed the
depression of the sympathetic system on final collapse. Elliott records
death with simultaneous extirpation under ether after 14 to 18 hours.
Bazett (112) has recently succeeded in shortening this time consider-
ably by decerebration, urethane anesthesia and sensory stimulation.
In these animals the fall of blood pressure occurred within a few hours
after the operation. Elliott (98), moreover, finds that the animal sur-
vives even if the adrenal tissue is separated from the splanchnics. He
concludes therefore that, whereas the increase of adrenalin in the blood
stream under splanchnic stimulation is not necessary to life, the animal
depends for its existence on the continual slow secretion of adrenalin
from the medullary cells. Elliott argues that this continual slow
secretion is independent of nervous impulses. Stewart and Rogoff
(113), (114), however, are unable to demonstrate any appreciable
adrenalin output under these conditions.

It seems that the repetition of the extreme procedure of occlusion is
able to hasten the onset of complete failure most surprisingly. In the
extreme conditions of these experiments Bazett's (97) already curtailed
time of survival after ligation of the adrenals is thus further shortened
by 6 or 8 hours. The only demonstrable factor in the failure under
these conditions is the inability of the sympathetic nervous mechanism
to maintain the normal state of the musculature of the blood vessels

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 39

after complete exhaustion of the reserve of adrenalin in the blood.
The necessity for the presence of adrenalin or of some other product of
adrenal activity in the blood for the maintenance of vasomotor tone, as
asserted by Elliott, seems again confirmed. The failure of blood pres-
sure alone seems able to carry with it the failure of all the other functions.

From the evidence, the relative degree of constriction of the vessel
walls seems, to a considerable extent, a function of the amount of some
adrenal product in the circulation. The loss of this product seems to
mean complete failure; blood pressure stays only a few millimeters above
base line when the available supply is low, but an increased liberation,
or possibly even a redistribution, may give any degree of tonic contrac-
tion of the vascular muscles, reaching to maximum constriction, the
entire reaction perhaps depending on conditions at the myo-neural
junction.

III. RELATION OF THE SPLANCHNIC SYMPATHETIC SYSTEM TO THE
CENTRAL NERVOUS SYSTEM. The central relations of the sympathetic
system have been tenaciously disputed, and cannot be entered into at
length. On the one hand, there has been the view defending its rela-
tive independence from the cerebro-spinal axis, originally advanced by
Bichat (115), and supported extensively by Volkmann (116). Goltz
in his latest work with Ewald (117) subscribed to this view, in his asser-
tion that the sympathetic peripheral ganglia could maintain normal
vascular tone, and mediate reflexes quite independently of the central
nervous system.

However, the theory that the nervous outflow is essentially dependent
for its activity on cells of central, and particularly bulbar origin, has
always enrolled some powerful supporters. Two of Goltz's contempo-
raries, Eckhard (118) and Mayer (119) have defended this conception.
Recently Gaskell (120) and Sherrington (121) and still later Ranson,
(122), also endorsed it.

Two points in the evidence on cerebral anemia will briefly cover the
relation of the medullary cells to the peripheral response. First, the
comparison of the splanchnic response with the other peripheral re-
sponses, and particularly the skeletal responses as controlled by the
medullary or higher cells, under the different functional conditions of
the nervous levels in these experiments; second, the behavior of the blood
pressure responses under recovery from various spinal lesions.

Comparison of splanchnic response with other peripheral responses.
The following table gives the various stages which can be distinctly
separated when different functional levels control the animal's reac-

40 CORA SENNER WINKIN

tion. The rough average of the level of blood pressure maintained is
given for each period. The exact correspondence of the involvement
of the splanchnic system and the degree of functional activity within
the medullary centers is indeed striking, especially in view of the po-
tency of the splanchnic system in maintaining blood pressure. It
appears from this tabulation that the splanchnic system behaves ex-
actly as do the respiratory, skeletal and ocular responses. When the
skeletal responses dependent on the higher levels are in abeyance, the
vasomotor responses of the splanchnic system are also absent. At
this time, moreover, that is, during the depression between occlusions,
the heart rate shows no appreciable change. The level of blood pres-
sure maintained is that shown by Gouty (16), Mayer (14), Pike (26)
and Langley (27) to be that held as long as the spinal cord itself remains
intact. Additional evidence that the depression of functional activity
is due to a complete interruption of conduction in the spinal cord, and
not to so-called spinal shock, is brought out by the behavior of the
animal in passing through these various stages. The bearing of the
validity of the shock hypothesis for any conception of the functional
organization of the nervous system has been discussed by Pike (123). A
.shorter statement of this relation is found in Yates's paper (36) .

Comparison of somatic and ocular responses with vascular responses

Control of the animal's responses by various nervous levels Average level of blood pressure

1. Normal intact animal: responds as a whole, pupils

narrow, corneal reflex, respiration normal 120 mm.

2. Head subjected to anemia: struggles — responses

under control of stimulated area (head) skeletal
' convulsions, respiratory spasms, corneal reflex lost. 180-200 mm.

