On the Mechanism of Epinephrine-Induced Pulmonary Edema* M ...
Transcript of On the Mechanism of Epinephrine-Induced Pulmonary Edema* M ...
On the Mechanism of Epinephrine-Induced
Pulmonary Edema*
M. WORTHEN, M.D., B. PLACIK, M.D., B. ARGANO, M.D.,
D. M. MACCANON, M.D., and A. A. LUISADA, M.D.
SUMMARY
The effect of a large dose of epinephrine in blood was studied in dogs. Pulmonary edema resulted both in the experiments in which injections were made into the carotid artery and in those with intravenous injections. Left ventricular systolic pressures rose more with intravenous than with in-tracarotid infusions. Left ventricular end-diastolic pressures rose drama-tically and rapidly but less with intravenous infusion. There was an increase of the dp/dt peak and ventricular dilatation in both types. Cardiac denervation followed by intracarotid infusion prevented or de-creased pulmonary edema in 4 out of 8 experiments.
It is concluded that the rise of left ventricular end-diastolic pressure is a primary factor for the increased pulmonary capillary pressure causing edema. This rise seems to be caused by adrenergic action and efferent sympathetic stimuli affecting both ventricular compliance and peripheral vasoconstriction rather than by myocardial failure in the usual sense.
Additional Indexing Words:
Heart failure Neurogenic pulmonary edema Left ventricular compliance
HE mechanism of the paroxysmal pulmonary edema which follows
surgical intervention on or lesions of the central nervous system has
caused considerable debate for a long time. Pulmonary edema has been suc-
cessively ascribed to •gacute left ventricular failure,•h31) •ga vasomotor crisis
of the lungs,•h129) or a •gvasomotor crisis of the systemic vessels•h with redistribu-
tion of blood19) (•gneurohemodynamic mechanism•h)25)-27) caused either
directly or through a carotid body reflex.18)
The present study will report on a new experimental method that has
been employed for the study of this condition.
From the Division of Cardiovascular Research, The Chicago Medical School, University of
Health Sciences, Chicago, Illinois.
This study was aided by Research Grant HE-09527 and was made during tenure of Training
Grants HE-5002 and HE-5182 of the National Heart Institute, U. S. P. H. S.
Received for publication October 26, 1968.
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134 MECHANISM OF EPINEPHRINE INDUCED PULMONARY EDEMA Jap. Heart J. March, 1969
METHOD
The total number of dogs used was 74. Three groups of experiments were
performed successfully on 29 mongrel dogs, weighing from 10 to 25Kg., anesthetized
with intravenous chloralose (100mg./Kg.) 30min. after premeditation with mor-
phine sulfate (5mg./Kg. subcutaneously). To these should be added 29 blood donor
dogs anesthetized with 10mg./Kg. of morphine sulphate. Local anesthesia was
also used in these animals.
Group I: In 12 experiments, 77ml./Kg. of blood (obtained from a donor dog)
containing 0.014mg./ml. of Winthrop •gSuprarenin•h (epinephrine) was infused
headward into the left common carotid artery of a closed chest, spontaneously
breathing animal at a rate between 25 and 55ml./min. The total dose of epine-
hrine was equivalent to 1.1mg./Kg. Both the donor and the recipient animal
were heparinized (10mg./Kg.). Prior to and during infusion, the blood was con-
stantly mixed by a magnetic stirrer and maintained at approximately 37•Ž. Number
7 or 9 Goodale-Lubin catheters were introduced into the left ventricle through the
left carotid artery for pressure recordings. The catheters were attached to Statham
P23Db pressure transducers, connected to Sanborn strain gauge amplifiers, and lead
II of the electrocardiogram was recorded. In some experiments, a third catheter
was used to obtain pulmonary •gwedge•h pressure; infusions of 10ml. of saline
in 9min. were made into the wedged catheter at various times during such experi-
ments. The first derivative (dp/dt) of left ventricular pressure was recorded in the
majority of the experiments. In some of the experiments, right ventricular pres-
sures were also measured through a venous catheter. Ten min. after the end of each
experiment, the chest was opened for evidence of foam in the trachea or in the cut
parenchyma and for the presence of hemorrhagic areas in the lungs. The lung/
body weight index was calculated in all experiments*.
Group II: This series of 10 experiments was the same as Group I except that
the infusion was given intravenously (femoral vein) rather than intraarterially.
