H[arry] Gideon Wells.

Chemical pathology; online

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We may consider it as follows : In the blood we have certain
proportions of readily diffusible crystalloids and of non-
diffusible colloids. If no metabolic processes were going on in
the tissues, we should have the diffusible substances leaving the
vessel-walls (leaving out, for the present, any question of activity
on the part of the endothelium) until an osmotic equilibrium
is established in the tissues and in the blood. As a matter of
fact, however, the blood proteids are not absolutely non-dif-
fusible, but small quantities do pass through the capillary walls,
and so lymph under such a hypothetical condition would consist
of a mixture of the same osmotic concentration as the blood
plasma, with about the same proportion of crystalloids, but a
smaller proportion of proteids ; this, it will be noticed, is just
about the composition of normal lymph. During life, however,
the cells of the tissues are causing metabolic changes in these
lymphatic constituents, and these changes consist chiefly in
breaking down large molecules of proteids, carbohydrates, and
fate into much smaller molecules. Now the osmotic pressure
of a solution is dependent upon the number of molecules and
ions it contains, hence by breaking down these few large mole-
cules with very little osmotic pressure into many small mole-
cules, the osmotic pressure in these cells and tissues becomes
raised above that of the blood-vessels, and consequently water
flows out of the vessels because of the increased pressure. We
see here the probable explanation of the stimulating influence
of metabolic products upon the formation of lymph,, noted by
Hamburger, Heidenhain, and others. For suggesting and urging
the importance of osmotic pressure in the formation of lymph
we are indebted particularly to Heidenhain, v. Korfinyi, 1 J.
1 Zeit. f. klin. Med., 1897 (33), 1 ; 1898 (34), 1.

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Loeb, 1 and Roth. 2 Loeb shows very clearly the relative greatness
of the water-driving force of osmotic pressure as compared to
that of blood pressure, by his statement that the osmotic pressure
of a physiological salt solution is about 4.9 atmospheres, which
is twenty times as great as the blood pressure with which we have
to do in ordinary physiological experiments. In varying osmotic
conditions we may readily see an explanation for the increased
lymph flow that occurs during tissue activity ; namely, it is due
to the increased formation of metabolic products. Many of the
lymphagogues may act similarly by stimulating metabolic activ-
ity, with resulting increase in the formation of osmotic pressure-
raising products of metabolism in the organs ; e. g., the increased
lymph flow from the thoracic duct that follows stimulation
of hepatic activity by injection of peptone (Heidenhain) or
ammonium tartrate (Asher and Busch 3 ). As we shall see later
in considering edema, osmotic pressure plays an important part
in the pathological formation of lymph.

Summary. — We see from the above discussion that
numerous theories have been advanced to explain the normal
formation of lymph, and as their basis exist several different
possible factors. Filtration, active secretion by the capillary
endothelium, attraction by the tissue-cells, osmosis in response
to formation of crystalloids outside the vessels ; all have been
shown to be possible causes of lymph formation. It is highly
probable that in a certain way all are involved, particularly if
we accept the view of the physical school that " secretion " and
" attraction " by the cells are merely the outcome of osmotic
forces ; the causes of lymph formation then reduce themselves
to two, filtration and diffusion. There has been, until recently,
no question but that lymph does escape from the vessels through
simple filtration, for the pressure inside the capillaries is pre-
sumably greater than outside, the capillary walls are not water-
tight, and they are not impermeable to the substances dissolved
in the plasma. 4 Likewise osmotic exchanges surely go on
between the vessels and the tissue-cells. The question that
remains is, do these two factors account for all of the lymph
formation, and are they sufficient by themselves to explain the

^Auger's Arch., 1898 (71), 457.
'Englemann's Arch., 1899, p. 416.

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physiological regulation and the pathological variations in the
lymph flow ? They are purely physical or mechanical causes,
and the " vitalist " school will claim that they are inadequate and
that " vital activities " of the cells play the deciding r6le. But
at present the evidence that is being accumulated seems to point
more and more strongly to the conclusion that these " vital activ-
ities " are but the result of simple well-known physical forces
acting under very complex conditions — complex because of the
large number of very different chemical compounds occurring
together, and the varying influence of circulation, food supplies,
cell structure, etc.


