Dull – Hypovolemia with Peripheral Edema: What is Wrong?

Dr. Randal O. Dull is a professor of anesthesiology with joint appointments in the departments of pathology, physiology, and surgery at the University of Arizona College of Medicine. With a […]

Episode Transcript

(00:00):
It's my pleasure to introduce, doctor Gell here.
He did his medical school at, UIC, and
subsequently he did his residency at, Massachusetts General
Hospital.
He is now currently professor of I guess,
looks like
here, in addition to anesthesiology,
pathology, physiology,
and surgery as well.

(00:23):
He's had a multiple peer reviewed papers. And,
you know, right now, I think we're very,
very excited to to hear,
from you today. This is obviously a very
a topic that has been I I've always
been really interested in, and,
I think, like, we were shit talking about
before, you know, volume status and critically ill
and and how this connects with, just overall

(00:43):
kind of in patients that are overloaded and
things like that. I think I'm
really excited to hear your talk.
Well, thanks for the introduction, and thanks for
the opportunity to talk with you guys. So
this, as you may have heard me talking
with doctor Chan, you know, my background is
all in capillary
permeability and endothelial permeability more at the molecular

(01:03):
level.
And for probably 15 years, I studied the
glycocalyx
more from a molecular mechanism trying to understand
how it regulated barrier function.
And like all things, my NIH funding went
away,
but my interest in, you know, these clinical
issues remained,
and I hooked up with
a very world renowned guy out of the

(01:26):
Karolinska Institute in Sweden named Robert Hahn who
is really sort of the guru of fluid
kinetics,
and we've been publishing,
you know, a whole series of papers together
on fluid kinetics and
sort of dysregulation
of
fluid leaking from the vascular system and the
problems that it encounters in getting back into

(01:47):
the vascular system, and that's really the genesis
of this little paper that we wrote. A
couple of quick disclosures.
I do have my own life science consulting
firm that I use to consult for Edwards
Life Science.
I do some health care consulting through a
international group called g 2,
And I'm also on the scientific advisory board

(02:08):
of Biofuze, which is a,
sort of tissue welding medical technology company that's
just a start up.
None of these
disclosures will really have any impact on what
I'm talking about today, which is all really
basic science.
So this is the paper that I'm gonna
talk about today that I think everyone is

(02:28):
is aware of,
hypovolemia
with peripheral edema, what went wrong. We published
this just about a year ago
in critical care medicine,
and I have to say despite publishing without
any funding, this paper may end up being,
the best work I've ever done.
In in about the 1st
year, it's had over 30,000

(02:50):
downloads,
and it's currently ranked in the 9th top
one percentile
of about 400,000
papers
in the literature and ranked in the top
4th percentile of papers in critical care. So,
it's nice to see that something hits the
mark and people actually really are interested in
it.

(03:11):
So
the general topic of hypovolemia
and peripheral edema, we're gonna be working within
this intersection of inflammation,
fluid kinetics,
interstitial physiology,
and lymphatic biology. And I'm gonna be pulling
together, you know, some newer topics that I
learned about while writing this paper. And and

(03:33):
since this has come out, we've actually
have several more manuscripts where we're doing a
deeper dive into understanding
how fluid moves through the interstitial space and
gets into the lymphatics.
And it's really quite fascinating because this area,
although made very popular by Arthur Guyton and
Granger and many of the luminaries in physiology

(03:53):
and critical care medicine back in the fifties
sixties,
really disappeared from the literature for quite a
long time. There's been some renewed interest to
it, and I hope, when I'm done today,
all of you will have some renewed
appreciation for this, physiology.
So, you know, as a clinician, I just
walked out of the operating room, ran over
to my office to give this talk, but

(04:14):
I think many people might see the title
and say, why even ask the question, what
went wrong? Because if I were to poll
all of us on this seminar
roster today and say, you know, what causes
edema? I would say probably every clinician would
say it's caused by increased capillary permeability.
And, you know, for the most part, we

(04:35):
would they would be right. If you think
about Virchow's triad
for,
inflammation,
it's Dolor,
Ruber, and tumor, which is, you know, redness,
heat, and edema.
And you know, no question that many states
have
increased capillary permeability as

