Analysis of an electrochemical blood glucose monitoring system with hematocrit compensation: improved accuracy by design

The article entitled “Hematocrit Compensation in Electrochemical Blood Glucose Monitoring Systems” by Teodorczyk and colleagues in this issue of Journal of Diabetes Science and Technology demonstrates that the OneTouch^® Verio™ glucose meter meets current regulatory expectations for glucose meter performance and is relatively free from interference by hematocrit. The lack of influence of hematocrit on whole blood glucose results is a valuable attribute for hospital applications, where greater variation of hematocrit among patients is anticipated. The choice of reference method for evaluation of glucose meters is an important consideration, and it is not clear to what extent reference methods used to evaluate glucose meters are also free from hematocrit interferences.     

Within-Individual Hematocrit Variations and Self-Monitoring of Blood Glucose

Many self-monitoring of blood glucose (SMBG) systems have generated artefactually increased glucose results in low-hematocrit patients (e.g., intensive care unit and renal failure patients); conversely, these devices could produce artefactually decreased glucose results in high-hematocrit patients (e.g., neonates). The introduction of hematocrit-independent SMBG systems permits more accurate testing in anemic or polycythemic individuals. In this issue of Journal of Diabetes Science and Technology, Ramljak and coauthors have created glucose bias graphs for 19 common SMBG devices and declared certain systems to be optimally accurate because of insensitivity to hematocrit variation over a broad hematocrit range. Luckily, the average within-individual variation of hematocrit is low (between 2.9 and 3.3%). As such, a larger spectrum of SMBG devices can be regarded as optimally hematocrit independent.     

Hematocrit Interference of Blood Glucose Meters for Patient Self-Measurement

Background

Abnormal hematocrit levels may interfere with glucose readings of patient self-assessment blood glucose (BG) meters. The aim of this laboratory investigation was to assess the potential influence of hematocrit variations on a variety of BG meters applying different measurement technologies.

Methods

Venous heparinized blood was manipulated to contain three different BG concentrations (50–90, 120–180, and 280–350 mg/dl) and five different hematocrit levels (25%, 35%, 45%, 55%, and 65%). After careful oxygenation to normal blood oxygen pressure (65–100 mmHg), each sample was measured (eight times) with the following devices: Accu-Chek® Aviva, Nano, and Active, Breeze®2 and Contour®, FreeStyle Freedom Lite®, GlucoDr. auto™, Glucofix® mio Plus, GlucoLab™, GlucoMen® LX Plus, Nova Max® Link, Nova Max® Plus, OneTouch® Ultra®2 and Verio®,On Call® Plus and Platinum, Optium Xceed®, Precision Xceed®, and TaiDoc Fora TD-4227. A YSI 2300 STAT Plus™ glucose analyzer served as reference method. Stability to hematocrit influence was assumed, with <10% mean glucose result bias between the highest and lowest hematocrit levels.

Results

Six of the investigated meters showed a stable performance in this investigation: Accu-Chek Active (7%), Glucofix mio Plus (5%), GlucoMen LX Plus (4%), NovaMax Plus (4%), Nova Max Link (7%), and OneTouch Verio (3%). All other meters failed this hematocrit interference test, with FreeStyle Freedom Lite (11%), and On Call Platinum (12%) being the better devices and On Call Plus (68%), GlucoLab (51%), TaiDoc Fora TD-4227 (39%), and Breeze 2 (38%) showing the worst performance.

Conclusions

Hematocrit may affect BG meter performance in daily routine. In case of interference, low hematocrit values (<35%) result in too high readings. Our results encourage use of meters that are not affected by hematocrit interference.     

External Quality Assessment of Blood Glucose Monitors: Measurement Quality of Blood Glucose Meters: Is There a Need for an Institution with an Unbiased View?