3. Head functionally dead, — animal spinal:— responses

under control of spinal cord only no corneal reflex,
pupils widely dilated. No spontaneous respira-
tion. No skeletal reflexes elicitable 50-70 mm.

4. Recovery of head centers : gradual return of responses

controlled by head area, pupils narrowing — no cor-
neal reflex — spontaneous respiration returns after
pressure has risen somewhat, but still sporadic.
Skeletal reflexes elicitable in part 70-90 mm.

5. Recovery completed; animal responds as a whole.

Pupils narrow, corneal reflex, respiration reestab-
lished; functions coordinately, skeletal reflexes
present 120 mm.

When a significant lesion in the splanchnic system has been inflicted
by the section of these nerves just before entrance into the coeliac

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 41

ganglion and the cerebral circulation shut off, no anemic increment is
obtainable. However, all other evidences of bulbar activity are present.
A vigorous corneal reflex is obtained prior to occlusion, and when the
clamps are adjusted, even though the level of pressure may remain more
undisturbed than that obtained under many minor manipulations, the
other symptoms of the asphyxial response are shown in full vigor.
There are marked respiratory spasms, skeletal convulsions, changes in
the pupils, etc.

In marked contrast to such a picture are the effects when, from some
physiological disturbance, the medulla itself is thrown out of activity.
Here the effects of the interruption of functional continuity are opposed
to the effect of anatomical separation. Such a condition is present
while the animal is still profoundly under the effect of an occlusion that
has just been done, or even during recovery from occlusion, when the
functions of the brain stem are not yet fully established. If, under such
conditions, the animal is subjected to a renewed occlusion, no response
at all can be aroused. Generalized asphyxia, inflicted by clamping the
trachea and thus acting directly at the periphery is, in this condition,
also impotent to produce any effect. Under this general depression
there are no skeletal convulsions, no respiratory gasps, and pressure
changes are extremely slight, 5 or 10 mm. The heart just quietly runs
down. The condition of the eyes remains unchanged throughout.

All the evidence of these experiments therefore would argue not only
for a normal release of the rise of blood pressure through the sympathetic
outflow, but also for a complete dependence of the activation of the
response on the integrity of the brain stem, and the maintenance of the
conditions of conductivity within it. The response transmitted by the
sympathetic system is functionally exactly on a par with all the other
physiological responses. When respiratory movements, eye move-
ments and skeletal reflexes are obtainable, the changes of blood pressure
can also be elicited.

The anatomical relations of the splanchnic outflow in its bearing on
recovery after section of the spinal cord. The complete dependence on
the brain rather than on the spinal cord is well illustrated by experi-
ments on recovery of blood pressure from high section of the spinal
cord. Goltz, (17), (18) and later Goltz and Ewald (117) sectioned the
cord of dogs in the midthoracic region and found normal blood pres-
sure responses to subsist. These were attributed entirely to the con-
trolling influence of the cord over the sympathetic system. These
experiments have been repeated by later investigators, notably Sher-

42 CORA SENNER WINKIN

rington (121), (124). In view of the very high level of the cord in which
a lesion must fall before it can definitely intercept the connections
between the medulla and the splanchnic effectors, there is a possibility
that -the agency concerned in this recovery is none other than the
splanchnic constrictors still in functional continuity with the brain stem.

Four early experiments were carried out with Doctor Pike's coopera-
tion in which a transection in the upper levels of the spinal cord was
done aseptically, the animal allowed to recover' and then the anemic
response tested. In two cats the transection was done at the level of
the 2nd thoracic. One animal died within 24 hours before the blood
pressure could be tested; the other lived 5 days and was then subjected
to the test of occlusion. Blood pressure, however, was very low, the
bulbar responses failed immediately and no rise was elicitable. Cat
63, however, in which section at the 3rd thoracic was made, recovered
fully and when tested a week later showed a level of blood pressure of
120 mm. and an anemic increment of 50 mm. in the first occlusion.
Cat 64 with a section at the 6th thoracic was tested 2 days later. Con-
trol level of blood pressure was 80 mm. The anemic increment of the
first occlusion was 45 mm.

This problem was subsequently taken up by Miss Yates under Doc-
tor Pike's direction, and has been reported on in detail in an earlier
issue of this Journal. Miss Yates (36) found that when one or two
segments of the thoracic region only are left intact there is a recovery
of blood pressure to an adequate level, and vigorous anemic or asphyx-
ial response is readily elicitable. This recovery is attributable to those
medullary cells still in connection with the peripheral splanchnic
neurones.

It was on the evidence of Goltz's experiments that Langley applied
the name "autonomic" to those peripheral mechanisms supplied by
ganglionic connection outside the nervous system which he thought
could function independently of the brain. The physiological evidence
that is now accumulating would gravely discredit this autonomy, and
would tend to place the sympathetic responses in the same category as
all others. This is of particular importance in connection with the
late appearance of the adrenal effect in cerebral occlusion, even after
the reflexes are no longer elicitable. However late its appearance, and
however independent of any parallel nervous activity, this effect cer-
tainly cannot be aroused unless the splanchnic fibers themselves have
been previously stimulated. When the splanchnic fibers are no longer
excitable because of an anatomical lesion the adrenal effect never
appears.'

