Fielding Chapter 24: Colloids

What are the two types of colloid solutions?

Natural

Synthetic

Natural Colloids

Plasma

Whole Blood

Albumin

Synthetic Colloids

• Hydroxyethyl starch solutions (hetastarch, Hextend, Voluven, VetStarch, pentastarch)

• Dextran

• Gelatin

• Polymerized hemoglobin

What are the three attributes of hydroxyethylstarch that determine its pharmacokinetics?

Molecular weight

Degree of substitution

C2/C6 Ratio

Attributes Determined by Molecular Weight of HES

• Lower molecular weight solutions exert a greater oncotic pressure (greater number of particles) but have a lower half-life in the circulation as they are more rapidly degraded and eliminated

Degree of Substitution of HES

• Indicates the average number of hydroxyethyl groups per glucose unit

• A-amylase can only degrade unsubstituted glucose units

• By changing the degree of substitution it is possible to influence the degree of enzymatic breakdown and control the extent and duration of the volume effect

• A higher degree of substitution results in slower breakdown and elimination of the molecule

C2/C6 Ratio of HES

• HES hydroxyethylation can occur at carbon positions C2, C3, C6 of the glucose molecules

• This higher the C2/C6 ratio (i.e. the greater the number of glucose molecules hydroxyethylated at the C2 atom compared to the C6 atom), the slower the starch is metabolized

• Hydroxyethyl residues bound at the C2 position of glucose inhibit plasma amylase, increasing the intravascular half life of HES

• Renal function has been shown to decrease after administration of HES with a degree of substitution of more than 0.62 in humans undergoing surgery as well as with the administration of 10% solution

What are the two main mechanisms by which HES is removed from circulation?

Renal excretion

Redistribution

Renal Excretion of HES

• 2 phases

  • Elimination, by glomerular filtration, of polymers with a MW of less than 50kDa

    • Occurs almost immediately after administration

  • Glomerular filtration as the HES molecules are metabolized by hydrolysis by a amylase

    • Once the product of a-amylase digestion is smaller than 72kDa it can be renally excreted

      • Some are also excreted in the bile but this is a much less important elimination route

What % of HES molecules does renal excretion remove?

70-80%

What % of HES molecules does redistribution remove?

20-30%

Redistribution of HES

• Consists of uptake and temporary storage of HES in the tissues

• Extravasated molecules are stored in phagocytic cells of the liver, lymph nodes, and spleen and degradation by lysosomal enzymes occurs over time

Distribution of HES After 24 Hours

• After 24 hours, only 38% of the initial dose remains in the intravascular space, 39% is excreted in urine, and 23% is sequestered in tissues

Effect of a-amylase on COP

• A-amylase due to intravascular hydrolysis of large polymers of HES, yields a greater number of osmotically active molecules and serves to sustain the increases in plasma colloid osmotic pressure (COP) associated with hetastarch administration

What are the three HES products available in the US?

Hetastarch

Pentastarch

Tetrastarch

Hetastarch

• 0.7 degree substitution

• MW 450 kDa

• Advantage is its relatively prolonged volume effect because of the larger MW colloid particles and the high degree of substitution

• Associated with dose dependent coagulation abnormalities

Pentastarch

• 0.5 degree substitution

• Available for leukapheresis in humans but not for fluid therapy

• MW 264 kDa

Tetrastarch

• 0.4 degree substitution

• MW 130 kDa

• Low molar substitution is the main reason for the benefits on pharmacokinetics, intravascular volume expansion, and hemodilution

• C2/C6 ratio is 9:1, which increases the half life

• Recommended dose for small animals is 20 ml/kg/day

• Contraindications include fluid overload, renal failure with oliguria or anuria, and severe hypernatremia

• Elimination is faster than pentastarch with lower persistence in tissue

• May be associated with fewer renal side effects

Hemoblobin-Based Oxygen-Carrying Solutions (HBOCs)

• Alternative to whole blood transfusions

• One commercial product, Oxyglobin

• Oxygen, carrying properties, excellent colloids, and decrease blood viscosity

• Purified hemoglobin is used in horses principally for the treatment of acute life-threatening anemia

• Due to cost, used primarily in newborn foals with NI

• No adverse effects and a good clinical response for the treatment of anemia

Beneficial Effects of HES Resuscitation

Increases colloidal osmotic pressure (COP)

Plugging of leaky vessels

Blunting of endothelial-neutrophil interaction

Beneficial Effects of HES Resuscitation - Plugging of Leaky Vessels

• Hydroxyethyl starch may have the ability to seal endothelial "pores" or gaps that develop in microvessels after different forms of endothelial injury, including sepsis and endotoxemia

  • HES may prevent leakage of plasma proteins (especially albumin) from the intravascular space, preventing secondary fluid extravasation

  • Medium MW particles between 100 and 300 kDa, may act as plugs at these endothelial "pores"

Beneficial Effects of HES Resuscitation - Blunting of Endothelial - Neutrophil Interaction

• Evidence suggests that HES has the ability to modulate the endothelial inflammatory response and attenuate the permeability increase associated with sepsis

  • May reduce the expression of adhesion molecules which reduces leukocyte adhesion

What is the recommended dose of HES in horses?

5-10 ml/kg

Adverse Effects of HES - Plasma Viscosity

• Plasma viscosity is determined by the number and physical properties of macromolecules in plasma

  • Plasma viscosity is an important contributor to the microcirculatory disturbances that characterize shock

  • Highly substituted HES is less desirable in this regard because it increases plasma viscosity

  • Medium MW HES with low C2/6 ratios and low MW starches decrease plasma viscosity and have better rheological properties

Adverse Effects of HES - Effects on Hemostasis

• Major effects of HES on coagulation are dilution of plasma clotting factors, an additional decrease in factor VIII, and accelerated fibrin clot formation in the last stages of clotting

  • In addition, platelet dysfunction associated with coating of their surface occurs

What % of the blood volume is plasma in horses?

55-65%

Functions of Albumin

• Maintains COP

• Transports endogenous and exogenous substances

• Mediates coagulation

• Inhibits oxidative damage

• Maintains the integrity, function, and repair of the GI tract

What synthesizes albumin?

Hepatocytes

What degrades albumin?

Reticuloendothelial system

What is the one of strongest stimuli for albumin release?

• Plasma COP at the hepatic interstitial space is one of the strongest stimuli for albumin synthesis

  • Supranormal administration of colloids suppresses albumin synthesis

What % of COP does albumin account for?

70-80%

What % of total albumin does interstitial space contain?

60-70%

What are the forces opposing fluid escape from the vasculature?

• Colloid osmotic pressure regulates transvascular fluid flow - is one of the forces opposing fluid escape from the vasculature

• Gibbs-Donnan effect also contributes to water's attraction to colloids - negative charges of albumin molecules attract sodium cations which causes water to follow across the semipermeable endothelial membrane

What does a plasma transfusion contain?

• Plasma transfusions are the only source of equine specific albumin replacement

  • Plasma also contains immunoglobulins used for foals with FPT as well as macroglobulins, coagulation protein s9II, VII, IX, and X), antithrombin III, elastase, and proteinase inhibitors

How much plasma is needed to raise the plasma albumin of a horse by 0.1 g/dL?

10-15 ml/kg