(04:56):
part of
the
consequence or ideology of edema, but there's actually
much more
to it than just simple capillary permeability,
and oftentimes when we look at the amount
of edema that's in tissues,
it's in great excess of the changes in
capillary permeability
that we can measure. So today we're gonna

(05:18):
do a deeper dive into the physiological
mechanisms
of Edema and particularly Interstitial Edema.
You know in general we always like to
think that more knowledge should inform better patient
care,
but in this particular area I would just
say that you know, an objective would be
that, it stimulates ideas for new therapeutic options
for everyone that's listening and maybe you know,

(05:39):
fertile ground for research,
in this area.
So you know, in general,
anytime
fluid in efflux
increases from a capillary,
there is an immediate increase in lymphatic flow,
and fluid flux can fluid flux
from the capillary
can

(06:00):
occur due to increase in hydrostatic
pressure,
changes
in venous outflow, which would increase capillary pressure,
lower oncotic pressure, etcetera,
even in the absence of a change in
endothelial permeability per se.
And so anytime there's edema forming, there's actually
something

(06:21):
wrong in the interstitial space.
It may be a really massive increase in
capillary permeability,
but in general,
the first point I wanna make is that
anytime there's an increase in fluid movement into
the interstitial space, lymphatic fluid
flow immediately increases.
So this is a classic paper from, Brace

(06:42):
and Powers 1983.
They were, giving dogs fluid boluses about 20
ml per kilo over 5 minutes of an
isotonic fluid, and you get this immediate increase
in lymphatic flow.
Hypotonic fluid was not
quite as stimulating
in generating lymph flow, but then hypertonic saline

(07:03):
which can pull fluid out of the intracellular
space
really dramatically
increase fluid flow. And the main point for
this is again just to get the recognition
that our our bodies
are designed that when there is an increase
in interstitial fluid, that lymphatic system should be
able to pick that up and start moving

(07:25):
it back towards,
the venous compartment.
Since we have a lot of critical care
folks,
on this meeting,
typically
classic work by Taylor
and others felt that
lung lymphatic flow could increase about tenfold
before alveolar
fluid, interstitial fluid breach the alveolar barrier, and

(07:48):
start causing pulmonary edema. So we have this
really large compensatory
mechanism
that should allow
lymph
flow to pick up and prevent interstitial edema.
So again, just trying to highlight the idea
that when we do have any sort of
fluid accumulation in tissue space, something's wrong, and
it may be more than just capillary permeability.

(08:11):
Interestingly,
when fluid leaks out of capillaries
and into the interstitial space and makes its
way into the lymphatics,
it participates in a process called interstitial
wash down. And this interstitial
flow of fluid picks up proteins most notably
albumin
and immunoglobulins,
and it washes them back into the lymphatics,

(08:33):
and that protein and fluid is then returned
to the venous system.
And so,
if you measure
total
plasma protein concentration
or mass, I should say, total protein mass,
it actually increases
after an increase in lymph flow because we're
picking
up interstitial proteins and returning them back to

(08:55):
the vascular space. In time,
renal clearance of the fluid component will result
in colloid oncotic pressure either increasing or at
least being maintained. So this idea of interstitial
washdown is an important way
to get proteins back into the vascular system
because about 5% of our albumin
leaks out of, the vascular system per unit

(09:18):
period of time and is actually fairly quickly
returned
to the vascular compartment.
And,
for anybody that might be interested in that,
we did a very,
complicated
and very thorough paper looking at interstitial wash
down from several 100,
human patients that got a fluid infusion

(09:39):
and could repeatedly show
that their total protein mass in the plasma
compartment increased,
every time we gave a fluid bolus.
So I think you can't talk about
any type of edema without at least mentioning
the Starling principle, and I'm sure most of
you are well aware of this, but I'll
go through it just for the sake of

(10:00):
completeness. You know, start up Starling principle basically
says that fluid flux, which is the volumetric
flux JV across the unit area of membrane
is related to
the difference in hydrostatic pressure
minus the difference in oncotic pressure. And we
have 2 permeability coefficients.
We have LP which is a permeability coefficient