Group III: In 8 experiments, surgical or pharmacologic cardiac denervation
receded the intracarotid infusion of epinephrine in blood. The denervations were
erformed in either of two ways: (1) by isolation of the roots of the aorta and
ulmonary artery followed by application of xylocaine to the area; or (2) by cutting
the cardiac branches of the vagus at their origin, the branches of the recurrent laryn-
geal nerves, the fibers arising from the stellate ganglia, the ansae subclaviae, and also
the trunks of the vagus and phrenic nerves. Alcohol and xylocaine were then
applied to the roots of the large arteries. In both cases, the effectiveness of the
denervation was tested by occluding the common carotid arteries, which yielded a
slight pressure rise and no change in heart rate. The epinephrine-blood infusion
was begun from 15 to 45min. after the end of the surgical preparation.
The lung/body weight index (1/10 of lung weight in Gm. divided by the body weight in
Kg.) of normal dogs is about 0.819. An index of 1 is evidence of congestion. An index above 1.2
is definite evidence of edema.19) Indices of between 1.5 and 4.5 were found in our experiments
resulting in pulmonary edema. The weight of the lungs was taken after clamping of the trachea close
to the bifurcation in order to avoid escape of foam. The lung vessels were cut and blood accumulated
was left free to escape prior to obtaining the weight.
Vol.10 No.2 WORTHEN, PLACIK, ARGANO, MACCANON, AND LUISADA 135
In 3 experiments, the left ventricular circumferential length changes were measured by means of a mercury gauge32) which was sutured to the left ventricle.
Cardiac output by the Fick principle was determined in 3 animals of Group I before and during blood-epinephrine infusion and, for comparison, in one where only epinephrine (standard dose in 50ml. saline) was injected intravenously (no pulmonary edema resulted from this experiment).
RESULTS
Group I: Pulmonary edema developed in all 12 experiments with lung/body weight indices ranging from 1.2 to 4.2 (Table I). In some experiments, those with a high lung/body weight index, bloody foam flowed from the mouth before the experiment was terminated while, in others, foam was present in
Table I. Summary of Findings
( ) indicate standard error.
P•…0.05
P•…0.01
Fig. 1. Standard experiment with intracarotid infusion. LV systolic
pressure rose to 250mm.Hg; LV end-diastolic pressure rose to 50mm.Hg. ulmonary edema resulted (lungs/body weight index=2.5).
136 MECHANISM OF EPINEPHRINE INDUCED PULMONARY EDEMA Jap. Heart J. March, 1969
Fig. 2. Standard experiment with intracarotid infusion (initial section). LV systolic pressure rose to 259mm.Hg; LV end-diastolic pressure rose to 33mm.Hg during 81sec., 42sec. after the injection. It rose later to 48.5mm.Hg. Pulmonary edema resulted (lungs/body weight index=3.8).
Fig. 3. High speed photographic recording in a standard experiment with intracarotid infusion. LV length was measured by a mercury gauge. LV dias-tolic pressure rose to 80mm.Hg and dropped to 57mm.Hg after the end of the infusion. The first derivative (dp/dt) of LV pressure had a remarkable increase throughout the experiment. Pulmonary edema resulted (lungs/body weight index=2.7).
Vol.10 No.2 WORTHEN, PLACIK, ARGANO, MACCANON, AND LUISADA 137
the trachea or was evidenced by squeezing the cut lung tissue. The left
ventricular systolic pressures increased by an average of 105.7mm.Hg and
the left ventricular end-diastolic pressure (LVEDP) by an average of 67.3mm.
Hg (peak). The rise of LVEDP was rapid (Figs. 1-3) and in some experiments
this pressure reached a level of 90mm.Hg. In a few experiments, in which
left atrial, pulmonary •gwedge•h*, pulmonary artery or right ventricular pres-
sures were also measured, such pressures increased like the left ventricular
diastolic pressures. The right ventricular systolic pressures increased by an
average of 70mm.Hg and the right ventricular diastolic pressures by about
one-half as much as the left ventricular diastolic pressures (peak values). The
first derivative of left ventricular pressure revealed a tremendous increase in
the magnitude of the early-systolic wave, which later decreased but remained
above control until the terminal stage (Fig. 3). The left ventricle was markedly
distended during these experiments, as noted from direct observation, as well
as the mercury gauge measurement of left ventricular circumferential length
(Fig. 3). Cardiac output was found to decrease by one-half in the two ex-
periments in which it was measured, and by three-fourths in the one experi-
ment in which a standard dose of epinephrine in 50ml. saline was injected
intravenously and did not result in edema. The electrocardiogram showed
sinus tachycardia, nodal bradycardia or tachycardia, multifocal ectopic beats
or ventricular tachycardia. Respiration became extremely shallow.
