Colloid: conundrums and conflicts (Proceedings)

Fluid therapy remains one of the essential components of critical care medicine with the goal being to restore intravascular volume. Several choices are available to optimize the treatment of these patients and controversy will undoubtedly continue. Crystalloids have many advantages including they are widely available, inexpensive, have minimal effects on the coagulation system, and do not cause allergic reactions. The disadvantages include formation of tissue edema by dilution of plasma proteins leading to lower colloid osmotic pressure. Additionally there is an increase in hydrostatic pressure contributing to edema formation.

Colloids contain large-molecular weight molecules that are restricted to the plasma compartment in patients with an intact endothelium. Colloids exert oncotic pressure to draw fluids into the intravascular space and maintain intravascular volume. Natural colloids include plasma, whole blood, hemoglobin-based oxygen carriers (Oxyglobin®) and both human and canine sources of albumin are available. Synthetic colloids include gelatins, dextrans, and hydroxyethyl starches. Advantages of colloid solutions include maintenance of extended duration of intravascular volume expansion and decreased risk of edema. As reflected in the Starling equation, they help maintain vascular volume by increasing oncotic capillary pressure (πc).

Starling Equation: Jv = (Pc – Pi) - σ(πc - πi)

Where: Jv = Net filtration; Pc = hydrostatic capillary pressure; Pi = hydrostatic interstitial pressure; σ = reflection coefficient; πc = oncotic capillary pressure; πI = oncotic interstitial pressure.

Disadvantages of colloids described in people include allergic reactions, possible renal injury, coagulation impairment, and significantly higher costs. Specific effects on coagulation include decreased factor VIII and von Willebrand factor, impaired platelet function, and interference with fibrin clot stabilization. Despite the potential disadvantages colloids have become widely used in critical care. However due to these concerns newer synthetic colloids have been developed with less serious complications.

Gelatin is produced from gelatin derived from bovine bone marrow. It undergoes enzymatic degradation, and is eliminated primarily via glomerular filtration and secretion into the feces. Administration increases IVF volume by twice the administered dose, with a plasma half-life of 2-4 hours.

Dextrans are polysaccharides composed of linear glucose residues produced during growth of bacterium Leuconostoc in sucrose media. Various molecular weights are produced by acid hydrolysis of the parent macromolecules. The half-life is dependent on the degree of acid hydrolysis. Smaller molecules are rapidly eliminated by glomerular filtration. Acute renal failure can occur with dextran 40 administration. Dextran 40 and Dextran 70 expand intravascular volume by 2.1X and 1.4X volume infused, respectively.

Oxyglobin, a hemoglobin based oxygen carrier derived from bovine hemoglobin. It is stroma free, ultrapurified, and highly polymerized. The high degree of polymerization delays renal clearance. Oxyglobin has a mean molecular weight (MW) of 200 KDa and is a very potent colloid with a COP of 43.3 mm Hg. Disadvantages of Oxyglobin includes plasma discoloration, nitric oxide scavenging and vasoconstriction, limited availability and dramatic costs.

Hydroxyethyl starches (HES) are highly branched polysaccharides made from maize or sorghum and composed primarily of amylopectin. Elimination involves absorption by tissues, gradual return to circulation, uptake by the reticuloendothelial system, degradation by amylase, and excretion via urine and bile. Solutions with high MW have a longer plasma half-life. HES can lead to coagulopathy that is dose-dependent and MW-dependent. There are chemical modifications that affect HES metabolism. A key modification is substitution of hydroxyl groups with hydroxyethyl groups which stabilize the polymer and prolong it's effect. A greater degree of substitution, or molar substitution, correlates with slower degradation; this also negatively impacts coagulation. The term hetastarch should not be used synonymous with hydroxyethyl starch (HES). Hetastarch is a type of HES with a high degree of substitution, between 0.6 and 0.7. Pentastarches and tetrastarches have substitutions of 0.5 and 0.4 respectively. Another modification is the degree of substitution on the C2 position versus the C6 position (expressed as C2/C6 ratio) which also conveys greater resistance to degradation.

There are several HES solutions available in Europe, while only 3 are available in the United States.

     • Hespan is a 6% hetastarch solution in 0.9% NaCl, mean MW of 600 KDa, 0.75 molar substitution, and C2/C6 ration of 5:1.

     • Hextend is a 6% hetastarch solution in a balanced electrolyte solution, mean MW of 670 KDa, 0.75 molar substitution, and C2/C6 ratio of 4.5:1.

     • Voluven, a 6% tetrastarch solution in 0.9% NaCl, mean MW of 130 KDa, 0.4 molar substitution, and C2/C6 ratio of 9:1.

Human Serum Albumin (HSA) is available commercially and has been used in veterinary medicine for several years. It is available as 5% solution with a COP of 20 mmHg or a 25% solution with a COP of 200 mm Hg. Dilution of the 25% solution is recommended prior to administration. Its use has been described in several veterinary reports. Amino acid homology between canine and human albumin amino acid sequences is 79.3%. Experimental studies in healthy dogs revealed significant immunologic reactions. Frances et al in 2007 reported administration of HSA to six healthy dogs. One had immediate hypersensitivity. All six developed signs of delayed hypersensitivity including lameness, edema, vasculitis. Two dogs died despite treatment, and all six developed anti-HSA antibodies. Cohn et all in 2007 reported similar findings in 9 healthy dogs. One dog developed anaphylactoid reactions; two dogs underwent repeat administration and both anaphylactoid reactions. Two dogs had signs consistent with delayed hypersensitivity. All dogs developed anti-HSA antibodies. Due to these significant immunological reactions, the author reserves the use of HSA for the direst cases.

Canine Albumin is available from a veterinary blood bank. However supplies have been low and the product is often on back order. No published reports exist of this products use in clinical cases. It is expected to be far safer than HSA.

Plasma products including fresh frozen and frozen plasma can be utilized for oncotic support. The advantages include they are widely available and relatively safe. Disadvantages of plasma products for oncotic support include expense, delay in administration due to thawing, risk of transfusion reactions, and volume required to affect the patient's albumin. Approximately 50 ml/kg of plasma is needed to increase a patient's albumin by 1.0 g/dl. This constitutes a noteworthy volume in most patients.

Conclusion

A variety of products are available to provide oncotic support to the critical patient. Many products have limited availability including Oxyglobin, dextrans, gelatins, and canine albumin. Human albumin administration is a highly effective method of increasing oncotic pressure, but not without considerable risks. Canine plasma products can be utilized in appropriate situations. Hetastarch solutions are the mainstay of providing colloid support in veterinary critical care. The solutions continue to be engineered to minimize patient risks and optimize the desired effect of maintaining vascular volume.

References available upon request.