PATHOGENESIS OF ACUTE PULMONARY EDEMA IN
SURGERY OF PULMONARY TUBERCULOSIS
Yanosuke SAGAW A
The Surgical Division of Tuberculosis Research Institute, Kyoto University(Received for publication July 30, 1960)

I.

INTRODUCTION

Backward heart failure due to weakness of the left ventricle was long thought
to be the chief cause of acute pulmonary edema.
In surgery for pulmonary tuberculosis there are certainly cases of pulmonary
edema which can be explained by this theory, but, on the other hand, we sometimes
meet cases in which the signs of pulmonary edema precede that of heart failure.
How are these cases to be explained? At least the theory of the backward heart
failure seems to fail in these instances.
Recently Altschule 1 ) gave his view on this matter. He concluded that thecause of pulmonary edema was an unbalance between transudation from pulmonary
vessels and absorption of the transudate into lymph canals.
This theory interested us so much that we began our researches by rediscussing it. But as we proceded we found out an important fault in this theory, too.
Histologically examined, the main changes in edematous lung occur in theperiarterial connective tissues, the interstitial tissues of the alveolar region and in
the alveolar spaces. In the periarterial connective tissues there are found the two
phenomena as Altschule referred to, transudation and absorption. In the alveolar
region, however, there are no lymph canals, and therefore there can be no absorption into lymph canals. Hence, we are afraid, Altschule's theory loses its validity,
too.
Thus the theories so far presented are not satisfactory, and we, through clinicaland experimental researches, have got a conclusion that will explain the processof pulmonary edema.
In the following we are going to report our researches.
II.

CLINICAL STUDY

In our institute and its affiliated hospital we have experienced 33 cases ofacute pulmonary edema during or after operations (Table 1). Studying them we
can reduce the thought-to-be inducing factors into two categories. One is ventilatory insufficiency and other is bleeding of a large amount of over-transfusion and14

Yanosuke SAGA WA
Table 1.

Operation methods performed

Operation methods

Cured

DeadTotal

Pneumonectomy
Lobectomy (including segmental resection)

17889

Thoracoplasty (including Cavernostomy)

35178

Table 2.
I)

II)

Inducing factors of acute pulmonary edemain pulmonary tuberculosis surgery

Ventilatory insufficiency(1)

Mechanical effects of ventilatory insufficiency(2)

Anoxia(3)Hypercapnia

Hemorrhage(1)

Acute bleeding of a large amount(2) Over-transfusion and -infusion after bleeding
Table 3.

Initial symptoms of pulmonary edema (in 33 cases)

Bloody and frothy sputa"
Wet rales· .. ·.. ·········
Cyanosis·24· .. · .. · .. ···· .. ·.. · .. · .. · .. · .. ··DyspneaHypertension···· .. ····· ·21·16···············118Paradoxical respiration
Coma···········································
Stridor
Edema on face.
.
. .. . .. .

3···························2
1.. . .. ... .
.. 1-infusion (Table 2). Initial symptoms on the onset are summarized in Table 3.
In them hypertension is worth consideration. It was at first thought to be theresult of hypercapnia due to the preceding pulmonary edema. But we found thaton high CO 2 breathing many tuberculous patients showed an increase of thepulmonary wedge pressure. One of them presented even as high pressure as thecolloid osmotic pressure of blood. This means that the retention of CO2 is not
the result but one of the causes of pulmonary edema.
III. EXPERIMENTAL STUDIES1)

Transudation of the blood components from the pulmonary vesselsa)

Lymphodynamics in dog's lung

Pulmonary edema, in short, begins with transudation from the pulmonaryvessels. Its onset and development are very acute. We wanted, therefore, toobserve the entire courses of the changes from the beginning to the end. For
this purpose we were at first going to employ Drinker's2)3)4)5) method: observing
the lymphodynamics of dog's lung at the site of the right lymphatic trunk. But
this method was not only artificial but also inconvenient because the experiment
was performed with the dog's chest opened and under regulated respiration. In