By no means all the fluid that escapes from the vessels,
nor all the products of cell metabolism are carried away in
the lymph — a considerable and perhaps the greater part of them
is absorbed back into the capillaries directly. A classical proof
of this is the experiment of Magendie, who observed that if
poisons were injected into the leg of an animal, which had been
separated from the body entirely except for the blood-vessels,
that poisoning developed in the usual manner. In such experi-
ments the lymph-vessels are severed and probably largely
occluded, hence it does not solve the question as to whether
substances are absorbed by the blood-vessels under normal con-
ditions. Orlow found, however, that during absorption of fluid
from the peritoneal cavity there is no perceptible increase in the
lymph flow from the thoracic duct. Addition of sodium fluoride,
a protoplasmic poison, was found to interfere with this absorp-
tion, for which and other reasons Heidenhain and Orlow con-
sidered that the absorption depended upon the " vital activity "
of the cells. More nearly reproducing normal conditions were
the experiments of Starling and Tubby, who found that
methylene-blue or indigo-carmine injected into the pleura or
peritoneum appeared in the urine long before it colored the
lymph in the thoracic duct. 1 Adler and Meltzer found evidence,
however, that not all the absorption is accomplished by the
blood-vessels, for obstruction of the thoracic duct retards absorp-
tion. That the absorption is not dependent solely upon the
circulation and blood pressure is shown by the fact that absorp-
tion from the peritoneal cavity occurs in dead bodies (Ham-
burger, Adler and Meltzer).

The nature of the mechanism by which fluids are taken into

1 See Mendel, Amer. Jour. Physiol., 1899 (2), 342.

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the blood-vessels is still unknown. We can easily understand the
entrance of injected poisons and coloring- matters from the tissues
into the blood, because they are more concentrated at the point
of injection than in the blood, hence they may diffuse directly
through the capillary wall. Likewise we can understand the
diffusion of water from a hypotonic solution into the blood, but
how a solution of the same concentration as that of the blood
can enter the blood is difficult to explain. Cohnstein and also
Starling attribute this absorption to the proteids of the blood
in the following manner : After a fluid is injected into the
tissues or serous cavities there occurs a diffusion exchange be-
tween this fluid and the blood, until the concentration of the
crystalloids in each is equal ; but the proteids of the blood can-
not diffuse, and as they exert a positive although very slight
osmotic pressure, this difference in osmotic pressure in favor of
the blood causes diffusion of the extravascular fluid into the
blood. Roth has also applied this idea in a rather complicated
manner to the absorption occurring in metabolic processes (see
Meltzer), but it must be admitted that it is an unsatisfactory
solution of the problem.

Passage of the fluid from the tissues into the lymph stream
was very easy to understand in the light of the older conception
of the lymphatic circulation, namely, that the lymph-vessels
were merely continuations of the interstitial spaces ; we could
then assume that as soon as the fluid left the blood-vessels it
was practically within the lymphatic system, and was crowded
along the lymphatic channels by the vis a tergo, aided by the
valves of the lymph- vessels and the intrathoracic vacuum. But
it now seems, particularly through the studies of MacCallum, 1
that the lymphatic vessels form a closed system, not in com-
munication with .the interstitial spaces. This being the case,
we have to explain the passage of the lymph through the walls
of the lymphatic vessels, and this is a problem which is not by
any means a simple one, and which has yet to be investigated.


With the facts and hypotheses mentioned in the preceding
paragraphs in mind, we may consider their bearing on the pro-
duction of abnormally large accumulations of lymph in the tis-
sues, that is, edema. We can imagine any one of the following
factors as causing or helping to cause such a pathological accum-
ulation :

1 Johns Hopkins Hosp. Bull., 1903 (14), 1.

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1. Obstruction to outflow through the lymph- vessels.

2. Increased blood pressure.

3. Decreased extravascular pressure.

4. Increased permeability of the capillary walls.

5. Increased filterability of the blood plasma.

6. Osmotic pressure changes— either an extravascular in-

crease or an intravascular decrease.

These may be taken up one by one, and considered in relation
to their bearing upon the general problem of edema.