The quality of self-monitoring of blood glucose (SMBG) with modern blood glucose meters is considered by many as not being a relevant topic anymore. However, in reality, a number of open questions about the quality of the measurement exists. Even if the meters fulfill the established quality criteria when they receive approval, there is no independent institution that performs a regular, critical comparison of the quality of the measurement of all blood glucose meters after their approval. Such an institute could also evaluate the quality of the different batches of test strips. In addition, it can evaluate the impact of other factors that are known to have an impact on the quality of measurement, e.g., the ambient temperature and the hematocrit. Such an institution will be very helpful to counterbalance complaints by the patients, physicians and authorities about an industry that earns a lot of money but does not provide solutions for the topics raised.     

Challenges in Glycemic Control in Perioperative and Critically Ill Patients: Challenges to Glycemic Measurement in the Perioperative and Critically Ill Patient: A Review

Accurate monitoring of glucose in the perioperative environment has become increasingly important over the last few years. Because of increased cost, turnaround time, and sample volume, the use of central laboratory devices for glucose measurement has been somewhat supplanted by point-of-care (POC) glucose devices. The trade-off in moving to these POC systems has been a reduction in accuracy, especially in the hypoglycemic range. Furthermore, many of these POC devices were originally developed, marketed, and received Food and Drug Administration regulatory clearance as home use devices for patients with diabetes. Without further review, many of these POC glucose measurement devices have found their way into the hospital environment and are used frequently for measurement during intense insulin therapy, where accurate measurements are critical. This review covers the technology behind glucose measurement and the evidence questioning the use of many POC devices for perioperative glucose management.     

Factors Affecting Blood Glucose Monitoring: Sources of Errors in Measurement

Glucose monitoring has become an integral part of diabetes care but has some limitations in accuracy. Accuracy may be limited due to strip manufacturing variances, strip storage, and aging. They may also be due to limitations on the environment such as temperature or altitude or to patient factors such as improper coding, incorrect hand washing, altered hematocrit, or naturally occurring interfering substances. Finally, exogenous interfering substances may contribute errors to the system evaluation of blood glucose.In this review, I discuss the measurement of error in blood glucose, the sources of error, and their mechanism and potential solutions to improve accuracy in the hands of the patient. I also discuss the clinical measurement of system accuracy and methods of judging the suitability of clinical trials and finally some methods of overcoming the inaccuracies. I have included comments about additional information or education that could be done today by manufacturers in the appropriate sections. Areas that require additional work are discussed in the final section.     

Clinical Evaluation of a Novel On-Strip Calibration Method for Blood Glucose Measurement

Background:This study evaluated a novel technology for improving accuracy of self-monitoring of blood glucose (SMBG). The technology calibrates each and every test by measuring the response from a predetermined amount of glucose present in the sample chamber of each test strip.Method:SMBG test strips were modified to include a lid coated with a fast dissolving formulation containing glucose. These test strips were characterized for hematocrit (Hct) and temperature induced error response to develop a calibration algorithm. The modified test strips were used in a clinical evaluation involving fingerstick blood samples from 160 subjects.Results:Experiments involving Hct and temperature induced errors show that the technology generates a signal characteristic of the error conditions in any particular test, but independent of glucose concentration, allowing a correction algorithm to be derived. The approach substantially reduced Hct and temperature derived errors. Clinical evaluation using fingerstick blood directly applied to prototype strips showed the error (measured as MARD) was reduced from 11.1 to 5.9% by the on-strip correction approach and the number of outliers reduced by approximately 90%.Conclusion:This technology could improve the accuracy and precision of glucose monitoring systems and so reduce decision errors particularly in clinical situations where hematocrit and temperature may be significant confounders.     

Development and Validation of a Rapid 13C6-Glucose Isotope Dilution UPLC-MRM Mass Spectrometry Method for Use in Determining System Accuracy and Performance of Blood Glucose Monitoring Devices

Background:

There is currently considerable discussion about the accuracy of blood glucose concentrations determined by personal blood glucose monitoring systems (BGMS). To date, the FDA has allowed new BGMS to demonstrate accuracy in reference to other glucose measurement systems that use the same or similar enzymatic-based methods to determine glucose concentration. These types of reference measurement procedures are only comparative in nature and are subject to the same potential sources of error in measurement and system perturbations as the device under evaluation. It would be ideal to have a completely orthogonal primary method that could serve as a true standard reference measurement procedure for establishing the accuracy of new BGMS.

