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.

133

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).


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).


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.


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


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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iol. 189: 132, 1957.

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No.2WORTHEN, PLACIK, ARGANO, MACCANON, AND LUISADA 141

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Documents

On the Mechanism of Epinephrine-Induced Pulmonary Edema* M