1. Obstruction to Outflow through the I,ymph-
vessels. — Because of the very abundant anastomosis of the
lymphatic vessels it is extremely difficult or impossible to cause
any appreciable obstruction to the lymphatic circulation by liga-
tion of lymphatic trunks in the limbs or organs of the body,
and in pathological conditions this possible cause of edema is
seldom actually observed. The chief instance of edema from
lymphatic obstruction is observed after occlusion of the thoracic
duct by tumors, tuberculous processes, animal parasites, or
thrombosis ; such occlusion is usually followed by rupture of
the duct or its tributaries, with the production of chylous ascites
or chylothoraz, and chyluria. Filaria or their ova may occupy
so many of the lymphatic channels of an extremity (leg) or part
(scrotum) that the anastomotic channels are thoroughly blocked,
with a resulting local edema that in course of time is followed
by the production of inflammatory connective tissue and ele-
phantiasis. 1 Chronic lymphangitis may also result in lymphatic
obstruction to such an extent that chronic edema results.

Another way in which edema may be caused or influenced by
lymphatic obstruction is generally overlooked, but it is possibly
of great importance ; namely, from pressure upon the lymph
channels by dilated vessels in hyperemia, or by cellular exu-
dates and swollen tissues in inflammation. We see evidence
of this in the rapid absorption of exudates that frequently fol-
lows the removal of but a part of the fluid in a chest cavity ;
apparently the decrease in pressure frees the paths of absorption
and permits them to take up the remaining fluid. In inflam-
matory edema the lymphatic obstruction is probably not great,
for Lassar found that the amount of lymph escaping from an
edematous extremity is much greater than from a normal one ;
but in the case of strangulated hernias or other conditions in
which edema results from circular constriction, obstruction of
the lymphatic vessels may be a factor of no mean importance.

There is no difficulty in understanding edema from the above
1 Manson, Allbutt's System, 1897 (ii), 1082.

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causes — it is simply a passive congestion of the lymphatic cir-
culation, and no chemical factors are involved. The nature of
the fluid found in such forms of edema will be discussed later.

2. Increased Blood Pressure. — This takes us back to
the filtration theory of lymph formation, and as it is generally
conceded that more or less fluid escapes from the vessels by this
mechanical process, the questions to be decided are : Can and
does increased blood pressure, alone and without other aiding
factors, cause edema? If not, does it play an auxiliary part
in producing edema, and hoW important a part may this be ?
Many experiments have been performed with the object of
answering these questions, with more or less conflicting results.
Cohnheim demonstrated that vasodilation (active hyperemia)
alone will never bring on an edema ; and many observers state
that ligation of the femoral or other large veins will not cause
edema in animals. However, when the vein is occluded, and
the arteries are dilated by cutting their vasoconstrictor nerves,
then edema may result (Ranvier, Cohnheim) ; but whenever
venous outflow is impeded, we have other factors than simply
increased pressure to consider, for the nourishment of the parts
is decidedly impaired, and, as we shall see later, this may be of
much greater importance than is the associated rise in blood
pressure. To produce edema in the lungs by mechanical forces
it is necessary to ligate the aorta and its branches, or the pul-
monary veins (Welch). As such high pressures do not occur
in any pathological conditions, it is safe to assume that increased
pressure alone is not capable of causing by itself the pulmonary
edema so frequently observed clinically. Welch, 1 however, has
supported the hypothesis that a disproportion between the
working power of the left ventricle and of the right ventricle
may lead to pulmonary edema through pulmonary hyperemia.
In the edema of passive congestion generally, increased blood
pressure would seem to be an important factor, and there is no
doubt that with an increased pressure of the degree observed in
such conditions some increase in the lymph flow would result ;
but from the evidence at hand it is improbable that the amount
of lymph so secreted would ever be more than the lymph- vessels
could carry away. Even the added obstruction to lymphatic
flow due to pressure upon the lymph capillaries by congested
blood-vessels, and the resistance to the lymph escaping from the
thoracic duct offered by the increased pressure in the subclavian
vein, would not satisfactorily account for the edema of cardiac
incompetence. Not to go into details here, it may be stated that
1 Virchow's Arch., 1878 (72), 375; see also Melteer {loc ciL).