Methods:

An isotope-dilution liquid chromatography/mass spectrometry (ID-UPLC-MRM) assay was developed using ¹³C₆-glucose as a stable isotope analogue to specifically measure glucose concentration in human plasma, and validated for use against NIST standard reference materials, and against fresh isolates of whole blood and plasma into which exogenous glucose had been spiked. Assay performance was quantified to NIST-traceable dry weight measures for both glucose and ¹³C₆-glucose.

Results:

The newly developed assay method was shown to be rapid, highly specific, sensitive, accurate, and precise for measuring plasma glucose levels. The assay displayed sufficient dynamic range and linearity to measure across the range of both normal and diabetic blood glucose levels. Assay performance was measured to within the same uncertainty levels (<1%) as the NIST definitive method for glucose measurement in human serum.

Conclusions:

The newly developed ID UPLC-MRM assay can serve as a validated reference measurement procedure to which new BGMS can be assessed for glucose measurement performance.     

Blood Glucose Measurement in the Intensive Care Unit: What Is the Best Method?

Abnormal glucose measurements are common among intensive care unit (ICU) patients for numerous reasons and hypoglycemia is especially dangerous because these patients are often sedated and unable to relate the associated symptoms. Additionally, wide swings in blood glucose have been closely tied to increased mortality. Therefore, accurate and timely glucose measurement in this population is critical. Clinicians have several choices available to assess blood glucose values in the ICU, including central laboratory devices, blood gas analyzers, and point-of-care meters. In this review, the method of glucose measurement will be reviewed for each device, and the important characteristics, including accuracy, cost, speed of result, and sample volume, will be reviewed, specifically as these are used in the ICU environment. Following evaluation of the individual measurement devices and after considering the many features of each, recommendations are made for optimal ICU glucose determination.     

Accuracy of point-of-care glucose measurements

Control of blood glucose (BG) in an acceptable range is a major therapy target for diabetes patients in both the hospital and outpatient environments. This review focuses on the state of point-of-care (POC) glucose monitoring and the accuracy of the measurement devices. The accuracy of the POC glucose monitor depends on device methodology and other factors, including sample source and collection and patient characteristics. Patient parameters capable of influencing measurements include variations in pH, blood oxygen, hematocrit, changes in microcirculation, and vasopressor therapy. These elements alone or when combined can significantly impact BG measurement accuracy with POC glucose monitoring devices (POCGMDs). In general, currently available POCGMDs exhibit the greatest accuracy within the range of physiological glucose levels but become less reliable at the lower and higher ranges of BG levels. This issue raises serious safety concerns and the importance of understanding the limitations of POCGMDs. This review will discuss potential interferences and shortcomings of the current POCGMDs and stress when these may impact the reliability of POCGMDs for clinical decision-making.     

Determination of Hematocrit Interference in Blood Samples Derived from Patients with Different Blood Glucose Concentrations

Background

We performed a blood glucose meter hematocrit (HCT) interference test with lower sample manipulation requirements by using blood samples from patients with different blood glucose (BG) levels.

Methods

Blood from five patients with different BG levels (2.8, 5.6, 8.3, 13.9, 19.4 mmol/liter) was manipulated to contain five different HCT concentrations (35/40/45/50/55%). Each sample was measured three times in parallel with 14 BG testing devices (reference method: YSI 2300 STAT Plus™ Glucose Analyzer). The largest mean deviations in both directions from the reference method (normalized to 100% at 45% HCT) were added as a measure for hematocrit interference factor (HIF). A HIF >10% was considered to represent clinically relevant HCT interference.

Results

Few devices showed no clinically relevant HCT interference at high/low BG levels: BGStar® (7.2%, 7.3%), iBGStar® (9.0%, 8.6%), Contour® (10.0%, 4.6%), OneTouch® Verio™ 2 (10.0%, 5.2%), and GlucoMen® LX (7.2%, 5.1%). Other devices showed interference at one or both glucose ranges: ACCU-CHEK® Aviva (12.6%, 10.7%), Aviva Nano (7.2%, 10.5%), Breeze2 (3.6%, 30.2%), GlucoCard G+ (12.6%, 7.0%), OneTouch® Ultra®2 (12.6%, 25.6%), FreeStyle Freedom Lite® (9.0%, 11.0%), Precision Xceed (16.2%, 15.3%), and MediTouch® (19.8%, 28.0%). The deviations in all devices were less pronounced in the HCT range of 35−50%.

