IFAD2017 Michel and Curry have pointed out the methodological difficulties in obtaining a meaningful value of glycocalyx volume. For the purposes of a paradigm that explains clinical experience, I have suggested that; a bolus of an isosmotic plasma substitute has a central volume of distribution which approximates the free-flowing plasma, while a bolus of an isotonic salt solution has a central volume of distribution that includes the intravascular gel phase and approximates the whole of the intra- vascular volume. Starling's observation: “Absorption of isotonic salt solutions by the blood vessels is determined by the osmotic pressure of the serum proteins.”

1. fluidphysiology.org
Plasma volume, tissue
oedema and the steady-
state Starling Principle
fluidphysiology.org
Dr Tom Woodcock,
Southampton

2. fluidphysiology.org
2

3. “Absorption of
isotonic salt
solutions by the blood
vessels is determined
by the osmotic
pressure of the serum
proteids.”
3
1896
Starling’s Observation.

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Bayliss and Fraser; gum saline for wound shock.
Van der Kloot W Notes Rec. R. Soc. doi:10.1098/rsnr.2009.0068
©2010 by The Royal Society
1917
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5. 5
1914-8
Looking for a
cure for wound
shock...
Gum from the
acacia tree!

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1942
“At the request of the Navy in 1940,
Edwin Cohn’s team isolated the
protein from human blood; the
resulting serum albumin was not only
pure, but exhibited remarkable
effects when administered to injured
persons as an antidote to shock.”
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A kinetic approach to the circulation of ECF
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We can infuse fluid to it’s central volume of distribution.
Colloids are restricted to the free-flowing plasma because
of limited penetration of the EG.
Crystalloid central volume of distribution is the whole
intravascular volume. They cause less haemodilution
than colloids at effective resuscitation dose.
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Small reductions in regional vascular resistance of a
tissue bed lead to substantial increases in Pcap and Jv.
We can protect Pcap and limit Jv by restoring tone to pre
capillary arterioles. Alpha-1 receptor agonist in sub-
hypertensive dose effective.
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Transendothelial resistance to flow of filtrate to
lymphatic collecting ducts due to EG, inter
endothelial junction breaks and the ECM.
Preserving or restoring EG and the tight
junctions limits hyper filtration.
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Spontaneous contractility of lymphatic smooth muscle
… is inhibited by sepsis and opioids.
… is stimulated by adrenergic transmitters.
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Diuretics.
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New insights
Michel and Curry have pointed out the methodological
difficulties in obtaining a meaningful value of glycocalyx
volume.
For the purposes of a paradigm that explains clinical
experience, I have suggested that;
a bolus of an isosmotic plasma substitute has a
central volume of distribution which approximates
the free-flowing plasma, while a bolus of an isotonic
salt solution has a central volume of distribution
that includes the intravascular gel phase and
approximates the whole of the intra- vascular
volume.
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16. Vc
Colloid central volume of
distribution
Vc
Crystalloid central volume of
distribution.
The concept is supported by consistent clinical reports that
adequate resuscitation with an isosmotic plasma substitute
can be achieved with slightly smaller volumes than
adequate resuscitation with a crystalloid, but at the
expense of much diluted haematocrit .
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17. ECF is ‘triphasic’;
1.
2.
3.
the free-flowing albumin solution; [Na+
] 150
gel-phase of proteoglycans, glycoproteins,
glycosaminoglycans; [Na+
] 148
•“plasma and lymphatic compartments and the triphasic
interstitium are dynamic interfaces for water distribution”.
collagen matrix; [Na+
] 400
Bhave G, Neilson EG. Body Fluid Dynamics: Back to the
Future. J Am Soc Nephrol 2011. 22:2166-2181
Interstitial [alb] typically 0.7 x plasma [alb].
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Lymphatic pumping.
There is smooth and striated muscle associated with
many lymphatics whose contraction and relaxation acts
as a pump to propel lymph. While inflammatory mediators
and opioids may inhibit lymphatic contractility, so
promoting oedema, norepinephrine is known to stimulate
contractility.
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Decrease in the interstitial pressure Pi as integrins change
the conformation and hydration of structural collagen fibres.
Delta P and Jv therefore increase, beginning the shift of ECF