Group II: The 10 experiments with intravenous infusion of blood and
epinephrine all resulted in pulmonary edema. The lung/body weight indices
ranged from 1.5 to 3.4 and averaged 2.02 (Table I). The left ventricular
systolic pressures increased by an average of 167.4mm.Hg, which was signif-
icantly higher (51.7mm.Hg) than in Group I (Table I). The average of the
control systolic pressures in this series, however, was significantly lower than
in the experiments of Group I. The average of the peak diastolic pressure
rise was 56mm.Hg, which was 11mm.Hg lower than in Group I. This
difference barely missed statistical significance because, in a few experiments,
the control LVEDP values were already slightly elevated. The early-systolic
Fig. 4. Experiment in an animal after cardiac denervation. LV systolic
pressure rose to 400mm.Hg. LV end-diastolic pressure rose only to 10mm.Hg. There was no pulmonary edema (lungs/body weight index=1.0).
No evidence of pulmonary venoconstriction was obtained.
138 MECHANISM OF EPINEPHRINE INDUCED PULMONARY EDEMA Jap. Heart J. March, 1969
wave of the first derivative of left ventricular pressure was greatly increased
in the first few min. of the infusion and then decreased to or near the level
of the control value.
Group III: •gCardiac denervation•h altered the results in 4 experiments
while, in the others, the results were similar to those of Group I. Pulmonary
edema was absent in 2 experiments in which the peak end-diastolic pressure
stayed above 40mm.Hg for only 2min. in one, and reached only 10mm.Hg
in the other (Fig. 4). There was minimal pulmonary edema in 2 experiments,
one in which the diastolic pressure remained above 40mm.Hg for 13min.
and reached only a peak value of 34mm.Hg in the other.
DISCUSSION
Following clinical observation of the frequency of pulmonary edema in
trauma to the skull,1),22) cerebrovascular accidents,8),30) and other neurological
conditions,8) several experimental procedures were employed in order to
study which mechanism caused this form of pulmonary edema.
Luisada16),17) tried high pressure perfusion of the •gisolated•h head with
saline or blood and obtained severe pulmonary edema. However, demonstra-
tion that venous channels along the medulla and spinal cord still connected
the head to the trunk led him to discount his results. Jarisch et al.12) described
a form of pulmonary edema caused by intracisternal injection of veratrin.
Subsequent studies with this method by one of the authors and his co-
workers,2),11) as well as with intracisternal injection of thrombin and fibrinogen
by others,5) revealed that paroxysmal systemic hypertension preceded pul-
monary edema. This seemed at first to shift the emphasis from the central
nervous system to the left ventricle and to support Welch's view.28) However,
soon a new concept was advocated, that of a redistribution of blood causing
active congestion and edema of the lungs (Sarnoff and Sarnoff25)-27)).
As the original method of Luisada16),17) was followed by introduction of
fluid into the animal's body, Luisada and Sarnoff19) employed rapid intraca-
rotid infusions of saline toward the brain and obtained pulmonary edema with
volumes of fluid which did not cause edema when injected intravenously.
While the role of the central nervous system seemed proved by the preventive
effect of hypnotics, sedatives, and ganglionic blockers, the exact mechanism
remained elusive. Emphasis was first placed on the carotid sinus,19) then on
the carotid body.18)
Following a different line of experiments, several authors have studied
the effect of damaging discrete areas of the middle brain of animals (Glass,9)
Borison and Kovacs,3) Gamble and Patton,7) Gutman et al.,10) Seager and
Vol.10 No.2 WORTHEN, PLACIK, ARGANO, MACCANON, AND LUISADA 139
Wood,28) Wood et al.,33) Magoun et al.20)). The most sensitive area of the
brain seems to be located in the preoptic area; previous destruction of this
area prevents development of epinephrine-induced pulmonary edema in rab-
bits9) while its stimulation is followed by pulmonary edema in animals of dif-
ferent species.3),7),10),20),28),33)
More recently Kovach and co-workers14),15) started again the controversy
with a new series of experiments. They performed complete isolation of the
head of a recipient dog and perfused it from the trunk of a donor dog. A
large dose of epinephrine injected in the trunk of the donor caused pulmonary
edema in the lungs of both this animal and the recipient where the heart and
lungs were not reached by the drug. Measurements of left atrial pressure
showed an increase up to 20mm.Hg in the recipient dog. This rise, caused
by neurogenic impulses, was attributed to •gleft ventricular failure•h.