Conclusions

The results of this trial with less sample manipulation (HCT only) confirmed previous examinations with HCT and glucose manipulation. The same devices showed HCT stability as previously observed. Artificial sample manipulation may be less crucial than expected when evaluating HCT interference.     

Performance of a New Meter Designed for Assisted Monitoring of Blood Glucose and Point-of-Care Testing

Background

Blood glucose (BG) meters used for assisted monitoring of blood glucose (AMBG) require different attributes compared with meters designed for home use. These include safety considerations (i.e., minimized risk of blood-borne pathogen transmission), capability for testing multiple blood sample types, and enhanced performance specifications. The OneTouch^® Verio™Pro+ BG meter is designed to incorporate all of these attributes.

Methods

Meter accuracy was assessed in clinical studies with arterial, venous, and capillary blood samples with a hematocrit range of 22.9–59.8%. The effect of interferents, including anticoagulants, on accuracy was evaluated. The meter disinfection protocol was validated, and instructions for use and user acceptance of the system were assessed.

Results

A total of 97% (549/566) of BG measures from all blood sample types and 95.5% (191/200) of arterial blood samples were within ±12 mg/dl or 12.5% of reference measurements. The system was unaffected by 4 anticoagulants and 57 of 59 endogenous and exogenous compounds; it was affected by 2 compounds: pralidoxime iodide and xylose. Bleach wipes were sufficient to disinfect the meter. Users felt that the meter''s quality control (QC) prompts would help them to comply with regulatory requirements.

Conclusions

The meter provided accurate measurements of different blood samples over a wide hematocrit range and was not affected by 57 physiologic and therapeutic compounds. The QC prompts and specific infection-mitigating design further aid to make this meter system practical for AMBG in care facilities.     

Estimates of total analytical error in consumer and hospital glucose meters contributed by hematocrit, maltose, and ascorbate

Background

Patients and physicians expect accurate whole blood glucose monitoring even when patients are anemic, are undergoing peritoneal dialysis, or have slightly elevated ascorbate levels. The objective of this study was to estimate analytical error in two consumer and two hospital glucose meters contributed by variations in hematocrit, maltose, ascorbate, and imprecision.

Method

The influence of hematocrit (20–60%), maltose, and ascorbate were tested alone and in combination with each glucose meter and with a reference plasma glucose method at three concentrations of glucose. Precision was determined by consecutive analysis (n = 20) at three levels of glucose. Multivariate regression analysis was used to estimate the bias associated with the interferences, alone and in combination. Total analytical error was estimated as |% bias| + 1.96 (% imprecision).

Results

Three meters demonstrated hematocrit bias that was dependent upon glucose concentration. Maltose had profound concentration-dependent positive bias on the consumer meters, and the extent of maltose bias was dependent on hematocrit. Ascorbate produced small but statistically significant biases on three meters. Coincident low hematocrit, presence of maltose, and presence of ascorbate increased the observed bias and was summarized by estimation of total analytical error. Among the four glucose meter devices assessed, estimates of total analytical error in glucose measurement ranged from 6 to 68% under the conditions tested.

Conclusions

The susceptibility of glucose meters to clinically significant analytical biases is highly device-dependent, and low hematocrit exacerbated the observed analytical error.     

Performance of the CONTOUR® TS Blood Glucose Monitoring System

Background

Self-monitoring of blood glucose (SMBG) remains an important component of diabetes management, engendering a need for affordable blood glucose (BG) meters that are accurate, precise, and convenient. The CONTOUR^® TS is a BG meter that endeavors to meet this need. It uses glucose dehydrogenase/flavin dinucleotide chemistry, automatic test strip calibration, and autocompensation for hematocrit along with the ease of use that has come to be expected of a modern meter. The objective of this clinical trial was to determine whether the CONTOUR TS system met these criteria.