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 43

This relationship is of particular interest with respect to the appear-
ance of Traube-Hering waves. These have been noticed by all ob-
servers in the downward course of the final fall of blood pressure in the
anemic response. Whether nervous centers are no longer excitable to
sensory stimulation and whether or not the output of adrenalin is a
factor concerned, remains to be tested. It must, however, be borne in
mind that such a condition as this where Traube-Hering waves have been
elicited, is preceded by an intense activity of the splanchnic outflow
as stimulated by the medullary cells.

In the disturbance of the internal medium which the excessive con-
centration of carbon dioxide in the occluded cerebral vessels brings
with it, the increased rate of flow is carried out and maintained by the
vascular musculature, and some product of adrenal activity probably
makes possible the maintenance of the increased impetus given the
blood flow through such a prolonged period of time. However, it is
only by virtue of the neurones within the central nervous system that
the response is initiated, that it is regulated by changes in the cardiac
musculature, and finally that the response is carried out as an integrated
whole. The retention of a constant tension of carbon dioxide in the
blood by means of an adaptive blood vascular reaction, is therefore
mediated in the mammal through its higher central nervous organiza-
tion, particularly the cells within the medulla oblongata.

To Prof. F. H. Pike the writer is greatly indebted for suggestions,
advice and criticism, extended throughout the research.

CONCLUSIONS

1. The nerves of the heart are not essential either for the activation
or for the persistence of the characteristic pressor phenomena of the
anemic rise.

2. In the early stages of cerebral occlusion the cardiac innervation
functions as a check on the rapid rise of blood pressure. In this modera-
ting action, accelerators as well as vagi are involved, since on excision
of the stellate ganglia, the vagi alone are unable to prevent an abrupt
and steep rise of pressure.

3. The activation and maintenance of the vascular response under
cerebral occlusion is controlled essentially by the splanchnic nerves.

4. Differential section in various regions of the splanchnic outflow
influences the level of the arterial blood pressure. The extent to which
the pressure falls on section is an approximate index of the degree to
which the anemic rise will be compromised by the lesion.

44 CORA SENNEE WINKIN

5. It is impossible to influence the vascular response to anemia by
indiscriminate sections within the splanchnic outflow. In order defi-
nitely to abolish the response, it is necessary to section either suffi-
ciently far out in the periphery, or sufficiently high up in the spinal cord
to interrupt completely the continuity between the medulla and the
coeliac ganglion.

6. The level at which the fibers of the splanchnic system leave the
spinal cord varies in different individuals. The greatest number of
fibers leave the cord in the lower thoracic, especially in the region of the
6th to 8th thoracic. However, constrictor fibers to the splanchnic
nerves leave the cord throughout the higher levels of the thoracic cord.
In certain individuals, fibers leaving as high as the 2nd and 3rd thor-
acic will maintain an appreciable level of blood pressure and activate
a significant anemic response.

7. Cerebral occlusion, carried out in repeated succession, is borne
indefinitely (as many as 18 times) in intact animals. The occlusion
time is in no way curtailed and the anemic increment of blood pressure
only slightly diminished.

8. The curve of the anemic rise under repeated cerebral occlusion
becomes dissociated into two distinct parts after eight or ten successive
occlusions have been inflicted.

9. The long-continued maintenance of blood pressure at an extremely
high level, characteristic of the anemic rise, is no longer possible after
any gross interference with the supply of some product of adrenal
activity.

10. An increased liberation of adrenalin under extreme splanchnic
stimulation cannot be demonstrated as necessary for the characteristic
contour of the anemic rise. This appears dependent on the amount of
circulating adrenalin.

11. An increased availability of some product of adrenal activity
appears demonstrable in intact animals under extreme splanchnic stimu-
lation, after eight or ten successive occlusions have been inflicted.

12. Survival after ligation of the adrenal glands may be reduced to
1 or 2 hours, when the animal is subjected to successive repeated cere-
bral occlusions. A complete failure of vasomotor tone seems demon-
strable in these animals.

13. The response of the splanchnic nerves is dependent for its release
on conditions of functional activity within the brain stem.

14. The vasomotor responses initiated by the splanchnic nerves of
the sympathetic nervous system are comparable with skeletal responses

CARDIOVASCULAR CHANGES DURING CEREBRAL ANEMIA 45

dependent on the higher nervous levels, in respect to their complete
dependence on these levels of the central nervous axis.

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CURRICULUM VITAE

Cora Senner Winkin was born in the city of New York, March 23, 1893.
She was prepared for college at the Ethical Culture High School, from
which she graduated in 1911. She received the degree of A.B. from
Barnard College in 1916, and was admitted to the graduate school of
Columbia University in the same. year.

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