CONCENTRATED CITRATE FOR CATHETER - LOCKS

Chronic central venous catheters (with subcutaneous cuffs) are used for dialysis access in over 10% of all patients on chronic hemodialysis. In order to prevent clotting of these chronic catheters between use, the catheter lumens are usually filled with concentrated solution of heparin after each use (up to 10,000 units per catheter lumen, for hemodialysis catheters). This solution must be withdrawn from the catheter before the next dialysis or use of the catheter for IV infusion, since administering this much heparin to the patient could result in bleeding of the patient. Heparin works by activation of anti-thrombin III, which is present in normal blood but is deficient in patients with malnutrition of hepatic insufficiency. Heparin is effective in concentrations as low as 1 unit per ml of blood. However, between uses of a catheter blood can slowly enter the tip of the catheter and wash out residual heparin, resulting in clotting of the tip of the catheter. Further, heparin has no antibacterial properties and in fact may help to promote growth of bacteria within the "biofilm" layer of protein on catheter surfaces (protamine has the opposite effect). Also, heparin is directly damaging to platelets and white cells, and paradoxically can induce clotting in some patients (the "white clot" syndrome). Finally, heparin is insufficient to prevent clotting within and around chronic catheters between uses. When chronic catheters become partially or completely occluded by clot, urokinase is instilled or infused in to the catheter to lyse the clot. The foreign surface of catheters create a smooth surface at which bacteria can grow, and at which the white cells are unable to surround or "phagocytize" the bacteria. Further, the "biofilm" coating of proteins on the catheters can protect bacteria from antibiotics and white cells. Since chronic venous dialysis catheters are uncapped and connected to dialysis machines so frequently, they have a propensity to become contaminated. Further, during bacteremia (bacteria in blood) catheter surfaces within the vein can become "seeded" with bacteria. In spite of intravenous antibiotics, the sepsis may not clear. At this point, the catheter is often removed on the presumption that it is the source of continued bacteremia.

Citrate is an alternative anticoagulant. Citrate works by binding calcium, and removing it from the many proteins of the coagulation system that require it to form a clot. Citrate is more "gentle" as an anticoagulant, avoiding damage to platelets and white cells, and for this reason it is used for extracorporeal blood treatments such as plasmapheresis, where preservation of cell elements is important; at the rate of infusion used, it is usually necessary to infuse calcium to the patient to avoid symptoms of hypocalcemia. The necessary minimum concentration of citrate is several times higher that total blood calcium on a molar ratio (0.2% or about 10mM). An advantage of citrate is that at much lower concentrations, it has no anticoagulant properties at all. Infusion of a few millimoles of citrate is immediately countered by the calcium within blood, and this calcium is replaced by calcium from the rest of the body. Citrate is also intrinsically antibacterial, especially in high concentration and at low pH. In fact, citric acid is routinely used to disinfect and de-scale dialysis machinery. Hyperosmolar solutions, especially near or above 200 mosm, are themselves antibacterial. High osmolality is what keeps honey, pickles and mincemeat pie from spoiling.

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