Methods

The system was evaluated at a single clinical site with 106 subjects with type 1 or type 2 diabetes. Blood glucose values ranged from 60 to 333 mg/dl over all subjects. Both lay users and health care professionals (HCPs) tested the meters, with test strips from three different lots. Results were compared to a reference analyzer of verified precision and accuracy. Forty-nine of the subjects also participated in a home study of the meter. Lay users learned to use the system without assistance and were surveyed on its use at the end of the study.

Results

When used with capillary blood, both subjects and HCPs obtained results that exceeded the International Organization for Standardization 15197:2003 criteria, (i.e., ≥95% of values fell within 20% or 15 mg/dl of the laboratory value for BG levels greater than or less than 75 mg/dl, respectively). Specifically, lay users achieved 97.9% and HCPs 98.6%. When used with venous blood, 99.8% of measurements were within the criteria. All measurements for both capillary and venous blood fell into zones A or B of the Parkes error grid, deemed clinically accurate. Hematocrit was found to have no influence on BG measurements. A large majority of the subjects found the system easy to learn and to use.

Conclusions

The CONTOUR TS BG meter system gave accurate and reproducible results with both capillary and venous blood; subjects learned to use the meter system by following the user guide and quick reference guide.     

Analysis of “Accuracy Evaluation of Five Blood Glucose Monitoring Systems: The North American Comparator Trial”

In an article in Journal of Diabetes Science and Technology, Halldorsdottir and coauthors examined the accuracy of five blood glucose monitoring systems (BGMSs) in a study sponsored by the manufacturer of the BGMS CONTOUR NEXT EZ (EZ) and found that this BGMS was the most accurate one. However, their findings must be viewed critically given that one of the BGMSs (ACCU-CHEK Aviva) was not compared against the reference measurement specified by its manufacturer, thus making it likely that it performed suboptimally. Also, the accuracy of the glucose-oxidase-based ONE TOUCH Ultra2 and TRUEtrack BGMS is likely to have been underestimated because of the expected low oxygen level in the glycolysed blood samples used to test the performance of these BGMSs under hypoglycemic conditions. In conclusion, although this study shows that EZ is an accurate BGMS, comparisons between this and other BGMSs should be interpreted with caution.     

Penny Wise and Pound Foolish: Will Shortsighted Cost Reduction Measures Compromise Patient Access to Promising Self-Monitoring of Blood Glucose Technology?

In this issue of Journal of Diabetes Science and Technology, Grady and coauthors enrolled 101 patients with type 1 and type 2 diabetes to evaluate new technology incorporated into the LifeScan VerioPro and VerioIQ blood glucose meters. The “pattern detection” software provides real-time, onscreen messages that alert users to patterns of high glucose (fasting and premeal) and low glucose as they are detected. The study showed that most participants possess a good understanding of the factors that can cause hyperglycemia; however, their understanding of the causes of hypoglycemia events was not as strong. Nevertheless, more than 70% of participants indicated they preferred to use a blood glucose meter that provides pattern detection capability. Although not designed to assess the impact of the pattern detection tool on clinical outcomes, the study highlights the value of continuous innovation in self-monitoring of blood glucose (SMBG) technology among manufacturers. Unfortunately, many patients may never have access to these systems due to reductions in Medicare reimbursement. Instead, they may be forced to use SMBG systems that are inaccurate and provide inadequate patient support. Stronger regulatory requirements are needed to ensure that all SMBG systems marketed to patients are accurate, reliable, and supported by adequate patient training, and current health care reimbursement policies should be restructured to encourage manufacturers to continue their efforts to develop innovative technology to further improve the utility and usability of their SMBG systems.     

Impact of epidemic rates of diabetes on the Chinese blood glucose testing market

China has become the country with the largest diabetes mellitus population in the world since the 1990s. About 100 million diabetes cases have been diagnosed since 2008. Handheld blood glucose meters and test strips are urgently needed for daily patient measurement. The glucose monitor with a screen-printed carbon-based glucose electrode has been in commercial production since 1994. Since then, approximately 20 companies have been involved in manufacturing and marketing meters and test strips in China. The current market and production volume and updates on technology issues are discussed in this article.     