(10:22):
for water. This is hydraulic conductivity
which is how much fluid
moves across the capillary membrane
per surface area per millimeter of mercury or
centimeter of water, whatever your pressure head is.
And Sigma is the reflection coefficient.
It's a dimensionless number between 0 and 1,
and it's 1 minus the concentration of lymph
over the concentration in plasma. So if a

(10:45):
membrane has a reflection coefficient of 0, that
means that particular solute moves freely across the
membrane
and is an impeded,
and a reflection coefficient of 1 would mean
that that protein or solute cannot move across
the membrane.
And so, you know, clinically,
we typically
think about the pressures that we can control

(11:05):
in the Starling equation is really being the
capillary hydrostatic pressure
and the capillary oncotic pressure
either by giving vasopressors
or by giving colloids.
As I move through today's talk, one of
the things that I really wanna focus on
is dynamic changes in the interstitial pressure,
that regulates

(11:25):
and can have a very profound effect on
fluid movement across the membrane and the volume
of fluid that exists in the interstitial space.
Just by way of historical note, there's a
picture of Ernest Starling, and Starling himself never
penned the Starling equation.
It was actually, written by Eugene Landis,
at the University of Pennsylvania

(11:46):
in the early 1900.
Starling laid all the foundations for determining
which factors
determine
fluid flux, but it was actually Landis who
wrote the equation.
So let's jump right into this and and
talk about the magnitude of fluid movement that
leaves the vascular system every day, moves through

(12:07):
the interstitial space, and then back into the
vascular system.
If we have a 7 this this is
a 65 kilogram adult
patient, has about 3 liters of plasma,
and that fluid and protein is moving into
the interstitial space approximately
10 to 12 liters a day,

(12:28):
which accounts for about a complete turnover of
3 to 4 times the vascular volume every
day. So you can imagine
that if there was a dysfunction in the
return flow of fluid from the interstitial compartment
back to the vascular compartment,
we would get hypovolemic
very quickly. And there's a really, large amount

(12:50):
of protein moving across the capillary wall as
well.
Net,
flux of protein may be about 10 grams
an hour, 240
grams a day.
So we have somewhere around
8 to 12 liters
of fluid leaving the vascular system,
moving through the interstitial space and into

(13:10):
the afferent lymphatics.
About half of that fluid will be reabsorbed
in lymph nodes and
reabsorbed back into capillaries and back into the
plasma volume, which leaves about another 4 liters
or so of efferent lymph that has to
make its way back through the collecting ducts,
and the thoracic duct and some of the
larger

(13:31):
lymphatic systems
to get back
into the vascular compartment.
And, again, you know, about 60 grams of
protein per liter,
is coming back into those collecting ducts. So
the main point of this slide is to
appreciate
that there's an enormous turnover
of body fluids from the vascular compartment

(13:52):
through the interstitial space
that has to get reabsorbed.
Otherwise, we would constantly be both hypovolemic
and hypoproteinemic
as well. And that fluid, if it was
not returned to the vascular compartment,
would exist in the interstitial space as edema.
So, again, we have tremendous compensatory mechanisms to
move this fluid around the body.

(14:14):
So
with that, we should really start to think
of edema
as a problem
between fluid inflow and fluid outflow
or outflow maybe I could call clearance.
And the inflow
primarily from a clinical standpoint is going to
be our capillary hydrostatic pressure,
endothelial permeability,

(14:36):
and tissue oncotic pressure that will all result
in fluid moving from the capillaries into the
tissue.
But the clearance mechanisms importantly are our lymphatic
system as well as our plasma colloid oncotic
pressure, and we can reabsorb
quite a bit of fluid from the tissue
space back across the capillaries by raising plasma

(14:57):
oncotic pressure.
So the interstitial space physiology is something that's
sort of been forgotten. For anybody that's interested
in this, I highly recommend you read, this
review article by Arthur Guyton. You know, our
former contemporaries Guyton and Granger and Taylor and
some of the luminaries in the physiological world
were absolutely brilliant experimentalists,

