Download Effect of Hypertonic Saline on the Pulmonary and Systemic Pressures

Effect of Hypertonic Saline on the Pulmonary
and Systemic Pressures
By
M. ELIAKIM, M.D.,
S. Z. ROSEXBERG, M.D.,
AXD K. BRAUX,
M.D.
The intravenous injection of 20 per cent saline in anesthetized closed chest dogs causes a
rise in pulmonary venous, pulmonary arterial, right ventricular and peripheral venous
pressures. Left atrial pressure does not change or falls, and systemic arterial pressure
decreases very markedly. These changes are shown to result from spasm at the pulmonary vein—left atrial junction. Stimulation of chemoreeeptors in this region is
assumed to be the cause of the spasm.
I
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atrial and the pulmonary venous pressures were
measured simultaneously after left thoracotomy
had been performed. Catheters were introduced
into the left atrium through the atrial appendage
and forwarded approximately into the middle of
the left atrium, and into one of the main left pulmonary veins, the tip lying about 3 cm. away
from the heart as verified by palpation. A free
flow was obtained from all catheters during the
experiment. The location of the catheters was
verified again at the conclusion of each experiment. In these open chest experiments, artificial
positive pressure breathing was maintained. Catheters were also introduced into the abdominal
aorta and the inferior vena eava. Blood pressures were measured by two electromanometei's
(Sanborn) and two strain gage transducers
(Statham), and recorded on a four-channel direct writer. Respiration was recorded by means
of a rubber chest pneumograph.
A 20 per cent saline solution was injected in
a dose of 1 nil./Kg. The total volume of fluid
was administered within 10 sec. The sites of injection were femoral vein or inferior vena cava,
pulmonary artery, common carotid artery, and
aorta.
A total of So injections were given: 62 into the
femoral vein or the inferior vena cava, 9 into
the pulmonary artery, 10 into the descending aorta, and 4 into the common carotid artery. Several types of experiments were performed after
injection into the peripheral veins or the pulmonary artery. Pressure was simultaneously
measured in the pulmonary artery, the aorta
and the inferior vena eava 25 times; pulmonary
artery and aorta 16 times; pulmonary artery,
aorta and left atrium 14 times; pulmonary artery> right ventricle and aorta 6 times; pulmonary
artery, pulmonary vein, left atrium and aorta
7 times; and pulmonary artery, pulmonary wedge
pressure and aorta 3 times. In all experiments in
which the injection was made into the descending
aorta or the common carotid artery, pulmonary
arterial, aortic and peripheral venous pressure was
T HAS been shown that the intravenous
injection of a 20 per cent saline solution
in dogs causes a decrease of systemic blood
pressure and a marked brief rise of pulmonary arterial pressure. 1 ' - This effect was
obtained when the injection was made into
the isolated lung in situ, perfused with a constant quantity of blood.1 The rise of pulmonary arterial pressure was attributed to spasm
of the pulmonary arterioles. 2
The present study was carried out in order
to clarify the mechanism of the effect of hypertonic saline solution on the pulmonary vascular tree in the closed chest dog.
METHODS
Twenty-five mongrel dogs weighing between 14
and 24 Kg. were used. Anesthesia was induced
by sodium thiopental, 0.03 Gm./Kg. intraperitoneally and was maintained, as needed by 0.08 to
0.16 Gra. of sodium pentobarbital intravenously.
Heparin, 0.03 to 0.05 Gm., was given intravenously at the beginning of the experiment to prevent
clotting in the catheters. Right heart catheterization was performed via the right jugular vein.
Left atrial pressure was measured in 2 dogs directly by introducing a needle through a bronchoscope and puncturing the anteroinedial surface
of the right main bronchus to enter the left
atrium. The location of the needle in these 2
cases was indicated by the low pressure, the presence of arterial blood and by recording a typical
atrial pressure pulse tracing. In 6 dogs the left
From the Cardiovascular Unit and Department of
Internal Medicine, Division B, Rothschild Hadassah
University Hospital, Jerusalem, Israel.
