Hematocrit and Interference Correction

Hematocrit and Interference Correction

Two things in a fingerstick sample can pull a test strip's reading away from the true glucose value. One is hematocrit, the percentage of the blood made up of red cells; the other is a group of substances the strip reacts to as if they were glucose [1]. Here's what surprised us: the hematocrit error runs in both directions. Several studies found that lower-than-normal hematocrit (below roughly 30% to 35%) makes meters overestimate glucose, while hematocrit above about 45% makes them underestimate it [2].

The mechanism isn't fully settled. Researchers have proposed thicker blood, red cells keeping plasma off the strip's reaction surface, slower diffusion, and red cells crowding out the plasma the test needs [2]. A 2010 review describes the diffusion effect directly. As hematocrit rises, blood becomes more viscous, everything in it diffuses more slowly, and the current an amperometric strip measures drops [3]. (An amperometric strip reports glucose as an electrical current.) Red cells can also block the electrode or the enzyme [1].

Meters handle this in different ways, and AC impedance is only one of them. In Roche's Accu-Chek Aviva Plus system, the meter first sends a small alternating current (AC) through the sample at four frequencies. It then applies a direct-current (DC) voltage, which produces a current proportional to the glucose, and combines the AC and DC information into a hematocrit- and temperature-compensated result [4]. FDA's summary for the Accu-Chek Guide says that meter also evaluates the sample using AC and DC signals; its labeling says not to use it below 10% or above 65% hematocrit [5]. Other designs measure hematocrit separately and apply a correction. Still others use dynamic electrochemistry, taking many measurements at changing voltages and frequencies so an algorithm can work out correction factors [2].

Correction still isn't universal. A 2011 laboratory test ran 13 meters across hematocrit levels from 25% to 60%. Apart from a hospital meter that measures and corrects for hematocrit, only four of the other 12 stayed under the study's 10% stability cutoff [2]. The same paper notes that many meters' instructions limit use to a stated hematocrit range, typically 30% to 60% [2].

Interference falls into two categories: enzymatic and electrochemical. Enzymatic interference happens when the strip's enzyme reacts with a sugar other than glucose. In August 2009, FDA warned that GDH-PQQ strips (glucose dehydrogenase with a pyrroloquinoline quinone cofactor) can't tell glucose apart from certain other sugars, including maltose. Those sugars push results falsely high, which can hide real hypoglycemia or lead to too much insulin. FDA had received 13 reports of deaths from 1997 to 2009, and ten of those patients were on icodextrin peritoneal dialysis solution [6].

The same notice named glucose oxidase, GDH-NAD and GDH-FAD as methods not affected by these sugars [6]. Many current strips use one of them: Accu-Chek Guide strips use GDH-FAD [5], and FreeStyle Precision Neo strips use GDH-NAD [7]. We found the switch isn't complete, though. As of October 2026, Roche's support pages still pair its Aviva meters with Accu-Chek Aviva Plus strips [8], and those strips use a modified (mutant) GDH-PQQ that FDA cleared in September 2011 [4]. Their FDA summary says galactose above 15 mg/dL causes overestimated results; maltose doesn't appear in its interference tables [4]. Roche says the Aviva meter will soon be discontinued but gives no date [9]. For someone receiving icodextrin dialysis or a maltose-containing infusion, which meter to use is a decision for their care team.

Electrochemical interference happens when a substance reacts at the electrode itself. Any molecule that is electroactive at the strip's operating voltage can add current that the meter counts as glucose [3]. Vitamin C (ascorbic acid) and high doses of acetaminophen can be oxidized directly at the electrode, raising the reading [3]. The direction depends on the chemistry. A 2009 review found these drugs tend to lower results on glucose oxidase meters that detect peroxide, while direct oxidation at the electrode can raise results on glucose dehydrogenase meters [10]. Aviva Plus labeling, for example, warns that intravenous ascorbic acid producing blood levels above 3 mg/dL will cause overestimation [4].

Because interference depends on the operating voltage, a low-potential mediator leaves fewer substances able to react. The mediator is the molecule that carries electrons from the enzyme to the electrode [1]. As their developers described them in 2010, Abbott's FreeStyle strips use an osmium mediator with a formal potential between 0.0 and −0.2 V against the strip's silver/silver chloride electrode [11]. A ruthenium compound, hexaammineruthenium(III), lets strips run at lower operating potentials than ferricyanide, the most common mediator in commercial strips [12]. Electrode layout matters too: the 2009 review notes that newer amperometric meters with a third electrode minimize interference from these drugs [10]. What the papers we read don't spell out is how each brand uses that extra electrode.