(15:19):
and the the experiments that they did,
you know, in the fifties sixties seventies
were really quite amazing and showed a tremendous
amount of insight. And when I wrote this
paper on, hypovolemia,
I went back to the 19 fifties and
read just about everything Guyton's written through the
fifties, sixties, and seventies. And this is an

(15:39):
absolutely
wonderful review
of interstitial physiology, and I would dare to
say that we probably haven't advanced our understanding
of it much more since 1971.
But there was a big change
in thinking about the interstitial space with this
paper by Neil Theiss who was the
senior author on this paper that came out

(16:00):
in 2018
in Scientific Reports. The structure distribution of an
unrecognized
interstitium
in human
tissue.
And Neil is a pathologist, most of the
folks on this paper were pathologists, and they
used a really robust number of techniques including
confocal microscopy,
lots of special histology staining.

(16:21):
They traced all sorts of
cancers through the interstitial space with, you know,
using carbon particles and dyes
and
electron microscopy,
and really describe the interstitial space in new
ways, that I don't think was very well
appreciated.
And in this paper actually discussed,
the description of the interstitial space as a

(16:43):
new organ system, which I thought was quite
interesting.
And just to summarize
what they found,
in their study,
They they they were looking at this
mostly at the skin interstitial space. The first
thing they found was these fibroblast like cells,
CD 34 staining cells on collagen fibers

(17:05):
you know in the substratum and on the
fiber matrix. But interestingly,
these cells live on these collagen bundles, and
I'll show you a picture shortly. You know
in an asymmetric fashion where they're only found
on one side of it, and that would
suggest that biomechanically,
they may be able to pull
this layer together and change the compression, actually

(17:26):
compress the thickness when they pull on these
fibers.
Under normal light microscopy,
the spaces between the collagen fibers
normally just appears to be water, but when
they stained it with their special stains,
the interstitial space is just absolutely full of
hyaluronan and it forms a gel space,

(17:47):
and that was relatively new.
And the third issue was that they found
continuity of the interstitial space across
organ boundaries and tissue planes, which was really
underappreciated.
Here are these large collagen bundles that exist
in the interstitial space, and you can see
these cells only exist on one space. And

(18:07):
here's a another example of it up here.
These matrix
these matrix or interstitial fibroblasts
bind to these collagen fibers
and collagen bundles through integrin mediated binding.
And I'm gonna show you in a couple
of slides that when these fibroblasts
contract, they can compress

(18:28):
tensile forces and actually contract the interstitial space.
And,
conversely,
during periods of inflammation and injury,
the fibroblast
can lose attachment to these bundles and actually
open up the interstitial space.
And those changes
in tensile
forces
on the interstitial matrix has large effects on

(18:51):
the interstitial pressure and therefore on starling forces,
you know, across the capillary wall.
Here's a light micrograph. I won't belabor this,
but the blue the blue are the collagen
fibers, and you can see these
CDs CD 34 staining cells
always somewhat asymmetrically
located,
but positioned appropriately

(19:12):
to cause
this change in tensile forces.
This is a the paper this is a
picture from our paper in critical care that
was stained for hyaluronan,
and you can see that the whole,
peridermal
space is just filled with a hyaluronan
gel.

(19:32):
These are lymphatic
channels that have been labeled with a green
dye, and then the magenta
structures are all capillaries and small blood vessels
that exist in the interstitial space. But you
can see even deep into the reticular dermis,
there's a lot of
hyaluronan
around the perivascular

(19:53):
bed,
and then deeper down,
a lot of the space is just simply
adipose tissue with
sort of a surrounding
bits of hyaluronan.
But this idea that there's a tremendous amount
of hyaluronan
in the interstitial space will become important in
just a a couple of slides.

