Prismaflex Technical Training Supplementary Material

Diffusion The molecules of a gas mixture or a solution are never at rest, but vibrate, drift and collide. This inherent movement, which requires no external force but is temperature dependant, is called Brownian Movement. As a consequence, a certain component of a solution that is abundant in one area will spread towards other areas where its concentration is lower. There is simply a tendency for the compound to spread as evenly as possible in the defined space. This phenomenon is referred to as diffusion. In solutions, the term diffusion is used to describe the physical process in which dissolved solutes move from an area of high solute concentration to another area of lower solute concentration in order to reach an eventual equilibrium. The driving force is the concentration gradient, and the net transport continues until equilibrium is reached and the solute concentration is the same everywhere. The rate of diffusion is much dependent upon the size of the solute. Bigger molecules move more slowly than smaller ones, and hence their diffusion rate is much slower. Therefore we can conclude that the larger the solute, the longer it takes before equilibrium is reached. Now consider that we create two separate fluid compartments by introducing a membrane which presents no barrier to small molecules, but which excludes larger molecules. Such a selectively permeable membrane is referred to as semipermeable. We can then observe that small solutes move freely between the compartments, behaving as if the membrane were not present at all. The process is analogous to diffusion in a solution without a membrane, and the driving force is the concentration gradient. Medium sized molecules are slowed down by the membrane and large solutes are entirely excluded from the other compartment. For example Small Solutes with a molecular weight below 300, such as the waste products urea (MW60) and creatinine (MW113), easily move across a membrane. The movement of solutes will continue as long as the concentration gradient is maintained. If the fluid on the low concentration side of the membrane is continuously replaced with fresh solution, the process will go on indefinitely. The solute removal rate by diffusion in hemodialysis is controlled by: • • • •

Blood flow rate Dialysis Fluid Flow Rate Concentration gradient between blood and dialysis fluid Dialyzer characteristics, such as membrane type, thickness and surface area. 1

Diffusion: The movement of solutes from a higher concentration to a lower concentration

Diffusion is defined as the movement of solutes from a higher to a lower solute concentration area. A membrane when fully permeable to the solute has little impact on diffusion. These cups, where the solutes are represented by black dots, schematically illustrate the principle. Observe how the initial concentration gradient is gradually eliminated as the solutes spontaneously spread in the fluid.

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Convection

Assume that we put a lump of sugar in a cup of coffee where it dissolves on the bottom. If we should wait for the sugar to spread in the cup by diffusion alone, the coffee would surely turn cold. Thus, in order to quickly get an even sugar concentration in the cup, we use the coffee-spoon to stir the coffee, making the fluid move in a turbulent manner. In this case the sugar molecules do not move by diffusion; instead they are transported by the movement of the solvent, the water. The same phenomenon can be observed when a solution is passing through a semipermeable membrane, dragging dissolved substances along. Convection is the term used to describe the movement of the solutes across the membrane caused by the passage of solvent; hence the term “solvent drag”. The solute transport is directly proportional to the solvent transport, and the solvent transport in turn depends on the pressure gradient. For the removal of very large solutes with a high molecular weight, such as beta 2 microglobulin (MW 11,800) for which the diffusion rate is extremely slow, convection is the only transport principle. Depending on the size of the pores in the membrane, solutes of different molecular weight will pass through to different extent. Small solutes, not inhibited by the membrane, will pass through the membrane at a rate and thus a concentration equal to that in the original solution. However, for larger solutes the membrane will act as a sieve, and certain large solutes will not pass through the membrane at all. The solute removal rate by convection is controlled by: • Ultrafiltration rate • Membrane sieving properties

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Convection: The movement of solutes with a water-flow, “solvent drag”, e.g. the movement of membrane-permeable solutes with ultrafiltered water.

When a solution is moving, the solutes dissolved in it will move along, a process referred to as convection. This phenomenon can be observed during ultrafiltration, where membrane-permeable solutes will follow the ultrafiltered water.

