Serum Potassium Is Unreliable as an Estimate of in Vivo Plasma Potassium

The in vitro release of potassium from cells and platelets during blood clotting [particularly in patients with blood dyscrasias(1)(2)] increases serum potassium, on average, by 0.4 mmol/L (3). This difference is considered to be independent of collection tube type (4). Following a change in the supplier of collection tubes, however, we observed an increase in the frequency of pseudohyperkalemia, which prompted a formal evaluation of the serum-plasma difference and the effect of different tube types. Free-flowing blood, taken without a tourniquet to avoid venous stasis, was collected from 40 hospital outpatients. Paired samples of clotted blood (5 mL) were collected in random order into the types of tubes listed in Table 1. One tube of each pair was selected at random, to prevent systemic bias, and centrifuged, and the potassium concentration was determined without delay (time 0). Potassium was measured using an automated discrete analyzer with an ion-selective electrode (Bayer Diagnostics). The second tube of each pair was left to stand for 3 h at room temperature before centrifugation and analysis (time+3), representing a typical delay in sample transport to the laboratory. The analytical imprecision (CV) was <0.5% for both serum and plasma within and between batches (n = 30). The significance of the differences between serum and plasma was tested using the Student t-test, and the relationship between this difference and the plasma potassium concentration was tested using least-squares linear regression. Effect of specimen tube and delay in separation on potassium concentration. NS, not significant. Effect of specimen tube and delay in separation on potassium concentration. NS, not significant. The mean plasma potassium concentration was 4.16 mmol/L (SD, 0.33 mmol/L; range, 3.49–4.77 mmol/L). When the blood stood for 3 h before centrifugation (time+3), the mean plasma concentration increased by a nonsignificant 0.01 mmol/L (95% confidence interval, −0.088 to 0.108 mmol/L). The differences between serum and plasma at baseline and at (time+3) are shown in Table 1. The mean difference between the serum and plasma potassium concentrations at baseline was similar for the different tube types (0.324–0.379 mmol/L). However, the variation between patients in the amount of potassium released during clotting was marked, as shown by the wide confidence intervals of the plasma-serum difference, which spanned 1.08 mmol/L for one type of sample tube (tube E). The 3-h delay in separation of serum from clot increased this difference, with the 95% confidence intervals spanning up to 1.5 mmol/L (tube C), although in one type of tube, the mean increased by a nonsignificant 0.079 mmol/L (tube D). The serum-plasma and the baseline to (time+3) differences were not related to the plasma potassium concentration or blood platelet count. The difference between serum and plasma potassium concentrations is well known, but we believe the clinical significance of the intra- and interindividual variability of the difference is not fully appreciated. This variability differs between types of blood collection tubes, possibly because of the extent of clot retraction induced by the surface of the tube or the clotting accelerator. Even for the sample tube showing the least variable potassium release (tube D; Becton Dickinson), serum remains an unsuitable medium for managing patients in whom potassium homeostasis is important, particularly because most standard medical texts base management on plasma concentrations(5)(6)(7). The extent of potassium release during clotting or during delays in the separation of serum from cells means that a true plasma potassium in the middle of the reference interval (4.16 mmol/L) may range from 3.82 to 5.44 mmol/L in a simultaneously taken serum sample (tube C); the variation is unpredictable, unrelated to the plasma concentration, and additive to the inherent biological variation in potassium concentrations. A reference interval derived from serum samples would be wider than the interval derived from plasma and would cause truly abnormal concentrations to be masked, e.g., hyperkalemia associated with a small release on clotting or hypokalemia associated with a large release on clotting. These studies were conducted on hospital outpatients, but because we instituted a policy of requesting plasma when a serum result fell outside the reference interval, we have observed even greater differences in hospital inpatients with disorders, such as diabetic ketoacidosis, in which the potassium balance may be critical. Plasma is the preferred medium for the determination of potassium concentration, although it is not ideal for many other biochemical analyses. When serum is to be used, laboratories should be aware of the additional variability observed with this medium and the extent to which this is affected by their choice of sample tube.