Editorials The Intensive Care Society 2012

Volume 13, Number 3, July 2012 JICS 188

L
ast year, in the New England Journal of Medicine, John
Myburgh called for a reappraisal of the basics of fluid
therapy for resuscitation of hypovolaemic patients.
1
The
widely-preached mantra of giving colloid boluses for plasma
volume resuscitation and colloid-free isotonic salt solution
(ISS) for extracellular fluid volume replacement does not
explain observations from blinded clinical trials of colloid vs
ISS, and the expectation of benefit for resuscitation with
colloids, particularly regarding oedema, has not materialised.
Now that there is a consensus that colloid volume therapy
should not be used in critically ill patients,
2
there is a pressing
need for a new paradigm for fluid therapy. I propose an
improved paradigm that takes into consideration the Starling
equation, which has been neglected by clinicians and revised
by physiologists in recent years.
3
The Revised Starling Equation
and Glycocalyx Model paradigm (RSE&GM) retires the view of
colloids as preferred plasma substitutes and focuses instead on
the central volume of distribution of an infused fluid, its rate of
distribution to a peripheral volume, and its rate of excretion.
4
In short, it emphasises volume kinetics.
5
RSE&GM brings
several novel physiological concepts to the fluid debate, which
help to explain why colloids are of little benefit for
resuscitation from hypovolaemia.
The human microvasculature is composed of four very
different types of capillary, whose distinct functions must be
appreciated:
1. The 1.5 kg liver takes around 1 mL/min of the healthy
cardiac output/gram of tissue. Like the spleen and bone
marrow, it has primitive sinusoidal capillaries which are
freely permeable to larger molecules, making the interstitial
fluid of these tissues an extension of the plasma volume. In
resuscitated septic shock patients, as much as 50% of the
cardiac output goes to this very leaky microcirculation.
2. The renal glomerular capillaries are fenestrated and filter
fluid to the renal tubules (the glomerular filtration rate).
3. Diaphragm-fenestrated capillaries are specialised to absorb
fluid from interstitium to plasma when needed, and are
found in absorbing tissues like the intestinal mucosa, the
endocrine glands and renal peritubular capillaries.
4. The non-sinusoidal, non-fenestrated capillaries have a
continuous endothelial surface layer which filters fluid via
occasional gaps in inter-endothelial cell junctions to the
interstitium of their tissues, including connective tissues,
lung parenchyma and brain.
There are three intravascular volumes: the first two, plasma
volume and red cell volume, which make up the circulating
blood volume, are well known; the third is the non-circulating
intravascular volume occupied by the endothelial glycocalyx,
which creates a fibre matrix scaffold for the endothelial surface
layer. Being on average about two microns thick, the fragile
glycocalyx layer can account for as much as 1.5 litres of the
intravascular volume in health.
Filtration (Jv) across non-sinusoidal, non-fenestrated
capillaries is much less than standard textbooks of physiology
suggest.
3
Figure 1 is a diagramatic representation of the
arrangement of the glycocalyx on the luminal aspect of
endothelial cells and basement membrane/extracellular matrix
in the interstitial aspect. The convection current of filtrate that
is almost protein-free keeps the colloid oncotic pressure of
fluid in the sub-glycocalyx inter-endothelial channel close to
zero, and much lower than the colloid oncotic pressure of the
interstitial fluid into which the filtrate flows. It is the colloid
oncotic pressure difference (delta-pi) across the glycocalyx that
opposes Jv, and it is larger than delta-pi between the plasma
and the interstitial fluid which has previously been considered
in the Starling equation.
The glycocalyx model, the protected region and
the no-absorption rule
With the exception of the diaphragm-fenestrated capillaries
which can absorb solutes at normal capillary pressure,
absorption of fluid from interstitium to plasma does not occur,
even at reduced capillary pressure.
8
The mechanism is the
glycocalyx model. The inter-endothelial cell channels are
normally capped by the intraluminal fibre matrix of
glycocalyx which filters fluid that is almost protein-free to the
sub-glycocalyx protected region. At reduced capillary
pressure, the velocity of the convection current through the
inter-endothelial channels (which is the greater part of Jv)
approaches zero and the colloid oncotic pressure in the
protected region rises as soluble proteins diffuse back from the
interstitium, reducing delta-pi between plasma and the
protected region that opposes Jv. With very acute fall of the
trans-endothelial pressure difference (delta-P), there may even
be a transient reversal of the convection current, carrying
Fluid therapy the basics, reappraised 1AO1
TE Woodcock
red cell and plasma
glycocalyx
endothelial cells
and junction gap
Basement
membrane
and extracellular
matrix
Figure 1 Diagramatic representation of the glycocalyx on the
luminal aspect of endothelial capillary cells.
JICS Volume 13, Number 3, July 2012 189
proteins into the protected region. The glycocalyx model
thereby preserves a state of minimal filtration even when
delta-P is low. Intravenous colloid therapy cannot promote
absorption and cannot help to prevent or treat interstitial
oedema. If endothelial injury is severe enough to destroy the
fibre matrix cap of an inter-endothelial channel, the protected
region is lost.
The J-curve and the J-point
As a consequence of the glycocalyx model, a plot of Jv against
delta-P based on the revised Starling equation demonstrates
that Jv remains close to zero with rising delta-P until the
convection current of filtrate through the inter-endothelial
channels is sufficient to bring the protected regions colloid
oncotic pressure close to zero. Delta-pi is then maximal, and
further increases in delta-P will widen the difference between
delta-P and the now-fixed delta-pi, causing a sharp rise in Jv.
This creates an inflection on the curve that makes it appear J
shaped. The inflection is called the J-point.
