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Bilirubin is tightly bound to albumin, making hemoperfusion an ineffective treatment for hyperbilirubinemia. By adding a safe unbinding agent to the blood (solutizer), which itself is adsorbed, hemoperfusion can become efficient and practical. Canines were made hyperbilirubinemic with an intravenous infusion of a 5 mg/ml solution (with Na2CO3) for 1 hour. Peak concentrations of 14-22 mg/dl were reached in adult dogs (25-35 kg). Hemoperfusion was then initiated with or without (control) the solutizer (sodium benzoate). The bilirubin unbinding effect of sodium benzoate was rapid and effective. Because of the simultaneous adsorption of sodium benzoate, a small activated carbon section that was presaturated with the solutizer was located proximal to the main hemoperfusion column, in addition to continuous infusion to reach 20 mM in the blood. Comparison of the normalized bilirubin concentration for benzoate augmented hemoperfusion with the average for control dogs, shows that benzoate results in a threefold decrease in the normalized bilirubin concentration after 1.5 hr of hemoperfusion. Sodium benzoate may also have the advantage of protecting platelets during hemoperfusion.

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Three different metabolic models were incorporated in a compartmental simulation of brain tissue pO2 response to rapid changes in arterial pO2. The first was the frequently utilized constant metabolism assumption. The second model was a 4-step kinetic simplification of glucose conversion to CO2 with an intermediate reversible reaction of pyrovate to lactate. The most sophisticated model was a new 11-step reaction scheme with the same start and end points accounting for glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. A unique representation was derived for the oxygen consumption depending on reduced cytochrome a3+(3) consistent with diverse observations in the literature. The theoretical predictions were compared to previously published cortical tissue pO2 recordings from detailed experiments with pentobarbital anesthetized cats. The 11-step metabolic model invariably provided the best match between the theoretical calculations and the observed responses. These results indicate that cellular metabolism rapidly adjusts to changes in O2 in a manner which reduces the tissue pO2 fluctuation. In concert with the large compensatory arterial blood flow response there was extensive damping of intracellular pO2 compared to arterial O2 changes.

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Exchange transfusions and phototherapy are used to treat hyperbilirubinemia, each method having its own disadvantages. Hemoperfusion with coated activated charcoal (CAC) produces low removal rates due to the strong binding of bilirubin to albumin. Biocompatible chemical agents were investigated to selectively unbind the bilirubin into solution just prior to CAC exposure. In batch mock solution tests, the addition of sodium benzoate resulted in a 69% equilibrium bilirubin removal at 50 mM and 96% removal at 100 mM. During flow tests, adsorptive removal of sodium benzoate was so rapid that the CAC had to be pretreated with sodium benzoate solutions. In the absence of sodium benzoate, the outlet bilirubin was 50% of the inlet concentration at the passage of one void volume, with a rapid increase to 70% (30% removal). With sodium benzoate at 100 mM, the same 50% outlet/inlet percent was observed at one void volume throughput, but the outlet concentration fell to 6% of the inlet at 12 column void volumes (94% removal). Similar experiments with bovine plasma/blood and human plasma resulted in an average increase in bilirubin removal of 25% for the bovine and human plasma and 35% for the bovine blood at 100 mM benzoate. A significant decrease in platelet aggregation was measured with the addition of sodium benzoate, which makes this augmented hemoperfusion removal of bilirubin clinically attractive.

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The hemofiltration/molecular separation (HFMS) artificial kidney concept, first proposed over a decade ago, involves continuous ultrafiltration from the blood stream followed by cleansing of the filtrate, with subsequent return to the body. Thus, the system is completely self-contained and portable. During recent preclinical trials on nephrectomized canines, HFMS was better than hemodialysis (HD) in several important ways. First, the removal or clearance of middle molecules was better with 0.34 m(2) HFMS than with 1 m(2) HD. Significant phosphate clearance was achieved, and the removal rate for creatinine was the same as that for urea. This uniform clearance extends to even higher molecular weight solutes and could potentially result in improved patient response. It mimics the real kidney, whereas membrane-limited dialysis undergoes a logarithmic decrease of clearance with molecular weight. This is due to the fact that solute transport through the membrane involves solution into its matrix followed by diffusion, and solute diffusivity decreases with molecular volume. In order to achieve this potential for hemofiltration-based systems, however, there are stringent requirements on both the membrane and the plasma proteins allowed to accumulate on the membrane surface.

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If adequate electrolyte adjustments are made, the only problems with the present HFMS system are the need to replenish divalent cations, add buffer, and remove the evolved CO2. Even with these deficiencies the system is portable, objectively and subjectively better than HD, and capable of being wearable in the foreseeable future.

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A naturally deposited protein layer is shown to be highly compressible as witnessed by its resistance to the passage of both water and dissolved molecules. This protein layer can easily be much more important than the underlying membrane. Hydrodynamic methods can be employed to control this protein layer, even to the extreme of its extinction in a continuous flow system. The rejection properties are shown to be a function of both the tracer molecular weight and type. Some of the physical property variations are reviewed for plasma amd serum as a function of protein concentration.

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Flow visualization experiments were performed leading to the development of a correlation for the vortex shedding from indentations perpendicular to the main stream flow and caused by the addition of a pulsed flow component. The peak pulse flow rate required for vortex shedding greatly exceeds the condition for flow reversal in the channel when the steady flow rate is low while the vortex shedding occurs close to the flow reversal condition when the steady flow rate is very high. The empirical correlation should be useful in assessing the practicality of utilizing this technique to augment mass transport in membrane separation processes. Vortex shedding provides substantial transport augmentation in the ultrafiltration of a flowing plasma stream, and recommendations for further study are outlined to improve our understanding of this phenomena.

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