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 care when it matters intensive care society The ntensive Care Society Churchill House, 35 Red Lion Square London WC1R 4SG T: 020 7280 4350 F: 020 7280 4369 E: events@ics.ac.uk www.ics.ac.uk www.intensivecarefoundation.org search: ntensive Care Society trainees follow us @CSMeetings Trainee CS members are invited to submit an abstract for a 10 minute presentation at the 2012 State of the Art Meeting. The session theme will be... SLAYING THE SACRED COWS OF ICU - WHICH ONE WOULD YOU ELIMINATE AND WHY? Following questions your peers and an invited expert panel will judge the selected presentations. The Cauldron Prize will be awarded to the best presenter, along with an New Apple iPad. The winning presenter will be invited to publish their presentations as an opinion article in JCS. Further information is available at: www.ics.ac.uk/education/trainee_committee/the_cauldron/ thecauldron2012 or by searching for ntensive Care Society trainees on Facebook The Cauldron The Intensive Care Society Trainee Committee Present DEADLINE: FRIDAY 31 AUGUST 2012, 5PM