balance from the intravascular to the extravascular
compartment.
Precapillary vasodilation increases the capillary pressure Pc
and so further increases Jv.
Arterial pressure is maintained by increased cardiac output
(capillary recruitment increasing the surface area for filtration
A), another factor increasing Jv in the early phase of
systemic inflammation.
Inflammation; more than just leaky capillaries
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- Histamine and other autocoids are known to increase the
length and number of intercellular junction breaks, especially
in the distal part of the capillary and the venules.
- The surface area for filtration within each capillary and the
hydraulic conductivity Lp are both thereby increased and
further increase the Jv.
- Fragmentation of the glycocalyx, and failure of the repair
mechanisms eventually reduce sigma so that the effective
delta Π (sigma delta Π) opposing filtration is reduced.
Inflammation; more than just leaky capillaries
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Even in health, there is at any moment much more
albumin within the interstitial fluid than in the
plasma.
During hyperfiltration and hyperpermeability, plasma
albumin concentration decreases because of net
redistribution of circulating albumin to the interstitial space.
Transfused albumin is also rapidly redistributed so that
there is soon more of it in the tissues than in the plasma
volume.
Transfusion of albumin will overload the
interstitium and cause oedema, every gram of
albumin holding about 18 ml water in the
interstitial gel.
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Resuscitation from low intravascular volume and low capillary pressure
The more severe the hypovolaemia, the greater the
case for preferring crystalloid resuscitation to repay
the autotransfusion and re-establish a subglycocalyx
protected space.
- This logic runs counter to the suggestion by some
authorities that colloid solutions may be preferred in more
extreme cases of hypovolaemia ‘because it stays in the
circulation longer’. Moreover, statim boluses will cause
transient peaks of Pc that lead to transient hyperfiltration.
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Plasma volume regulation by natriuretic peptides
Intra-renal GC-A receptor stimulation brings about
natriuresis by increasing glomerular filtration pressure (the
efferent arterioles constrict) and inhibiting tubular sodium
reabsorption.
Extra-renal GC-A receptor stimulation increases the
TCER of albumin (Js), so that the delta Π opposing Jv is not
increased by the loss of salt and water from the circulation.
GC-A receptors generally relax vascular smooth muscle.
An important endocrine regulator of plasma volume is atrial natriuretic peptide (ANP)
whose actions are essentially the reverse of aldosterone. ANP is secreted in response to
vascular distension and acts on intra-renal and extra-renal guanylate cyclase (GC-A)
receptors to reduce the effective plasma volume by at least three important actions.
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Tonic regulation of capillary permeability
ion unit needs almost continuous maintenance to preserve tonic regu
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25. ... the layered structure of the
endothelial barrier requires
continuous activation of signalling
pathways regulated by
sphingosine-1-phosphate (S1P)
and intracellular cAMP. These
pathways modulate the adherens
junction, continuity of tight
junction strands, and the balance
of synthesis and degradation of
glycocalyx components.
... baseline permeability is maintained by constant activity
of mechanisms involving the small GTPases Rap1 and Rac1. In the
basal state, the barrier is compromised when activities of the
small GTPases are reduced by low S1P supply or delivery. Acta Physiol 2013, 207, 628–649
REVIEW
Tonic regulation of vascular permeability
F.-R. E. Curry and R. H. Adamson
Department of Physiology & Membrane Biology, School of Medicine, University of California at Davis, Davis, CA, USA
Ras-related C3 botulinum
toxin substrate 1
Ras-related protein 1
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Special microcirculations
PULMONARY
Continuous.
Exposed to the whole right ventricular output, but
perfused by much lower arterial pressure.
It has been observed that increase in Pcap activates a
heparan sulphate–nitric oxide-dependent pathway that
fragments the glycocalyx layer and reduces
transendothelial resistance, so accelerating the increase
in Jv which causes oedema formation.
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•Fluid from the brain drains into
the cerebrospinal fluid through
the glymphatic system.
•Cerebral lymph vessels carry
fluid and immune cells from the
cerebrospinal fluid, along veins
in the sinuses, and into deep
cervical lymph nodes.
https://www.nih.gov/news-events/nih-research-matters/lymphatic-vessels-discovered-central-nervous-system
X