(20:14):
One important thing to know about the interstitial
space is Guyton was the first one to
report that it has a negative pressure.
He implanted,
perforated capsules deep into the interstitial space probably
down into the reticular dermis,
Left them in the left them in the
dermis for several weeks and then was able
to access the interior of these perforated capsules

(20:36):
and measure the pressure in them. He measured
a pressure of around minus 7 millimeters of
mercury.
Wig and Reed and colleagues
were able to do with sharpened pipettes. We're
able to make measurements,
in the
immediate subdermis space of a pressure somewhere around
minus 1 to minus 3,

(20:58):
millimeters of break free. So the dermis is
slightly or the interstitial space is slightly
sub atmospheric pressure.
That negative pressure is caused by the inhibition
forces or forces that exist due to this
large amounts of hyaluronan,
which is able to suck fluid into the
gel phase. And some of that negative pressure

(21:19):
is caused by these tensile forces
of the
matrix being constricted,
by these fibroblasts.
But important to note, this is a paper
by
Guyton.
When
the fibroblasts
or the tissue starts to expand due to,
large amounts of accumulation of fluid, the pressure

(21:41):
rises from a negative number closer to 0.
And once that
interstitium starts to expand,
the resistance to fluid movement
drops precipitously.
The conductance can go up several 100000
fold, and you can start really moving large
amounts of fluid into the tissue. So at

(22:01):
normal interstitial pressures, the resistance to fluid, movement
into the interstitial space is high, but very
small changes
in the interstitial pressure can open up that
matrix and allow large amounts of fluid
to fill the interstitial space and probably why
we get pitting edema.
Under normal circumstances,

(22:23):
it's estimated that only about 1%
of the entire interstitial space is free fluid,
and the rest of the 99% of the
fluid is bound up in this hyaluronan
gel phase.
And we we think that the hyaluronan
exists basically to be a buffer.
Fluid small amounts of fluid can move into

(22:44):
the space,
through the interstitial space and get into the
lymphatics and wash it out, but the the
gel phase
is this buffer to prevent a lot of
free fluid,
from getting in there. And hyaluronan,
you know, has been reported to be able
to bind, you know, hundreds of times its
weight in fluid, and therefore, again, seems to

(23:06):
act as buffer.
So I wanna talk just a little bit
about how,
these,
fibroblasts
in relationship to the collagen fibers
can change interstitial pressure because it's an area
that I think as clinicians we never really
think about. Again, we think a lot about

(23:28):
capillary
hydrostatic pressure and colloid
oncotic pressure, but we don't really think very
much about the interstitial pressure.
So again, we have these
cells that are on the collagen fibers.
When they're contracted, they're able to
raise tensile forces, but if they relax or

(23:49):
inflammation,
releases
this integrin binding,
it's much like a bellows. The interstitial space
can
expand
that creates a large negative interstitial pressure, and
that can suck water in from the capillaries.
So here's a really interesting article
by Ralph Reed and colleagues

(24:10):
showing the interstitial pressure,
and again normally under control conditions it was
minus 1, minus 2 millimeters of mercury.
But what they did was they injected
monoclonal
antibodies
against the beta integrins, and the integrins of
the molecules that are linking
the fibroblasts
to

(24:31):
the collagen bundles.
And these antibodies
released
the fibroblasts, and you can see you get
this
negative
pressure down to, like, minus 6
millimeters of mercury. So, you know, a 5
or 6 fold increase
more negative in the interstitial pressure, and that
would act to increase

(24:53):
filtration forces,
and suck fluid from the capillary
into the interstitial space.
Now just injecting
monoclonal antibodies only caused a relatively small increase
in fluid pressure, but the same group was
able to measure
interstitial pressure during burns
where there was a significant amount of inflammation,

(25:16):
and they were able to measure interstitial
pressures of minus 40.
So
when we think of burns, we always think
of, you know, this
massive amounts of tissue edema, and we always
assume that most of it is due to
changes in capillary permeability,
but based on the work of Wig and
Rolf Reed and others,
it it appears that there is a very

(25:38):
rapid
negative pressure,
created by the in the interstitial
space by the loss of this tensile forces.
And in fact, they had one paper,
one of their animals, they actually had a
inhibition pressure of minus a 120 millimeters of
mercury in an interstitial space.
And what happens is that sucks fluid out

(25:59):
of the capillaries,
the volume of the interstitial space expands very
very dramatically,
and that pressure volume curve brings the interstitial
pressure back up to essentially atmospheric pressure, and
then fluid movement stops.
So I think, you know, from a clinical
standpoint, this is very interesting
to think about the fact that the interstitial

(26:20):
pressure
plays such a dynamic role in fluid movement
and maybe even fluid clearance,
out of the interstitial space.
Right after our paper came out, this group
published
a very, very nice review article
on the role of the interstitium during septic
shock. Our paper was more geared at just

(26:41):
looking at inflammation in general,
but for anybody on, in the meeting, this
is a really outstanding review of the interstitial
space
during septic shock.
They did a really deep dive into it,
and it's an excellent paper.
And they summarized it very nicely, and I
really just wanted to go over this figure
again to reinforce what I'm talking about.