Application of the Reference Method Isotope Dilution Gas Chromatography Mass Spectrometry (ID/GC/MS) to Establish Metrological Traceability for Calibration and Control of Blood Glucose Test Systems

Self-monitoring of blood glucose (BG) by means of handheld BG systems is a cornerstone in diabetes therapy. The aim of this article is to describe a procedure with proven traceability for calibration and evaluation of BG systems to guarantee reliable BG measurements. Isotope dilution gas chromatography mass spectrometry (ID/GC/MS) is a method that fulfills all requirements to be used in a higher-order reference measurement procedure. However, this method is not applicable for routine measurements because of the time-consuming sample preparation. A hexokinase method with perchloric acid (PCA) sample pretreatment is used in a measurement procedure for such purposes. This method is directly linked to the ID/GC/MS method by calibration with a glucose solution that has an ID/GC/MS-determined target value. BG systems are calibrated with whole blood samples. The glucose levels in such samples are analyzed by this ID/GC/MS-linked hexokinase method to establish traceability to higher-order reference material. For method comparison, the glucose concentrations in 577 whole blood samples were measured using the PCA-hexokinase method and the ID/GC/MS method; this resulted in a mean deviation of 0.1%. The mean deviation between BG levels measured in >500 valid whole blood samples with BG systems and the ID/GC/MS was 1.1%. BG systems allow a reliable glucose measurement if a true reference measurement procedure, with a noninterrupted traceability chain using ID/GC/MS linked hexokinase method for calibration of BG systems, is implemented. Systems should be calibrated by means of a traceable and defined measurement procedure to avoid bias.     

The Business of Self-Monitoring of Blood Glucose: A Market Profile

The market for self-monitoring of blood glucose (SMBG) approached $8.8 billion worldwide in 2008. Yet despite dramatic double-digit growth in sales of SMBG products since 1980, the business is now facing declining prices and slower dollar growth. Given that SMBG meters and test strips are viewed by consumers and insurers as essentially generic products, it will be extremely challenging for new market entrants to displace well-entrenched existing competitors without a truly innovative technology. Also, in the face of declining glucose test strip prices, market expansion can only occur through identification of more of the undiagnosed diabetes population and convincing existing diabetes patients to adopt glucose testing or to test more frequently. Ultimately, a combination of technology innovations, patient education, and economic incentives may be needed to significantly expand the SMBG market and build sustainable long-term dollar growth for SMBG vendors.     

Considerations on blood glucose management in Type 2 diabetes mellitus

In recent years the benefits of more intensive management in preventing or delaying the development and progression of diabetic complications have been well documented. What is not as well documented is how to motivate the person with diabetes to manage the condition, how to set, assess and quantify glucose goals, and the glucose variables that should be routinely measured. This review discusses the importance of setting targets and communicating them in a way that the patient understands. When aiming for a glycaemia target, balance is required (1) between achieving reduction of complications and causing an increased degree of hypoglycaemia, and (2) between what is achievable and what degree of benefit is gained. Target values given in guidelines should be adapted by the clinician to take into account the patient's susceptibility to hypoglycaemia, stage and type of complications, age and life expectancy, co-morbidity, social environment, understanding of the steps required and level of commitment to the treatment. Several suggestions are given regarding possible improvements and amendments to existing guidelines for diabetes management in treating to glucose goal. For example, attention should be drawn to the need to individualize goals and to consider education, long-term support, patient needs and treatment outcome when formulating diabetes management plans. The relative properties of the different glucose variables-fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated haemoglobin A(1c) (HbA(1c)), and glycated protein-in terms of their convenience of measurement, usefulness and relevance to the physician and patient are also evaluated. When prioritising the variables to be measured it is suggested that where feasible, HbA(1c) should be the standard measurement by which to gauge risk and treatment efficacy. Serial measurements should be made and, where possible, the use of blood glucose meters encouraged, in order to obtain a blood glucose profile for the patient.