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Thank you
fluidphysiology.org

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Traditional pore theories presumed the existence of small
(Stokes radius <2 nm) and large (Stokes radius >3 nm)
cylindrical pores through the capillary barrier. The Stokes radius
of albumin is about 3 nm, and hypothetical large pores allow
albumin to move through them in either direction.
Thousands of small
pores
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Mathematical analysis of physiological measurements and electron
microscopic studies now point to the linear discontinuities (breaks) in the
interendothelial junctional strand rather than cylindrical pores being the
major route of transendothelial fluid flux Jv, the overlying glycocalyx
layer being the major filter.
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- acute reduction in capillary pressure to less than sigma delta
Π upsets the steady state and results in an immediate reversal
of capillary filtration to reabsorption, but this physiological
autotransfusion is transient (<30 min) and limited (<500 ml in
the 70 kg adult) before a new steady-state condition of reduced
filtration is re-established.
As interstitial fluid flows back up the interendothelial cleft and
enters the subglycocalyx protected space, it carries with it
proteins which cannot pass through the glycocalyx layer, so
that delta π across the glycocalyx is rapidly diminished until
absorption ceases. This mechanism has been called the
glycocalyx model or the Michel–Weinbaum model.
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Filtered solvent fluid leaves the plasma at a rate of 5-10 ml/ minute
(Jv) to enter the extracellular matrix.
By bolusing 1000 ml isotonic salt solution in 10 minutes, Jv can be increased to
100 ml/ minute.
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Filtered solvent fluid leaves the plasma at a rate of 5-10 ml/ minute
(Jv) to enter the extracellular matrix.
By bolusing 1000 ml isotonic salt solution in 10 minutes, Jv can be increased to
100 ml/ minute.
Enters collecting lymphatics, to afferent lymphatics, to lymph nodes.
Lymph node capillaries can absorb solvent.
Efferent lymphatics conduct remaining solvent to thoracic duct.
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Thibedeau, G. A., & Patton, K. T. (2006). Anatomy & Physiology (6th ed.). St. Louis: Elsevier Health Sciences.
x
xx
blood capillary
x no reabsorption
blood capillary
x no reabsorption
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Thibedeau, G. A., & Patton, K. T. (2006). Anatomy & Physiology (6th ed.). St. Louis: Elsevier Health Sciences.
Pulmonary
Lymphatics
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70 kg adult has about 3 litre of plasma which contains
around 210 g protein (70 g litre−1
)
capillary pressure is greater than interstitial, causing
glycocalyx-filtered solvent with its small lipophobic solutes
to flow to the interstitial space via infrequent breaks in the
junction strand which fuses adjacent endothelial cells
together.
microdomains of very low protein interstitial fluid are
found at the intercellular cleft exits. Beyond these cleft exit
microdomains, the 70 kg adult has about 12 litre interstitial
fluid in a gel phase which contains 240–360 g protein (20–
30 g litre−1
).
The distribution of ECF between intravascular and extravascular compartments
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Expressed as a mathematical formula, the mass flow of a solute
such as albumin (Js albumin) is the sum of the convective and
the diffusive components. Js can be measured as the
transcapillary escape rate (TCER) of a radio-labelled marker.
Using I131
, TCER albumin is about 5% h−1
, or about 10 g h−1
when
the plasma albumin concentration is normal. In health, while Jv is
low, transcellular pathway for Js predominates.
However, when paracellular hyperfiltration occurs this pathway
for Js predominates. TCER albumin increases by up to 300% (i.e.
to 15% h−1
) in surgical patients, in cancer patients, and in sepsis.
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44. Direct observation of direction of fluid exchange in capillaries in which Pc is maintained below Πp.
Levick J R , Michel C C Cardiovasc Res 2010;87:198-210
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For
permissions please email: journals.permissions@oxfordjournals.org.
•Autotransfusion of
up to 500ml due to
transient absorption
with acute
hypovolaemia or
noradrenaline
•In steady state,
filtration ceases at low
capillary pressure, and
absorption does not
occur
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45. Acta Physiol 2013, 207, 628–649
Inflammation reduces Rap1 and
Rac1 activation.
When S1P or intracellular cAMP are
elevated at the time of inflammatory
stimulus, they can buffer changes
induced by inflammatory agents and
maintain normal barrier stability.
REVIEW
Tonic regulation of vascular permeability
F.-R. E. Curry and R. H. Adamson
Department of Physiology & Membrane Biology, School of Medicine, University of California at Davis, Davis, CA, USA
Ras-related protein 1
Ras-related C3 botulinum
toxin substrate 1
Elevated S1P or intracellular cAMP can restore the
functional barrier by first reestablishing the
adherens junction, then modulating tight junctions
and glycocalyx.
S1P is a potent angiogenic factor that enhances
lung endothelial cell integrity and an inhibitor of
vascular permeability and alveolar flooding in
preclinical animal models of ALI.
Therapeutic potential for RBC
and PDEI !
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46. Acta Physiol 2013, 207, 628–649
More extreme
inflammation;
-loss of the inhibitory actions
of Rac1-dependent
mechanisms may promote
expression of more
inflammatory endothelial
phenotypes by contributing
to the up-regulation of
RhoA-dependent contractile
mechanisms
-sustained loss of surface
glycocalyx allows access of
inflammatory cells to the
endothelium.
REVIEW
Tonic regulation of vascular permeability
F.-R. E. Curry and R. H. Adamson
Department of Physiology & Membrane Biology, School of Medicine, University of California at Davis, Davis, CA, USA
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Special microcirculations
CENTRAL NERVOUS
Continuous with several lines of tight junction in every
interendothelial cleft forming a very impermeable blood–
brain barrier. Cleft exit microdomains appear to be
associated with closely placed pericytes.
Newly-discovered lymphatic vessels drain the interstitial
fluid of the central nervous system, and a lymph-like flow of
interstitial fluid around glial cells has been reported (the
glymph system). Anaesthesia and sleep are associated with
increased glymph flow, which is speculated to wash
potentially neurotoxic metabolites away.
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