Supported by a grant from the Hadassah Medical
Organisation Research Fund.
Received for publication January 17, ]958.
357
Circulation Research. Volume VI, May 1958
358
ELIAKIM, ROSENBERG AND BRAUN
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FIG. 1. Twenty per cent saline (1 ml./Kg.) intravenously. Closed chest experiment. Time
of injection in figures 1-4 is marked at bottom of record. Time in seconds. Note the
marked rise in pulmonary arterial pressure, the decrease in aortic pressure, the rise in
peripheral venous pressure and the apnea, followed by hyperpnea. These immediate changes
are followed by a second wave of similar changes.
measured. Respiration was recorded in almost
all experiments, and electrocardiograms in 10
experiments.
Control experiments with the same quantities
of normal saline and a 50 per cent solution of
glucose were performed.
RESULTS
Injection of hypertonic saline solution into
the femoral vein or the inferior vena cava
(fig. 1) was followed within 4 to 8 sec. by a
long period of apnea usually succeeded by
slight hyperpnea. In all experiments the
aortic pressure fell very markedly, sometimes
reaching 5 to 10 mm. Hg. This effect lasted
about 20 sec. A second fall of aortic pressure,
usually less pronounced, was frequently observed approximately 10 sec. later. The aortic
pressure returned to normal within 60 to 90
sec. Sometimes, when the first wave of pressure fall persisted, it fused with the second
wave.
Marked changes were observed in the lesser
circulation. Pulmonary venous (fig. 2) and
wedge pressures showed a marked rise, followed one beat later by an increase of pulmonary arterial pressure (fig. 3) and a fall
in left atrial pressure (fig. 2). The left atrial
pressure, however, sometimes showed no
change (fig. 3). The right ventricular and
the peripheral venous pressures (fig. 1)
showed changes similar to those in the pulmonary artery. The rise of pulmonary arterial pressure and the fall in left atrial pressure preceded the fall in aortic pressure. The
change of pressures in the lesser circulation
and in the peripheral veins usually lasted
less than 20 sec. and was frequently succeeded by a second wave of similar changes,
simultaneous with the second bout of aortic
pressure fall. The electrocardiogram showed
bradycardia and other marked changes which
will be described separately.
Following vagotomy, the injection of hypertonic saline solution no longer caused apnea,
and resulted in either no change or a slight
increase or decrease in the respiratory rate.
Bradycardia was also abolished. However,
vagotomy did not affect the changes in blood
pressure following hypertonic saline (fig. 4).
Atropine and phentolamine (Regitine) also
had no effect on the pressure changes caused
by hypertonic saline solution. However, in
PULMONAEY VENOUS CONSTRICTION
359
LATKtUM
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FIQ. i. Twenty per cent saline intravenously following bilateral cervical vagotomy. Closed chest experiment. Time in seconds. Note lack of response of
respiration and absence of bradycardia. The pressure
response is not altered by vagotomy.
FIG. 2 Top. Twenty per cent saline intravenously.
Open chest experiment. Time in seconds. Note the
very marked rise in pulmonary venous and pulmonary
arterial pressures, and the fall in left atrial and
aortic pressures. Bradycardia follows the injection.
The dog died after this injection.
FIG. 3 Bottom. Twenty per cent saline intravenously. Open chest experiment. Paper speed 25
mm./sec. The rise in pulmonary venous pressure
precedes the rise in pulmonary arterial pressure by
one beat. Left atrial pressure shows no change.
Marked braycardia follows the injection.
•3 experiments, the administration of hexamethonium appeared to accentuate the response to the hypertonic saline solution.
Injection of hypertonic saline into the pulmonary artery resulted in changes in respiration and pressures similar to those seen after
an intravenous injection, but the response
occurred only after a latent period of 2 sec.
Repeated injections of hypertonic saline into
either the peripheral veins or the pulmonary
artery of the same dog usually caused a lesser
response (tachyphylaxis).
Control experiments with injection of a 50
per cent glucose solution or isotonic saline
into the peripheral veins or the pulmonary
artery had no effect on respiration and on the
pressures at the various points of the circulation.
