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Analytical Interferences and Physiological Limitations of Blood Glucose Meters. Ken Ervin. Package inserts Review articles (partial list) Boren and Clarke Tonyushkina and Nichols Pitkin and Rice Montagnana et al Wahl Dungan Arabadjief and Nichols Heller and Feldman.
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Analytical Interferences and Physiological Limitations of Blood Glucose Meters Ken Ervin
Package inserts Review articles (partial list) Boren and Clarke Tonyushkina and Nichols Pitkin and Rice Montagnana et al Wahl Dungan Arabadjief and Nichols Heller and Feldman Specific articles (partial list) Kimberly, et al Fiore and Delanghe Lyon, et al Kazmierczak and Catrou Goudable, et al Zheng, et al Vesper, et al Katelijne and Delanghe Tang, et al Published information Ken Ervin Consulting Services
Package inserts address “Procedural limitations” • Sample related • e.g. Hct, pO2, DKA, HHNK, etc. • Endogenous compounds • Exogenous compounds • Environmental • Temperature • Humidity • Altitude Ken Ervin Consulting Services
The limitations of a product are dependent upon the choice of technology to achieve the design goals. Ken Ervin Consulting Services
Accurate and precise Highly specific *Stable at room temperature *Rapid test (use whole blood directly) *Very easy to use Small blood volume *Inexpensive meter *Cal code strategy Low cost/test More recently No pO2 dependence No maltose interference No hematocrit effect BGM Design GoalsDrive the specifications and choice of technology Ken Ervin Consulting Services
To meet the specifications, technologies are chosen for the measurement device and its method of production Ken Ervin Consulting Services
BGM measurement based on combining technologies • Method of introducing sample to device • Most devices now rely on capillary action, sometimes in two directions • Method to identify glucose in sample (specificity) • Enzymatic reaction (GO, GDH, Hexokinase/G6PDH) • Method to quantify glucose • Colorimetric • Electrochemical • Method of calibration • Methods to assess performance of the test or correct results Ken Ervin Consulting Services
Interferences and physiological limitations are related to choices of sample type and technology Ken Ervin Consulting Services
Interferences result from • Analyte specificity issues or • Sample and environmental influences on the measurement reaction Ken Ervin Consulting Services
Analyte specificity • Use of enzymes specific for glucose • GO • GDH • Hexokinase/G6PDH Ken Ervin Consulting Services
Sample influences on measurement • Endogenous substances • Uric acid • Bilirubin • Lipemia, Hemolysis • Exogenous substances • Acetominophen • Ascorbate • Maltose, Icodextrin metabolites • Mannitol • Dopamine Ken Ervin Consulting Services
Sample influences • DKA, HHNK • pH and/or Viscosity • Hyperosmolar, flow effects • Less water volume to reconstitute reagent Ken Ervin Consulting Services
Environmental influences • Analytical Variability • Temperature • Humidity • Altitude (i.e. oxygen availability) Ken Ervin Consulting Services
Physiological limitations • Sample choice • Capillary, venous, or arterial • Actual concentrations are different and relationship may vary • If capillary; hypotension, perfusion and other conditions such as Reynaud’s syndrome disturb normal relationship • Alternate site time lag • pO2 differences • Hematocrit • Smaller sample sizes increase the potential for residue to influence results Ken Ervin Consulting Services
Some relevant examples • How a pO2 dependence became a maltose interference • Hematocrit effects Ken Ervin Consulting Services
The pO2 effect glucose + O2 + H2O GO (YSI and Beckman Glucose Analyzer) gluconic acid + H2O2 HRPO H2O2 + dye precursor dye color + H20 (colorimetric) GO glucose + med (ox) gluconolactone + med (red) (electrochemical) Epot med (red) e- + med (ox) Ken Ervin Consulting Services
How a pO2 interference became a maltose interference • Original methods based on glucose oxidase coupled to a colorimetric indicator system. • Oxygen available from atmosphere • blood removed by blotting, wiping etc. • exposed to air during the reaction time • Electrochemical methods used mediators • Systems calibrated for capillary blood • Oxygen would interfere competitively • Use of venous or arterial blood exacerbated this competition • Venous reads higher; less 02 competition • Arterial reads lower; more 02 competition • pO2 effects generally greater at lower glucose concentrations Ken Ervin Consulting Services
How a pO2 interference became a maltose interference • Second Generation products • GO • Open to atmospheric oxygen • Oxygen blocked by windows or capillary design • Hexokinase/G6PDH Ken Ervin Consulting Services
How a pO2 interference became a maltose interference • GDH-PQQ systems introduced to alleviate pO2 • GDH reaction does not involve oxygen • RT stable enzyme • However, GDH-PQQ less specific for glucose • Recognizes maltose, galactose, xylose and other sugars with glucose moiety, with false elevation of glucose results. • Recent versions of GDH with NAD or FAD cofactor are more specific and stable. Ken Ervin Consulting Services
Hematocrit effects • For a rapid test, WB is preferable if not necessary • Most systems now report “plasma equivalent” • Systems are calibrated at normal hematocrit. • WB sample hematocrits may vary significantly (~15 to >70) • Glucose content of whole blood as compared to plasma is inversely related with hematocrit. Ken Ervin Consulting Services
Hematocrit dependence Little method effect Greater method effect Ken Ervin Consulting Services
Hematocrit effects • Hematocrit may influence access of plasma or diffusion of glucose to measurement system suppressing results. • Hematocrit effects generally greater at higher glucose concentrations • Hematocrit can be measured and corrected for • Greater imprecision? Ken Ervin Consulting Services
In Conclusion • Limitations and interferences are related to the particular technologies chosen. • The unique goals of a BGM system make it unlikely they will ever completely match a lab based system. • The evolution of BGM devices is a demonstration of achieving a balance between a high degree of performance with a rapid, more versatile, easy to use system. • Using a WB sample and reporting plasma (unless corrected for) introduces a ± 6% error in the range 25-65 hct. Ken Ervin Consulting Services