(27:03):
We have these collagen fibers,
you know, in the interstitial space and the
fibroblasts
bound to the collagen fibers through these beta
integrin,
mediated protein complexes.
This whole
space between all of fibers
is filled with hyaluronan,
and the interstitial space here they show is

(27:24):
0. It's probably well minus 1 they have
on the dial. And then during inflammation
through the actions of TNF alpha,
nitric oxide,
probably proteases that actually disrupt some of these
bonds,
the fibroblasts are able to let go of
these collagen fibers.
The interstitial space
expands

(27:44):
dramatically,
and it acts like a bellows
to lower
the interstitial pressure. And you can see here
they slight the same values close to what
I just mentioned,
minus 4 to minus 100.
That can suck in huge amounts of fluid
into the interstitial space,
expand
that space,

(28:04):
and, ultimately, some of the safety mechanisms are
that interstitial pressure rises back to 0 and
then shuts off,
further filtration out of the capillary.
And then it really will depend on
the endothelium sealing back up to allow that,
fluid to be reabsorbed
back across the capillary membrane or requires the

(28:26):
lymphatics
to pick up all that fluid and protein
and get it back into the vascular system.
So that leads me into talking about the
lymphatic system, which is really the main controller
of interstitial volume.
This is typically how we think of the
lymphatic system.

(28:47):
We have arteries,
forming into capillaries,
capillaries into small venules, and the venules,
you know, coalescing into,
veins.
And intermixed
with this network
are our lymphatic ducts that essentially start out
as capillary sized
vessels,

(29:09):
all
layered around the
the small microcirculation
to pick up fluid and proteins,
and ultimately get them back into the vascular
system.
If we take, you know, a a physiological
look at these, these small
blind
capill capillary like structures that form the terminal

(29:29):
lymphatics, they're a single endothelial layer. They have
very loosely opposed,
endothelial cells that can open in response to
changes in tissue pressure.
So these terminal lymphatics
can pick up fluid and proteins.
They start to coalesce into secondary
lymphatics,
which actually have smooth muscle cells and valves.

(29:51):
And the smooth muscle cells start to generate
small forces,
you know, a few centimeters of water pressure.
And as the
ducts get bigger and gain more smooth muscle
cells, they can generate more force, and they
propel fluid,
forward
into collecting ducts and then ultimately things like

(30:11):
the mesenteric duct and the thoracic duct.
So as the lymphatics get bigger, the pressure
gradients get bigger, and the functional unit is
really called the lymphangion,
which is the area of a lymphatic between
two valves.
So lymph flow rate is determined by both
the frequency
and the amplitude

(30:31):
of lymphatic pumping.
Stimulants for lymphatic pumping include include,
adrenergic stimulation, and interestingly,
it's primarily alpha adrenergic receptors
stimulate pumping.
But
what I was
really surprised to learn is that inflammatory

(30:52):
mediators actually inhibit lymphatic pumping. Now you would
think in a situation where inflammation
promotes
edema,
one wouldn't expect that those same inflammatory mediators
would inhibit the clearance mechanism,
but in fact they do. Nitric oxide
be, affects lymphatic smooth muscle cell just like
it like it affects any other smooth muscle

(31:13):
cell to diminish its pumping capabilities or its
contractile
properties,
and also through cyclic GMP mechanisms can shut
down the ion channels that are involved in
spontaneous
depolarization
of the smooth muscle cells that contribute to
pumping.
So during inflammation, if you learn nothing else
from today's talk, during inflammation, nitric oxide,