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the impression is growing that uncomplicated rise in blood
pressure is not sufficient by itself to produce edema. Some of
the reasons for belittling this factor will be brought out in the
subsequent discussion.

3. Decreased Intravascular Pressure. — This factor
is particularly prominent in the so-called " edema ex vacuo,"
which occurs after the absorption of an area of tissue which is
so located that the surrounding tissues cannot contract or fall
in to fill the gap, e. <;., brain softening, serous atrophy of fat
A still better example, however, is the edema that follows local
decrease in atmospheric pressure in "cupping." In these
instances the edema depends partly upon increased transudation,
and partly on the retention of the fluid in the tissues, because
it cannot well leave them against the atmospheric pressure.
The idea advanced by Landerer that decreased elasticity of the
tissues was a possible cause of edema has been disproved by
Bonniger, 1 who found but little alteration in the elasticity of
tissues the seat of edema. Edema ex vacuo is again an illus-
tration of edema due to purely mechanical causes, but it is of
little practical importance.

4. Increased Permeability of the Capillary Walls.
— The importance of this factor in the production of edema was
first demonstrated by Cohnheim and Lichtheim, who found that
the production of an enormous increase in the amount of fluid
in the blood (hydremic plethora) by injecting large quantities of
salt solution, caused an edema of the viscera and serous cavities,
but not any subcutaneous edema until the skin had been irritated
by some means, such as hot water, iodin, etc. By this irrita-
tion the capillary walls are injured, and an excessive escape of
the blood fluids follows. Magnus also showed that poisoning
with arsenic, which injures the vessels, favored the experimental
production of edema by transfusion. Starling, as noted before,
observed that the permeability of the capillaries varies normally
in different organs and tissues, which determines quantitative
and qualitative differences in the lymph normally flowing
from various vascular areas. Heidenhain's " lymphagogues
of the first class," which are all poisonous substances, prob-
ably act by increasing the permeability of the capillaries, and
in this way they produce local urticaria, which is often
observed as a result of poisoning by these same lymphagogues,
e. g. 9 shellfish and strawberry poisoning. Just what changes
are produced in the capillary walls that renders them more per-
meable we do not know. Possibly in some instances it is a

1 Zeit. exp. Path. u. Ther., 1905 (1), 163.

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partial solution of the intracellular cement substances, possibly
an enlargement of the stomata through loss of tonicity of the
endothelium (Meltzer), sometimes it may be actual death of the
endothelial cells, or, as Heidenhain and Cohnheim thought, it
may be a stimulation of the endothelial cells to increased
secretory activity.

Under pathological conditions increased permeability of the
capillary walls is probably one of the chief factors in the pro-
duction of certain forms of edema. We see evidence of it
particularly in inflammatory edema, with its proteid-rich ex-
udate. It cannot be doubted that in such conditions actual
physical alterations take place in the capillaries, when we see
that the slightly diffusible proteids escape from the vessels in
the same proportions as they exist in the plasma ; there can be
here no question of heightened cell activity or increase in
osmotic pressure, especially not when we note the indistinguish-
able transition of such an inflammatory exudate into one con-
taining leucocytes and red corpuscles, which must pass through
openings of some kind in the vessels. Edema due to inflam-
mation and poisoning certainly depends to a large degree upon
alterations in the vessel-walls. The question remaining is, do
edemas that are not associated with distinct' inflammatory or
toxic influences depend also upon the vascular permeability ? —
does increased permeability ever lead to the formation of proteid-
poor transudates ? Cohnheim was inclined to attribute nearly
all edema to this cause, for in passive congestion, or nephritis,
or any of the common causes of edema, it is easy to find reason
for the belief that poisons may be present in the blood ; and as
there was good evidence that the blood pressure alone could not
account for the edema, it was natural to ascribe all these forms
of edema to the action of toxic substances upon the capillary
walls, leading to increased permeability ; or, whatimight amount
to the same thing, increased secretory activity of the endothe-
lium, as understood by Heidenhain. It is impossible at this
time to eliminate as non-existent this secretory-activity doctrine,
but, as we hope to show later, there exist other factors in all
these non-inflammatory edemas that are sufficient to account for
the edema without our having recourse to this hypothesis. For
the present, therefore, we may consider altered capillary perme-
ability as an essential factor in edemas characterized by
proteid-rich fluids (exudates), and state that the influence of
altered permeability in the production of proteid-poor fluids
(transudates) is not proved, and is perhaps not of impor-