For solutions of molecules which, by virtue of their size and
charge, do not freely permeate the glycocalyx, the central
volume of distribution is the plasma volume, while the central
volume of distribution of ISS is the sum of the plasma volume
and glycocalyx volume.
This could be the main reason why the observed volume
equivalence of isotonic salt solution to an iso-oncotic colloid
solution for IV resuscitation is about 1.5:1
4
rather than the 4:1
or 5:1 rule asserted by BAPENs current British Consensus
Guidelines.
6
Manipulating capillary pressure
The focus on capillary pressure brings a new perspective on
the role of low-dose arteriolar pressor therapy in intensive care
practice. Typically, the goal is to maintain an adequate mean
arterial pressure after adequate resuscitation of the
intravascular volume and stroke volume, allowing more
restrictive use of fluids. In terms of the RSE&GM, arteriolar
pressors are expected to lower capillary pressure and so
reduce Jv,
3
keeping more of the extracellular volume
intravascular. Now we can see alpha-1 agonists as part of a
potential anti-oedema strategy. Concern that capillary
hypertension is injurious will make us more cautious about
employing rapid boluses. RSE&GM predicts high capillary
pressures during rapid transfusion which will cause
excessively raised Jv, reducing the intravascular contribution
of whatever resuscitation fluid we choose. A slower infusion
rate will cause lower capillary pressure peaks, minimising
hyperfiltration and maximising efficient resuscitation of the
intravascular volume.
Interstitial fluid circulation
No longer is the interstitial fluid and lymphatic network to be
seen as a passive overflow system; interstitial fluid circulates
and is returned to the plasma via lymphatic capillaries and
lymphatics which incorporate contractile proteins and one-way
valves. To quote Rodney Levick, Charles Michel and William
Harvey: Although doggedly persistent in textbooks and
teaching, the traditional view of filtrationreabsorption balance
has little justification in the microcirculation of most tissues.
Tissue fluid balance thus depends critically on lymphatic
function in most tissues. In making these forceful statements,
we are mindful of William Harveys remark in his classic, De
Motu Cordis (1628): I tremble lest I have mankind for my
enemies, so much has wont and custom become second
nature. Doctrine once sown strikes deep its root, and respect
for antiquity influences all men.
3
By international standards, British intensive care
resuscitation practice in the past has been liberal with synthetic
colloids and frugal with blood and ISS.
7
We need a better
understanding of plasma colloid oncotic pressure during
anaesthesia and critical illness, and of the effect of IV fluids.
For example, we know that plasma albumin concentration is
posture-dependent in healthy subjects, and recent data from
veterinary canine clinical practice has shown that general
anaesthesia reduces plasma COP by around 20%.
8
The authors
reported that IV fluid therapy did not explain the changes. A
laboratory finding that the ability of colloids to inhibit
filtration was unrelated to their effect on colloid oncotic
pressure, was described as the COP paradox.
9
Looking at the
problem of leaky capillaries through the RSE&GM paradigm
reveals an urgent need to understand the resistance to fluid
flux (represented in the Starling equation as its reciprocal, the
hydraulic conductance) imposed by the fibre matrices of the
glycocalyx layer, basement membrane and extracellular matrix.
There is an urgent need to investigate whether COP-directed
therapy is of any clinical benefit at all. It may be that looking
for a Holy Grail of resuscitation among maize starch molecules
has distracted our attention from more promising avenues of
investigation. RSE&GM opens up a whole new approach to
understanding pathophysiology and fluid therapeutics, and
needs enthusiastic teachers and investigators to refine and
develop it further. It may even lead to a unification of fluid
resuscitation practices around the world!
Conflict of interests
The author has no interests to declare and has received no
payment or funding for work on the revised Starling equation
and glycocalyx model paradigm.
References
1. Myburgh JA. Fluid resuscitation in acute illness time to reappraise the
basics. N Engl J Med 2011;364:2543-44.
2. Reinhart K, Perner A, Sprung CL et al. Consensus statement of the
ESICM task force on colloid volume therapy in critically ill patients.
Intensive Care Med 2012;38:368-83.
3. Levick JR, Michel CC. Microvascular fluid exchange and the revised
Starling principle. Cardiovasc Res 2010;87:198-210.
4. Woodcock TE, Woodcock TM. Revised Starling equation and the
glycocalyx model of transvascular fluid exchange: an improved paradigm
for prescribing intravenous fluid therapy. Br J Anaes 2012; 108: 384-94.
5. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology 2010;113:
470-81.
6. Powell-Tuck J, Gosling P, Lobo DN et al. British Consensus Guidelines on
Intravenous Fluid Therapy for Adult Surgical Patients 2009. http://
www.renal.org/pages/media/download_gallery/GIFTASUP%20FINAL_05_
01_09.pdf Accessed April 2012.
7. Finfer S, Liu B, Taylor C et al. Resuscitation fluid use in critically ill
adults: an international cross-sectional study in 391 intensive care units.
Crit Care 2010;14:R185.
Editorials
Volume 13, Number 3, July 2012 JICS 190
8. Dismukes DI, Thomovsky EJ, Mann FA, Middleton JR. Effects of general
anesthesia on plasma colloid oncotic pressure in dogs. J Am Vet Med Assoc
2010;236:309-11.
9. Jacob M, Bruegger D, Rehm M et al. The endothelial glycocalyx affords
compatibility of Starlings principle and high cardiac interstitial albumin
levels. Cardiovasc Res 2007;73:575-86.
Editorials
Thomas Woodcock Consultant Intensivist, Critical Care
Directorate, University Hospital Southampton NHS Foundation
Trust
tom.woodcock@me.com
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