Pathogenesis of Acute Pulmonary Edema in Surgery of Pulmonary Tuberculosis

15

our experiments this method was improved so as to be done with the animal'schest kept unopen. Moreover there was a question in Drinker's method whether
the lymphodynamics at the site of the right lymphatic trunk represented directly
and exactly the transudation from the pulmonary vessels. Our answer to thisquestion was yes. In the periarterial region there were recognized not only
retention of the transudate and bleeding, but also reabsorption of the transudate
into the lymph canals nearby so much as to make hemolymph. This phenomenon
gives us an affirmative proof for the answer.
During under anesthesia the respiration of the dog was calm, and no remarkablechange in lymph flow and protein content of lymph was recognized. As therespiratory frequency increased, lymph flow also increased without any change inthe protein content.
On low oxygen breathing of about 10 vol.% O 2 an increase of lymph flow
together with a decrease of protein content occured promptly (Fig. 3). Thisshows an increased transudation from the pulmonary vessels. These changes
reduced their degree gradually and swung down back to the former levels promptly
after the room air respiration was recovered. But these both changes occurred
to the various degrees under other conditions also, such as high CO 2 breathing ofabout 10 vol.% CO 2 , bleeding of 20 cc/Kg. Wt. and liquid infusion of 100 cc/Kg. Wt.
Compared with these, under double loaded condition of simultaneous low
oxygen and high CO 2 breathing respectively of about 10 vol.% or during low
oxygen breathing under any respiratory resistance, lymph flow increased abruptly
so much as to make hemolymph and, besides, often did not diminish as time
passed and the hemolymph remained as it has been even after the load wasremoved (Fig. 2). In such a case pulmonary edema was established.
We classified pulmonary edema into four stages according to the degrees of
the histologic changes in the alveolar region. But the degree of changes seemedI----.. . ....--......oo-----r-----t-_--+.: __4

Protein (':?o)room Iair

30.12

low:-low O 2 - - - - - - " - ro<?m --;- O 2 - ; - ro<?mmrII
airiII0.10IIIIIII0.080.06
I0.04

:I

0.02

Lymph' flow (cc/min.)
IO'-----...l.---'--...L......--...L......--~--_c::!_::_--'----'-L---__:l__-JoFig. 1.

10203040506070Time (minutes) - - - Effect of low oxygen breathing (9.8 vol.%) upon thepulmonary lymph flow (dog).

16

Yanosuke SAGA WAI4II

3
0.26
0.24
0.22
0.20
d 0.180.16~ 0.14~ 0.120r;:::::0.10..c:0a 0.08>..
0.06-:l0.04

IProtein: low O2
room air ihigh COI2

roomairIIIIII·sIII

arterial blood lC02 : 4.18---+--' 49.5vol%{ O : 14.8 I
12.8vol%
2III

0.02
10Fig. 2.

2030
40Time (minutes) ------

Effect of simultaneous low oxygen (11.9 vol. %)and high CO 2 (12.7 vol. %) breathing upon thepulmonary lymph flow (dog).

in turn to be grossly determined by sort of the condition loaded. In the case ofthe single loaded breathing of low oxygen or high CO 2 , there was no changefound at all or, if any, of the first or the second stage at most. But under thedouble loading of simultaneous low oxygen and high CO2 breathing or underrespiratory resistance, changes of the third or the fourth stage, namely the verychanges of typical pulmonary edema, were often brought about.
b)

Water content of rabbit's lungAll experiments above were performed on dogs. As for rabbits, however, it
was difficult to observe the lymphodynamics of the lungs, so instead of that wemeasured the water content of the organ.
Because the method of measuring it so far used had some faults we havedevised a method employing the radioactive isotope p32 as a tracer.
The results gained in the experiments on rabbits were rather unexpected.
Even under the double loaded conditions as well as under the single, the watercontent of the lungs was within the normal range, and histologically there wasalso no or, if any, very slight change of within the second stage. Much the same
was true after bleeding or infusion. In these cases the water content of thelungs changed temporarily for a time but by and by returned to the normal value,
and the histologic changes were also very slight.

Pathogenesis of Acute Pulmonary Edema in Surgery of Pulmonary Tnberculosisc)

17

Summary of the preceding two sections

Now we can summarize the results of our experiments so far as follows.
(1) No pulmonary edema is caused in lungs of dogs nor rabbits by either
low oxygen or high CO 2 breathing of within clinically available vol. % and byvenesection (bleeding) or infusion of clinical volume.
(2) Pulmonary edema is caused in lungs of dogs but not of rabbits by thedouble loading of simultaneous low oxygen and high CO 2 breathing and by anoxia
under respiratory resistance.
d)Reserve vessels

Where does this difference as above between the two animals come from?
As is well known, somewhat increased pulmonary blood flow or blood volume
does not always bring about a rise of the pulmonary arterial pressure. This fact
has been explained by assuming that dilation of the vessels and recanalizationof the reserve vessels meet enough the increased pulmonary blood flow or volume.
The assumption was ascertained to be true by our microscopic observation on
the living peripheral pulmonary vessels of rabbits which revealed blood arrests
here and there which suggested the existence of reserve vessels.
Injection of adrenalin and physiological saline solution can give rise to atypical pulmonary edema. By a continuous observation through the course we
could see a row of changes continuing one after another, in the order of the process
recanalization of the reserve vessels, filling up of arterioles, venuoles and capillaries by erythrocytes and their leakage into the alveolar spaces.
Recanalization of the reserve vessels was demonstrated also under the single
loading of low obygen or high CO 2 breathing, under the double loading of thesetwo conditions and after liquid infusion.
On dogs, however, microscopic observation of the living lungs was not available and we could not but employ Aviado's6) method in an attempt to measure
20001500if)......

room airc;:l0uhigh CO~low O~

room air

1000

500

arterial blood{ O2 : 14.5
CO2 : 45.2

10.3vol(Jo• 49.9voI%
3040
Time (miniutes) - - - - -Fig. 3.