The present study was attempted to clarify many unexplained points of
Kovach's study. In one group of our experiments, epinephrine in blood was
directly injected headward where it had the highest concentration. It then
reached the other body tissues in lesser concentration, being diluted by the
animal's endogenous venous blood. In another group of experiments, epine-
hrine in blood was injected into a vein and presumably entered the vascular
beds of the head and trunk at similar concentrations. The most striking result
noted was a tremendous rise of left ventricular diastolic pressures to levels of
50 to 90mm.Hg. This rise was significantly less in the intravenously infused
animals than in those receiving intracarotid infusions. When the aforemen-
tioned experimental procedures were performed in open-chest, open-pericar-
dium animals, the LV diastolic pressure rise also occurred and marked dilatation
of the heart was noted. This rise of diastolic pressure might be considered
as related to left ventricular failure. However, the following facts do not
support such contention, at least in regard to the accepted meaning of this
expression:
a) In the first period of these experiments, this rise was reversible, in
spite of the presence of epinephrine in the blood.
b) The first derivative (dp/dt) of LV pressure showed a sharp increase
in the early-systolic wave, which persisted higher than control values almost
to the end. It is known that this derivative provides an index of myocardial
contractility.
c) Cardiac output decreased less in the standard experiments (Group
I) than in the controls with i.v. epinephrine that did not result in pulmonary
edema.
Both the injected volume of blood and the presence of circulating epine-
hrine were undoubtedly contributing factors. Increase in blood volume
140 MECHANISM OF EPINEPHRINE-INDUCED PULMONARY EDEMA Jap, Heart J. March, 1969
causes ventricular dilatation and an augmentation in the amount of blood contained in the pulmonary vessels. Epinephrine in massive doses causes systemic arteriolar and venular constriction13) and a shift of blood from the systemic to the pulmonary circulation.6) However, the additional blood alone had little or no effect, and the epinephrine alone caused moderate changes of LV diastolic pressure when injected into the carotid artery. The left ven-tricular systolic rise was significantly higher in the intravenously infused animals than in those receiving the headward infusions, even though LVS control values were significantly lower in the 4 infused dogs (Table I). This could be due to either the effect of the higher epinephrine concentration on the carotid sinus baroceptor mechanism in the headward infused dogs or some direct central nervous system stimulation. The greater left ventricular dias-tolic pressure rise in the headwardly infused dogs might also result from the same mechanism, being caused by the decreased cardiac sympathetic stimula-tion combined with the increased blood volume. Length-volume measurements were performed on one animal, comparing the infusion of blood and the infusion of blood with epinephrine. Epinephrine seemed to decrease the complianceof the left ventricle. Decreased distensibility as a result of epinephrine has been noticed by others.23) The tremendous increases in left ventricular diastolic
pressures observed in our experiments can be explained, at least in part, by this effect of epinephrine.
Cardiac denervation is often incomplete24) and thoracic ganglionectomy was found effective only in 4 out of 8 dogs tested.24) Therefore, the altered results obtained in this series of experiments in 4 out of 8 animals in preventing or decreasing both left ventricular end-diastolic pressure rise and pulmonary edema require explanation and should be considered significant. This seems to confirm an important role played by the cardiac nerves in the mechanism of pulmonary edema.
These findings are in line with observations made by others in rats,21) which suggest that lesions of the preoptic area result in pulmonary edema by releasing impulses from post-chiasmatic hypothalamic structures, which are normally inhibited by impulses from the preoptic area. Epinephrine might affect these reflexes, which would be abolished by cardiac denervation.
Other experiments including cross-circulation are being conducted in an attempt to further clarify the mechanisms of pulmonary edema.
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