The injection of hypertonie saline into the
descending aorta caused, within 5 sec. respiratory arrest which lasted several seconds.
During the period of apnea there was a
marked rise of peripheral venous pressure
and a slight rise of aortic and pulmonary
arterial pressures. All changes in blood pressures disappeared with resumption of respiration. Similar changes in respiration and
blood pressures were caused by the injection
of a 50 per cent glucose solution into the
descending aorta while equal quantities of
isotonic saline were completely without effect.
The injection of 20 per cent saline into the
common carotid artery caused apnea, bradycardia, a fall in aortic pressure, a slight rise
of pulmonary arterial pressure and no appreciable change in peripheral venous pressure.
ELIAKIM, ROSENBERG AND BRAUN
360
DISCUSSION
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The results presented demonstrate that the
rapid intravenous injection of a 20 per cent
saline solution causes a very marked rise in
pressure in the pulmonary veins, the pulmonary artery, the right heart and the peripheral veins. Left atrial pressure either does
not change or decreases, and aortic pressure
f alls to very low levels. Apnea and bradycardia appear as well. The pressure gradient
between the pulmonary veins and the left
atrium suggests very strongly that the cause
of this profound changa in pressures is spasm
at the pulmonary vein-left atrial junction.
Spasm at this site leads to trapping of blood
in the lung VPS^PIS and diminished inflow to
the left heart, thus causing a rise of prassure
in the lesser circulation and a fall of pressure
in the systemic circulation. We have no evidence for additional factors leading to systemic arterial hypotension, though such factors may exist.
The presence of a sphincter at the venoatrial junction has been known to anatomists
for many years,3 and a "throttle valve"
action has been ascribed to it.4 Its activity
in man has been demonstrated by angiocardiography.5 Spasm of the large pulmonary
veins in vitro has been produced by acetylcholine, epinephrine and histamine.8 A venoconstrictive effect of carbon dioxide in the
isolated perfused lung of the cat7 and of the
dog8 has been also demonstrated.
As mentioned, pulmonary venous spasm
leads to pulmonary vascular congestion and
possibly to pulmonary edema. Some data
obtained in animals with pulmonary edema
suggest an increase in pulmonary arterial
pressure which might be due to venoconstrictiou."~u It is evident from the very marked
effect of the hypertonic saline solution that
pulmonary venous spasm may play an important role in the development of pulmonary
edema. Lung biopsy taken at the heights of
the pulmonary arterial pressure rise following the injection of hypertonic saline solution shows extreme congestion of the pulmonary capillaries (fig. 5).
The mechanism by which hypertonic saline
Flo. 5. Top. Lung biopsy before injection of 20
per cent saline intravenously. Bottom. Lung biopsy
takon at peak of blood pressure rise in the pulmonary
artery after the injection. Note marked congestion
of capillaries. X 100. H. & E. stnin. (By courtesy
of Dr. A. Bechar, Department of Pathology.)
causes pulmonary venous spasm is still not
clear. It has been shown that raising the
pressure in the pulmonary artery, by perfusion or by ligatiug the pulmonary veins, will
cause a fall in systemic pressure and bradycardia.12 Sensory fibers in the venous side
of the pulmonary vascular tree have been suggested as receptors of this reflex reaction.
However, this reflex is abolished by vagotomy.
There is no doubt that the rise of pulmonary
arterial pressure and the other phenomena
caused by the injection of hypertonic saline
solution are not due to the mechanical effect
of the injection. Any mechanical effect of
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PULMONARY VENOUS CONSTRICTION
361
such a small volume of fluid administered into
the peripheral veins would most likely be dissipated before reaching the pulmonary circulation. Furthermore, experiments with similar quantities of normal saline solution had
no effect. Similarly, injections into the pulmonary artery gave rise to no effect which
could be ascribed to mechanical causes since
such a mechanical effect would have been
abolished by vagotomy. The rapid infusion
of large quantities of normal saline, isotonic
glucose, whole blood or dextran solutions in
man have been shown to raise the pulmonary
arterial and capillary pressures.13 This rise,
however, appears slowly, lasts longer, and is
accompanied by no change in systemic pressure, respiration and pulse rate. An increase
of blood volume has been considered the cause
of this phenomenon. It ma}' be argued that
the hypertonic saline elevates the pressure in
the pulmonary vascular bed by increasing pulmonary blood volume by virtue of its hypertouicity. However, this mechanism of action
is improbable because it does not explain
either the drastic fall of systemic pressure or
the apnea. Furthermore, control experiments with injections of a hypertonic glucose
solution had no effect whatsoever.