Pulmonary blood volume under simultaneous low oxygen(9.6 vol. %) and high CO 2 (10.1 vol. %) breathing (dog,measured by P32).

18

Yanosuke SAGAWA

the blood volume in the alveolar vessels.
Under the single loading of low oxygen or high CO2 breathing both in theconcentration of about 10 vol.%, the count number increased for a short time
but soon followed the normal pattern of the decaying curve.
Under the double loading the count number remained increased continuously
through the period (Fig. 3). This means in dogs the double loading may causea lasting unususal dilation of the peripheral pulmonary vessels.
e)Summary of the preceding section

In case when the pulmonary blood flow or volme increases(1) The unusual dilation of the peripheral pulmonary vessels occurs for ashort time,(2) The recanalization of the reserve vessels and physiologic dilation of thestanding vessels soon meet the increase,(3) Then, when at last the balance is lost the vessels dilate again unusually,
and,(4) If that state continues the transudation begins, and then pulmonary edema
is established.
Thus, for the development of pulmonary edema regardless of the inducing
factors, the determinant role is always played by the breakdown of the balance
between the pulmonary blood flow or volume and the reserve of the pulmonary
vascular bed. Thinking of this it appears to be amount of conditions loaded
rather than sort that matters primarily.
In pulmonary tuberculosis surgery every operation does essentially reduce
the pulmonary vascular bed and every patient has the reserve vessels which have,more or less, already diminished before operation. Under such a situation, anyothe surplus unfavorable factor readily gives rise to the unbalance as above mentioned and works enough to induce pulmonary edem.
f)Electron microscopic evidence

It is easy to presume that a long lasting unusual dilation of the peripheral
vessels brings about their rupture. We ascertained this by electron microscopic
observation.
Under pulmonary edema the endothelial covering of capillaries loses its continuity, alveolar cells fall off detached from the endothelium, and the endothelial
cells are vacuolated. These changes represent the very rupture of the vessels.
2)

Reabsorption of the transudatea)

Absorption into blood vessels

After physiological saline solution containing p32 was injected into the alveolar
spaces through the respiratory tract, absorption into blood vessels was measured
in comparison with density in blood after intravenous injection. It was unexpectedly revealed that the physiological saline solution could be absorbed from

Pathogenesis of Acute Pulmonary Edema in Surgery of Pulmonary Tuberculosis

19

alveolar spaces as fast as in the case of intravenous injection.
This result, together with the fact that absorption into lymph canals takes
place only so little, is thought to suggest that absorption of any liquid fromalveolar spaces is performed chiefly through alveolar blood capillaries. On low
oxygen or high CO2 breathing the absorption diminishes temporarily, but when
the load removed it increases again. This means that while the local changes
are reversible liquid goes out or comes into the blood capillaries versatilely. But
when the local changes become of so high degree as to be irreversible thetransudated liquid can no longer be absorbed into blood vessels even after theload is removed.
b)Absorption into lymph canals

Absorption of physiological saline solution into lymph canals much delays ascompared with into blood vessels. It seems that in absorption of liquid in alveolar
region lymph canals do not take almost any role in any instances. Lymph canals
are available only in absorption of transudate in bronchioles proximal of theperipheral parts of terminal bronchioles and in the periarterial connective tissues.
Altschule's theory, as previously mentione, fails in the alveolar region just wherepulmonary edema takes place.
IV.

SUMMORY

In pulmonary tuberculosis surgery pulmonary edema is induced when thebalance between the intrapulmonary blood flow or volume and the reserve of thepulmonary vascular bed comes to be broken. The former increases by anoxia,
hypercapnia, blood transfusion, liquid infusion and so forth (extrinsic factors).
The later decreases in pulmonary-diseased patients and after chest operation.
(intrinsic factor).
As to the direct cause of acute pulmonary edema in pulmonary tuberculosis
surgery we give a leading role to a decrease or extinction of the reserve vessels
and the diminished dilatability of the peripheral vessels.
REFERENCES
1)
2)
3)
4)
5)
6)

Altschule, M. D.: Acute Pulmonary Edema., Grune and Stratton, 1954.
Drinker, C. K.: ]. A. M. A., 122: 269, 1943.
Drinker, C. K. et al: ]. Exper. Med., 86: 7, 1947.
Drinker, C. K.: Am.]. Physiol., 156: 35, 1949.
Drinker, C. K.: The Clinical Physiology of the Lungs., (Japanese translation K. Tadai) 1954.
Aviado, D. M. et al: Am.]. Physiol., 169: 460, 1952.