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Hyperkalemia is a common complication in neonatal diarrheic dairy calves and is corrected by administration of glucose or sodium bicarbonate. Although the hypokalemic effect of glucose is well established in other species, controversial results are reported for sodium bicarbonate. Our objective was to study the effect and mechanism of action of glucose and sodium bicarbonate on the potassium homeostasis of healthy neonatal dairy calves. Nine healthy neonatal Holstein-Friesian calves underwent 3 oral treatments with 2L of NaHCO(3) (150 mmol/L), glucose (300 mmol/L), and glucose+NaHCO(3) solution (300 mmol/L+150 mmol/L) in randomized order. Blood was obtained before treatment (T(0)) and at 30-min intervals thereafter. Changes between each time point and T(0) were determined for all parameters. Urine was collected volumetrically to determine total renal potassium excretion over an 8-h posttreatment period. Plasma volume changes were extrapolated from changes in plasma protein concentration. Treatment and time effects were tested with repeated-measures ANOVA. Multivariate stepwise regression analysis using dummy variable coding was conducted to identify associations between changes in plasma potassium concentration ([K]) and changes in plasma glucose concentration ([glucose]), blood base excess, and plasma volume. Oral glucose and sodium bicarbonate treatments decreased [K] by 25 and 19%, respectively, whereas the combination of both compounds caused an intermediate [K] decline (22%). For the glucose treatment, the decline in [K] was only associated with changes in plasma [glucose] (partial R(2)=0.19). In NaHCO(3)-treated calves, [K] decline was associated with change of extracellular volume (partial R(2)=0.31) and blood base excess (partial R(2)=0.19). When glucose and NaHCO(3) were combined, [K] decline was associated with changes in plasma volume (partial R(2)=0.30), BE (R(2)=0.22), and [glucose] (partial R(2)=0.03). Our results indicate that glucose lowers plasma [K] mainly through an insulin-dependent intracellular translocation of K, whereas NaHCO(3) causes hypokalemia through hemodilution followed by intracellular translocation of K caused by the strong ion effect. The combination of glucose and NaHCO(3) at the dosage used in this study does not have an additive hypokalemic effect. When combined, hemodilution and strong ion effect have the strongest effect on plasma [K], whereas the insulin-dependent effect of glucose appears to be blunted.