ble for the latter effect. Xonvagal reflexes
leading to systemic vasodilatation have been
described by Moe and Gruhzit.1"' The receptor
area for this reflex is probably in the thoracic
aorta, and thoracic sympathectomy abolishes
the reflex. However, the change in pressures
produced by hypertonie saline solution is not
affected by hexamethonium and phentolamine.
This speaks against a mechanism similar to
that of the reflex described by Moe and
Gruhzit.
The most probable explanation of the
mechanism of the Drofound changes caused by
hypertonic saline solution is that the spasm
of the pulmonary vein-left atrial junction is
a direct result of the high concentration
of NaCl. Cells sensitive to a high concentration of either Na+ and/or Cl~ may be
present in this area, and their response to this
stimulus may he spasm. Our current experiments show that equivalent hypertonic solutions of sodium iodide, sodium fluoride,
sodium thiocyanate, sodium sulfate and lithium chloride have a similar effect on the pulmonary circulation.
The effect of hypertonic saline solution injected into the descending aorta is mediated
through a different mechanism, the nature of
which is unknown. It is probably dependent
on the hypertonicity of the solution, since
hypertonic glucose solution produces similar
results. No further attempt was made to
clarify this mechanism since injection of both
hypertonic saline and glucose solutions into
the descending aorta served as control experiments in this study.
The syndrome of apnea, bradycardia and a
fall of systemic blood pressure has been experimentally produced by the injection of
veratrine derivatives, nicotine, adenosine triphosphate, heterologous serum, various amidiiies and 5-hydroxytryptamiue. 14 The last
substance has been shown to cause a rise of
pulmonary arterial pressure as well. The
reflex action caused by these substances has
been shown to originate in the left ventricle
and in the lungs.14 The effect of all these
substances is abolished by vagotomy, in contrast with the changes produced by hypertonic saline. In our experiments vagotomy
abolished only the apnea and the bradycardia,
but did not affect the change in pressures.
This fact indicates that the effect of hypertonic saline on the respiration and the heart
rate is dependent on a mechanism different
from that of the effect on the pressures. A
nonvagal reflex mechanism may be responsi-
SUMMARY^
The effect of intravenous injections of 20
per cent saline on the pulmonary and systemic pressures was examined in 25 anesthetized dogs.
Marked rise of pulmonary venous, pulmonary arterial, right ventricular, and peripheral venous pressures followed the injection.
Left atrial pressure did not change or decreased and aortic pressure dropped to very
low levels. Apuea and bradyeardia were also
observed.
362
BLIAKIM, ROSENBERG AND BRAUN
The changes in pressure and respiration
were not affected by the administration of
atropine or phentolamine. Hexamethonium
apparently accentuated the pressure response.
Vagotomy abolished the respiratory response
and the bradycardia, but did not alter the
response of pressures.
It is assumed that the change in pressures,
following the intravenous injection of hypertonic saline, is caused by spasm at the pulmonary vein-left atrial junction, as a result
of stimulation of chemoreceptors at this site,
sensitive to high concentrations of Na+ and/
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or cr.
SOMMAKIO IN INTERLINGUA
Le effecto de injectiones intravenose de un
solution salin de 20 pro cento esseva studiate
in le pressiones pulmonar e systemic de 25
canes in stato anesthesiate.
Le injection esseva sequita per marcate augmentos del pressiones pulmono-venose, pulmono-arterial, dextro-ventricular, e peripherovenose. Le pression sinistro-atrial remaneva
le mesme o decresceva. Le pression aortic
descendeva a multo basse nivellos. Apnea e
bradycardia esseva etiam observate.