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5. Increased Filterability of the Blood Plasma. —

This takes us back to Richard Bright's conception of renal
dropsy. He imagined that through the great loss of albumin
in the urine the blood became so thinned and watery that it
could filter through the vessel-walls, while normal plasma, he
thought, was too thick and viscid to do so. The same idea was
applied to the edemas of cachexia in cancer, etc., chlorosis, and
all forms of edema associated with a decrease in the corpuscular
or proteid elements of the blood. With our present knowledge*
of diffusion of crystalloids and colloids we can readily appreci-
ate that a decrease in the blood colloids, such as might occur in
these diseases, could not modify the passage of fluids through
the capillary walls to any considerable degree. Stewart and
Bartels considered that in renal dropsy the increased filterability
of the plasma was not due so much to the loss in albumin as to
retention of water, which caused an hydremic plethora. But
this factor was soon eliminated, for it was found that complete
anuria, produced by ligating both ureters, does not cause edema ;
and also that to produce an edema by increasing the water of
the blood it was necessary to increase it many times as much as
it can ever be increased by disease. Simply increasing the
proportion of water by removing part of the blood and inject-
ing a corresponding amount of salt solution did not cause
edema (Cohnheim and Lichtheim). We may, therefore, look
upon the hypothesis of increased filterability of the blood as
chiefly of historic interest, and not an important factor in the
causation of edema.

6. Disparity of Osmotic Pressure in Favor of the
Tissues and I^ymph over the Blood. — On a preceding
page we have already considered the means by which changes
in osmotic pressure in the tissues are brought about, and how
they may lead to an accumulation of fluid. The importance of
osmotic pressure in causing pathological edema was suggested
by Loeb l in his studies on the physiological action of ions.
He stated that edema occurred when the osmotic pressure was
higher in the tissues than it was in the blood and lymph, and
the cause was to be sought in conditions that lowered the osmotic
pressure of the blood and lymph or raised that of the tissues.
This condition he found in the accumulation of metabolic prod-
ucts : — in the case of muscle, tetanization of a frog's muscle
for ten minutes raised the osmotic pressure over one atmosphere ;
separating a muscle from its blood-supply led to such an increase
in osmotic pressure that it took up water from a 4.9 per cent.

1 Pfluger's Arch., 1898 (71), 457.

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NaCl solution, which has a pressure of over thirty atmospheres.
When we consider that in his studies on lung edema Welch
was able by ligation of the aorta to raise the blood pressure
less than -fa atmosphere, we begin to appreciate how much more
powerful are the forces of osmotic pressure that are at work in
the body than is the blood pressure, even of the aorta itself.

Loeb found that whenever oxidation is impaired in a tissue its
osmotic pressure rises, due to the accumulation of incompletely
oxidized metabolic products, particularly acids, and as a result the
muscle takes up water and becomes edematous. On this basis
we may explain the edema of venous stagnation as due to accu-
mulation of products of metabolism, partly because of impaired
oxidation, partly, perhaps, because of their slow removal in the
blood on account of the circulatory disturbance. The so-called
" neurotic " edemas may possibly be explained by local increase
in metabolic activity brought about by nervous stimuli, which
causes increased formation of substances raising osmotic pressure
in the stimulated tissues. In renal edema the retention of water
also seems to depend rather on osmotic pressure than on cir-
culatory disturbances or alterations in the vessel-walls, for it
has been shown that retention of chlorides, which the diseased
kidneys do not eliminate normally, is an important cause of the
dropsy. The chlorides accumulating in the tissues lead to an
increased osmotic pressure, which causes the abstraction of water
from the blood and its retention in the tissues. (The details of
this subject will be considered later.) Conversely, Meltzer and

Online LibraryH[arry] Gideon WellsChemical pathology; → online text (page 29 of 57)