The medical and metabolic consequences of administration of sodium acetate

Abstract 1. 1.|The standard total parenteral nutrition, peritoneal dialysis, hemodialysis and many surgical fluids in use today contain 36 to 45 m m d,l -lactate or 2 to 140 m m acetate whereas the normal blood level of d -lactate is 0.02 m m l -lactate 0.5 to 5 m m and acetate 0.1 m m . The reasons for the continued use in patients of such unphysiological concentrations of these anions appear to be historic. 2. 2.|Administration of similar concentrations of these anions to the rat causes widespread metabolic disturbances which mimic many of the untoward complications associated with current parenteral and dialysis therapy. Understanding of the mechanisms attendant upon the metabolism of these anions may serve as a guide for designing improved parenteral fluids for human patients. 3. 3.|Elevation of blood d -lactate to 5 m m is associated with cerebral dysfunction in human patients. 4. 4.|Acetate stimulates the release of the inflammatory leukokine, interleukin-1 from human monocytes. Use of 35 to 45 m m acetate in peritoneal dialysis fluids led to peritoneal fibrosis. Patients exposed to acetate containing hemodialysis fluids have 12-fold elevation in their plasma interleukin-1 levels. 5. 5.|Administration of 20 m m sodium acetate to rats leads to a number of metabolic disturbances similar to those seen in human dialysis patients: 5.1. (a)|Acetate elevates blood glucose in the rat and may contribute to the exacerbation of the carbohydrate intolerance seen in uremic patients. 5.2. (b)|Acetate increases the levels of hepatic malonyl CoA, the rate controlling substrate of fatty acid synthesis and may exacerbate the hypertriglyceridemia characteristic of dialysis patients. 5.3. (c)|Acetate administration in the rat leads to a decrease in the cytosolic phosphorylation potential, reduction of the redox state of the free cytosolic NAD couple and paradoxical oxidation of the mitochondrial NAD couple in a pattern analogous to that produced by uncouplers of oxidative phosphorylation and may account in part for the elevation of temperature reported in patients undergoing hemodialysis with acetate. 5.4. (d)|Acetate administration in the rat leads to an increase in intracellular phosphorylated intermediates, adenine nucleotides, inorganic phosphate, inorganic pyrophosphate, calcium and magnesium. On cessation of acetate metabolism, the inorganic phosphate and calcium accumulated intracellularly leave the intacellular space. In patients undergoing hemodialysis, the blood phosphate returns to predialysis levels, within 6 hr after the completion of treatment, leaving significant numbers of patients with chronic hyperphosphatemia and the multiple complications attendant to that state. 6. 6.|The major site of calcium and magnesium accumulation in the rat to which sodium acetate has been administered is the mitochondrial matrix where they form insoluble pyrophosphate precipitates. The reason that this occurs is that the concentrations of free mitochondrial [Ca 2+ ] and [Mg 2+ ] are both about 10 −3 m within the mitochondrial matrix in vivo . 7. 7.|A consequence of the free mitochondrial [Ca 2+ ] being about 10 −3 m is that the distribution of free Ca 2+ across the mitochondrial membrane appears to be in near equilibrium with a mitochondrial membrane potential of about 125 mV. The square of the gradient of free [Ca 2+ ] across the mitochondrial membrane is also in near equilibrium with the free cytosolic [ΣATP]/[ΣADP][ΣPi]. 8. 8.|Consideration of the effects of the composition of parenteral fluids upon the energy status and metabolism of cells may improve the therapeutic efficiencies of traditional fluids.