(31:37):
endotoxins,
beta agonists,
all act to reduce lymphatic pumping
and results in decreased fluid clearance from the
interstitial space.
Now one other thing that also has a
really deleterious effect on lymphatics
are anesthetics,
and all anesthetics including inhaled gases,

(31:59):
local anesthetics,
and propofol,
significantly reduce lymphatic pumping. And I have a
large review article right now in review in
anesthesiology
where we've gone through the physiology of anesthetics
on lymphatics, and this may be explained why
under anesthesia patients need,
seemingly larger amounts of fluid than we would

(32:20):
expect,
because that fluid is leaving the vascular system
and cannot get back to the vascular system.
It's essentially trapped in the interstitial space.
So let's just do a quick midpoint summary
here.
I wanna emphasize that there's more to tissue
edema than just increased endothelial permeability.

(32:41):
A really important part of this is that
negative interstitial fluid pressure is a key dynamic
factor
in inflammatory in, edema,
and reduced fluid clearance that is lymphatic function
is likely to play a major role
in the formation of both edema
and hypoproteinemia

(33:01):
because both fluid and plasma proteins are getting
trapped in the interstitial space.
So let's get really to the to the
guts of the talk. How do we measure
the impact of lymphatic dysfunction
on plasma volume
and whole body edema?
And the answer to that is using fluid
kinetic modeling

(33:21):
that, I'll talk about for the remainder of,
you know, the hour.
So this is my colleague, Robert Hahn. He
is a professor at the Karolinska Institute in
Sweden. He's an MD PhD
anesthesiologist.
He is really the world's authority
on fluid kinetics. He has
over 570 peer reviewed publications in PubMed,

(33:43):
several textbooks
on fluid management and fluid therapy,
and he's just been an absolutely,
become an absolutely wonderful friend and colleague over
the last 5 or 6 years and,
really enjoyed working with him,
to publish this. And we've attacked this problem
of lymphatic dysfunction during inflammation

(34:03):
using fluid kinetic modeling.
And the way this works is we can
think of
the body basically or the
physiology of fluid using a 2 compartment model.
We have the vascular compartment.
So if we have an infusion of fluid
into the vascular compartment, we can stress that
compartment
and

(34:24):
have excess fluid in there, and that fluid
is gonna move relatively quickly from the vascular
compartment into the tissue space.
Most of as clinicians, you should know that
crystalloid does not stay in the vascular compartment
very long. The half life of crystalloid
in the vascular compartment is only about 20
to 30 minutes, and then it's leaking out

(34:46):
into the tissue space
and has to come back either through reabsorption
from the capillaries or back through the lymphatics.
The clearance mechanism
for this excess fluid in the vascular compartment
is through the kidneys.
So
we can measure
and follow fluid movement

(35:06):
by frequently sampling hemoglobin from the vascular compartment.
If you give a big bolus of fluid,
the hemoglobin will be diluted. And if we
sample hemoglobin
every 5 minutes for hours, we can watch
hemoglobin
rising,
which is indicative of fluid leaving the vascular
compartment.
And if we measure urine
and we measure hemoglobin,

(35:27):
we know where the fluid is. And if
it's not in the vascular compartment in the
urine, it has to be in the tissue
space. Okay? And if anybody has questions about
that, we can talk about it during question
and answer.
So here's what these experiments would look like.
We would give a relatively large bolus of
fluid,
maybe a liter and a liter half over
30 minutes, and you get this plasma volume

(35:48):
expansion.
And by following the hemoglobin concentration,
you know, every 5 minutes
in the plasma,
you can watch the hemoglobin
or the plasma volume expansion fall
over time. And, again, the half life of
crystalloid fluid is only about 20 to 30
minutes under normal circumstances.
At the same time,

(36:09):
we can measure urine output
and
see
urine output depending on how long the fluid
staying in the vascular system. And if it's
not in the vascular compartment and it's not
in the urine, it has to be in
the tissue compartment. Okay?
So what happens when lymphatic pumping is reduced?