Le alterations del pression e del respiration
non esseva afficite per le administration de
atropina o phentolamina. Hexamethonio
accentuava apparaentemente le responsa
pressori. Vagotomia aboliva le responsa respiratori e le bradycardia sed non alterava le
responsa de pression.
Es postulate que le alteration de pression
post le injection intravenose de un hypertonic
solution salin es causate per spasmos al junction del vena pulmonar con le atrio sinistre,
resultante del stimulation de chimoreceptores
in iste sito que es sensibile a alte concentrationes de Na+ e/o de Cl~.
REFERENCES
1.
L., AND BUBSTEIN, M.: Sur Faction
vasoconstrictrice du serum sale hypertonique an niveau de la petite circulation.
Compts. rend. soc. de Biol. 145: 1766, 1951.
2. —, AND —: Sur les effets cardio-vasculaires
BINET,
du serum sale hypertonique. Compts. rend,
soc. de Biol. 147: 1997, 1953.
3. STIEDA, L.: Ueber quergestreifte Muskelfasern
in der Wand der Lungenvenen. Arch. Mikr.
Anat. 14: 243, 1877.
4. BUBCH, G. E., AND ROMNEY, R. B.: Functional anatomy and "throttle valve" action
of the pulmonary veins. Am. Heart J. 47:
58, 1954.
5. KJELLBERG, S. R., AND OLSON, S. E.: Roent-
genological studies of the sphincter meehism of the caval and pulmonary veins. Acta
Radiol. 41: 481, 1950.
6. SMITH, D. J., AND COXE, J. W.: Reactions of
isolated pulmonary blood vessels to anoxia,
epinephrine, acetyleholine and histamine.
Am. J. Physiol. 167: 732, 1951.
7. NISELL, 0 . : Reactions of the pulmonary ven-
ulea of the cat with special reference to the
effect of the pulmonary elastance. Acta
physiol. scandinav. 23: 361, 1951.
8. BEAN, J. W., MAYO, W. P., O'DONNELL, F.,
AND GRAY, G. W.: Vascular response in dog
lung induced by alterations in pulmonary
arterial C d tension and by acetyleholine.
Am. J. Physiol. 166: 723, 1951.
9. PAINE, R., BUTCHER, H. R., AND HOWARD, I.
A.: Heart failure and pulmonary edema
produced by certain neurologic stimuli. Circulation 5: 759, 1952.
10. AVIADO, D. M., JR., AND SCHMIDT, C. F . :
Respiratory burns with special reference
to pulmonary edema and congestion. Circulation 6: 666, 1952.
11. —, AND —: Pathogenesis of pulmonary edema
by alloxan. Circulation Research 5: 180,
1957.
12. — , Li, T. H., KALOW, W., SCHMIDT, C. F.,
TUBNBULL, G. L., PESKIN, G. W., HESS,
M. E., AND WEISS, A. J.: Respiratory and
circulatory reflexes from the perfused heart
and pulmonary circulation of the dog. Am.
J. Physiol. 165: 261, 1951.
13. DOYLE, J. T., WILSON, J. S., ESTES, E. H.,
AND WARREN, J. V.: The effect of intra-
venous infusions of physiologic saline solution on the pulmonary arterial and pulmonary capillary pressure in man. J. Clin.
Invest. 30: 345, 1951.
14. DAWES, G. S., AND COMBOE, J. H.: Chemoreflexes from the heart and lungs. Physiol.
Rev. 34: 167, 1954.
15. —: Reflex factors in the regulation of the
circulation. In Transactions of the Third
Conference on Shock and Circulatory
Homeostasis. H. D. Green, Ed. New York,
Josiah Macy, Jr. Foundation, 1954, p. 96.
Effect of Hypertonic Saline on the Pulmonary and Systemic Pressures
M. ELIAKIM, S. Z. ROSENBERG and K. BRAUN
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Circ Res. 1958;6:357-362
doi: 10.1161/01.RES.6.3.357
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