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Ultrafiltration Ultrafiltration is the physical process in which fluid is transported through a semipermeable membrane. The driving force is s pressure gradient across the membrane. The pressure gradient can be applied in three different ways. A hydrostatic pressure, created e.g. by a piston or a pump, can either be positive or negative. A positive hydrostatic pressure(1) is created when the fluid is pushed through the membrane, and a negative hydrostatic pressure(2) is created when fluid is sucked through the membrane. In hemodialysis the combination of both positive (on the blood side) and negative pressures (on the dialysis fluid side) make up the total pressure gradient over the membrane. This pressure gradient, referred to as transmembrane pressure (TMP), is used to remove excess water. The third alternative is to create an osmotic pressure. By adding a solute of large molecular weight, i.e. a non-permeable solute, to the “suction side” of the membrane, fluid will move from the compartment with high water concentration to the one with lower water concentration. This principle is used to remove fluid in peritoneal dialysis, where glucose is the solute giving osmotic pressure. Footnote: 1. Positive Pressure: above atmospheric pressure 2. Negative Pressure: below atmospheric pressure

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Ultrafiltration: The movement of fluid through a membrane caused by a pressure gradient.

a. positive pressure

b. negative pressure

c. osmotic pressure

Ultrafiltration is the process in which fluid is transported through a semipermeable membrane. The driving force is a pressure gradient across the membrane which can be created in different ways: a. Positive pressure on the left compartment, represented by the large arrow, will “push” fluid through the membrane. b. A negative pressure on the right compartment, will “suck” fluid through the membrane. a. Non-permeable solutes create an osmotic pressure. Thus, water will move from the area of high water concentration to the area of lower water concentration

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Adsorption

A recently described mechanism of solute removal is adsorption. This is the final way in which solutes may be removed from the blood. Adsorption occurs in two different ways: • Surface adsorption where the molecules are too large to permeate and migrate through the membrane; however can adhere to the membrane • Bulk adsorption within the whole membrane when molecules can permeate it. It must be noted that movement of fluid is required for adsorption to occur. Molecules that can be effectively adsorbed include: • B2 Microglobulin • Cytokines • Coagulation factors • Anaphylatoxins

Note: Not all membranes possess the capabilities of adsorption and it is necessary to identify the specific properties of a membrane which predict whether adsorption is possible.

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Adsorption: Molecular adherence to the surface or interior of the membrane.

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Fluid Removal To remove excess fluid from blood by ultrafiltration, a pressure gradient across the membrane is needed. In the blood compartment of the dialyzer, a positive pressure is created by the blood pump. In the dialysis fluid compartment there is usually a negative pressure created by a suction pump in the dialysis machine. The resulting hydrostatic pressure gradient across the membrane is called the Transmembrane Pressure, TMP, normally measured in mmHg (millimetres of mercury). Note that the TMP is not a pressure but a pressure difference. The TMP is the difference between the pressure in the blood compartment and the pressure in the dialysis fluid. TMP = Filter Pressure + Return Pressure - Effluent Pressure 2 The pressure gradient is the driving force for fluid transport across the membrane, a process referred to as ultrafiltration. Fluid moves from the higher to the lower pressure area, i.e. from the blood into the dialysis fluid. The ultrafiltration rate, i.e. the amount of fluid removed per unit of time, is decided by two factors: the pressure gradient across the membrane (TMP) and the membrane’s permeability to water. When estimating the total pressure gradient, osmotic pressures sometimes need to be considered. The plasma proteins create a small osmotic pressure of 20-30mmHg which is necessary to maintain the volume of the blood. It is referred to as the oncotic pressure. To obtain any ultrafiltration, this oncotic pressure needs to be overcome by a higher hydrostatic pressure gradient. If the hydrostatic pressures in the two chambers were equal, there would be a net flow of water from the dialysis fluid into the blood caused by the oncotic pressure, Osmotic pressures cannot be measured or controlled by the dialysis machine and are normally not taken into consideration in standard hemodialysis. Each membrane type has its own permeability properties. The more permeable a dialysis membrane is to water, the higher the ultrafiltration rate obtained at a given TMP. Standard hemodialysis membranes are called low flux membranes, whereas membranes that are highly permeable to water and used in the ICU setting are referred to as high flux membranes. In summary, the fluid removal rate in hemodialysis is controlled by: • •

Total pressure gradient across the membrane (expressed as TMP) Water permeability characteristics of the specific dialyzer

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References Daugirdas, J.T. & Blake, G. & Todd, S. Handbook of Dialysis. 3rd Ed. Lippincott Williams & Wilkins, Philadelphia. 2001. Gambro BASICS : Gambro 2002 Hospal Power Point Presentation: Continuous Renal Replacement Therapy. Kathy DiMuzio. Tournier, M.D. & Delaunay M. (Hospal) “The AN69 Dialysis Membrane” 1995.

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