(36:29):
We have fluid moving from the blood into
the interstitial
space that's,
has a rate constant or a kinetic parameter
of called k 12,
and that fluid has to move from the
interstitial space primarily back into
the vascular compartment through the lymphatics
against a pressure gradient of about 3 to

(36:49):
5 in
the,
subclavian
vein.
And the I won't go into all the
math because the the math is very
complicated,
but been very well validated over the last
20 or 30 years.
And what we can see is if we
in if we inject a liter of fluid
over 30 minutes into a person and then

(37:09):
model this as a function of the percent
lymphatic
dysfunction,
These numbers show
the degree of reduction in lymphatic pumping. And
at 25, 50, and 75%,
you can see by the time
lymphatic pumping is inhibited by 90%,
this fluid is leaking out into the interstitial

(37:30):
compartment.
Some of it's being, peed out by the
renal system,
and you will become hypovolemic
if your lymphatic system
is not working.
Likewise,
we can have kinetics for the expansion of
the extravascular
volume also as a function
of lymphatic inhibition.
Under normal circumstances,

(37:51):
fluid leaks out into the lymphatic system and
gets returned rapidly to the vascular system account,
which accounts for
this higher line, the maintenance of plasma volume.
And
the greater lymphatic
function is inhibited,
the more fluid will accumulate
in the tissue space.
So fluid kinetics allows us a very good

(38:14):
macroscopic
way to look at what's happening in the
whole body.
And so, again, here is essentially the same
curves now adding
plasma albumin measurements to it,
with
reductions in lymphatic pumping. And plasma albumin
will continue to fall

(38:36):
when there's a greater dysfunction in lymphatics because
albumin is constantly leaking out of the vascular
system, getting into the interstitial volume, and has
to come back into the vascular compartment,
with with the fluid. Okay?
So
any
problem in fluid clearance from the interstitial space

(38:57):
will result in hypovolemia
and hypoproteinemia.
So what are the next steps?
We've,
taken this compartment, and we've actually looked at
the serial connection between,
the the
small amounts of free fluid
and the the hyaluronan space, and we've added
a third compartment and measured fluid movement in

(39:18):
and out of
the
hyaluronan
gel phase, and it actually fits quite nicely
with fluid kinetics,
that we can measure in humans.
And
this
slow
pool of fluid,
looks like this may be the 3rd space
that people have talked about for years.

(39:40):
Historically, the 3rd space in fluid
is some tissue compartment
where fluid is leaking into.
It's not the tissue space per se because
that can be measured. It's not in the
vascular compartment, and it's called the 3rd space
because it seems to be hidden tissue.
And our analysis that just came out in,
anesthesia and analgesia

(40:00):
would suggest that the hyaluronan
gel that exists
in the interstitial space
is the very slow compartment. It can suck
up lots of fluid. It takes it a
very long time to re equilibrate,
and it looks like
this hyaluronan gel may be the 3rd space
that we all talk about.

(40:21):
So I'm gonna start to wrap things up
here so we have some time for
questions.
So the clinical take home message from today's
talk is that we we recognize that edema
is a consequence of both acute and chronic
inflammation,
but not all edema requires a change in
capillary permeability.
There are other factors

(40:41):
like the in the interstitial space
and
the dynamic regulation of this fibroblast matrix interaction
that can
influence,
starring forces across the vessel.
This plas the,
interstitial pressure can be affected by inflammation and
create very large negative swings that can actually

(41:03):
suck fluid out of the capillaries,
and result in massive amounts of fluid in
the interstitial space.
And surprisingly
inflammatory mediators reduce lymphatic pumping
door through an no mechanism
so that much of inflammatory
induced edema
is fluid clearance because the lymphatic system has

(41:23):
been inhibited.
Finally, lymphatic inhibition has a profound effect on
both plasma volume and plasma protein concentrations.
Even modest changes in lymph flow 25 to
30% can have a major effect on plasma
volume over time
and lead to both hypovolemia
and peripheral edema.

(41:44):
So our unmet clinical challenges
really at this point would be therapies that
can modulate Interstitial fibroblasts and Interstitial pressure,
and even, lymphatic targeted therapies that might be
able to enhance lymphatic pumping in the setting
of edema. And with that, I'm gonna stop
and we'll have some time for questions.