Blood Glucose Point-of-Care Testing Quality

POSTER PRESENTATION

Blood Glucose Point-of-Care Testing Quality Assessment and Harmonization With Central Laboratory Assays Ellis Jacobs, PhD,* Jerzy W. Naskalski, MD, PhD,Þ Niels Fogh-Andersen, MD, PhD,þ Christoph Ritter, PhD,§ Andrezj Lewenstam, PhD,|| Anton Maas, PhD,¶ Gerard Mager, PhD,# and Anthony O. Okorodudu, PhD**

Abstract: Quality assessment programs use internal and external quality control monitoring to assess test performance and emphasize adequate user training through periodic assessment of their competency. For pointof-care testing (POCT) of glucose within an institution, a 2-step quality assessment procedure is suggested. The first step of point-of-care (POC) glucose analyzer quality control involves the use of appropriate control materials to assess analyzer functionality, and the next step involves POC sample result confirmation by the central laboratory, to ensure consistent resulting for patients. Point-of-care glucose measurements and routine control material analysis are to be performed by the POCT personnel. The second step of quality assessment for glucose POCT involves qualified personnel from the central laboratory and requires periodic confirmatory testing of patient samples using appropriately qualified and traceable procedures of known analytical performance (eg, the routine chemistry analyzer glucose assay). Key Words: blood, plasma, glucose, quality assessment, POCT, precision, trueness, harmonization, traceability (Point of Care 2009;8: 82Y86)

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he measurement of blood glucose concentrations at sites alternate to the central clinical laboratory (eg, the admission room, intensive care units, neonate wards, operation rooms, and clinics) has become an integral component of current medical practice.1,2 Ensuring appropriate quality of the test results regardless of where they are produced within an institution is of paramount importance.3,4 Because point-of-care (POC) glucose testing usually occurs in hospitals in parallel with routine glucose measurements in the hospital central laboratory, discrepancies in results (due to systematic intermethod differences or random variation) may result in confusion that can lead to inappropriate medical care.5,6 Therefore, quality assessment processes that validate the trueness of glucose results are necessary, especially in the harmonization assessment of results between the POC testing (POCT) devices and those from the central laboratory. From the *Department of Pathology, Bellevue Hospital Center/New York University School of Medicine, New York, NY; †Collegium Medicum, Jagellonian University, Krako´w, Poland; ‡Herlev Hospital, University of Copenhagen, Herlev, Denmark; §Roche Diagnostics, Graz, Austria; ||Center ˚ bo for Process Analytical Chemistry and Sensor Technology (ProSens), A ˚ bo, Finland and Faculty of Material Science and Akademi University, Turku-A Ceramics, AGH-University of Science and Technology, Krakow, Poland; ¶Eurotrol BV, Ede, The Netherlands; LFresenius Medical Care, Bad Homburg, Germany; and **University of Texas Medical Branch, Galveston, TX. Reprints: Ellis Jacobs, PhD, Department of Pathology, Bellevue Hospital Center/New York University School of Medicine, 4W1, 462 First Ave, New York, NY 10016. E-mail: [email protected]. None of the authors have a financial relationship with any company that would constitute a conflict of interest. Copyright * 2009 by Lippincott Williams & Wilkins ISSN: 1533-029X

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Hospital staff with no specific laboratory training, who operates glucose POCT devices, should be knowledgeable of the purpose and method of the quality control (QC) procedures. The hospital POCT coordinator or the laboratory unit responsible for the quality of biochemical examinations should issue a Bhospital alternate site blood glucose examination guideline,[ available in sites using POC glucose measuring devices. Guidelines should contain instruction for use of the POC glucose analyzer used, information on the given result units (millimoles per liter or milligram per deciliter of blood or plasma), and a list of preanalytical conditions affecting blood glucose measurements. In addition, the guidelines should inform operators about the recommendations that require the expression of glucose concentration in terms of plasma, regardless of the material actually used for testing.7,8 This should be explained by pointing out differences between glucose concentration in venous and capillary blood and the differences between blood and plasma glucose concentration. Use of QC materials dedicated for POC glucose testing must be applied in cooperation with clinical laboratory to ascertain harmonization of both monitoring systems. Once trained, the operator must perform glucose POC measurements with enough frequency to keep up his/her knowledge of the problems and build up the experience in proper running of the near-patient glucose testing. Establishing a direct communication system between the operators and laboratory person responsible for the QC of glucose analyzers used in the alternate sites is necessary, to have feedback in solving operational problems.

Purpose The reliability of POC glucose measurements depends on the analytical performance of the glucose analyzers as well as on the knowledge and experience of the persons performing the tests.5 Hospital laboratories are obliged to perform regular internal QC testing and should participate in external proficiency assessment to ensure the trueness and precision of their offered test results. The traceability of POCT glucose results to certified reference material is maintained through harmonization with the central laboratory. The central laboratory provides the comparative method and expertise necessary for evaluation of the quality of glucose POC measurements in terms of trueness6 and should ensure that POC device operators stay in compliance with regulatory requirements. In addition, glucose POCT quality assessment must include documented periodic evaluation of device operator competency. Point-of-care testing glucose analyzers are designed for use with blood samples, which presents challenges in terms of QC.9 Most calibrators and QC materials for POCT devices differ from human blood with respect to their matrix. In addition, QC materials designed for routine laboratory analyzers (which may or may not be blood based) may not be suitable for use with POCT glucose analyzers.10 Thus, the manufacturers of POC Point of Care

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glucose analyzers must provide appropriate control materials for their QC, and the regular and proper use of this material by testing personnel is a primary step in the quality assessment of the POCT system.

POC GLUCOSE ANALYZER PERFORMANCE CHECKS Routine Check of Glucose Analyzer Functionality and Materials Point-of-care glucose analyzer performance should be verified at least once per working day or, preferably, before use. Because the performance of glucose analyzers depends on environmental conditions where the measurement is done (eg, ambient temperature and humidity), the operator must determine whether the glucose analyzer has been influenced by such external conditions before any glucose testing in patients. If changes have occurred, then the operator must confirm proper device functionality before proceeding with patient testing. The assessment of analyzer functionality must include answering the following questions (if applicable): & Does the glucose analyzer look normal (ie, clean), without signs of physical damage, excessive moisture, or heat damage, which might have occurred since its last use? & Have all disposable test materials (eg, strips, cuvettes, QC solutions) been stored properly? & Has the correct strip or cuvette code number been confirmed before testing? & Are all materials being used within their expiration dates? & Does the glucose analyzer perform normally, or are problems (eg, slow readouts, results drifting, fading display) evident? & Does the electronic control check (if available for given type of device) indicate that the device is functioning properly? & Are the glucose analyzer user’s manual and any pertinent record books present and available to the operator? & Has the glucose analyzer been tested with the appropriate QC materials, and are the results within the manufacturer’s Ballowable range[? If the answer to any of the above questions is no, then action is required to prevent use of the glucose analyzer for the measurement of patient samples.

Check of Glucose Analyzer Performance Using Manufacturer’s Recommended Control Materials Every glucose analyzer should be individually checked each day before analyzing patient samples. At the beginning of each working day and before using a new lot of sensor strips, the operator must analyze the glucose control solutions, following the manufacturer’s instructions, and record the results in a daily control book. If electronic acquisition of control data is available, this method of record keeping is preferred so as to reduce transcriptional errors. Failure to attain acceptable results, that is, control results within the manufacturer’s established acceptance interval, must result in the removal of the device from service until problems are fixed or resolved. Control results that are out of the allowable range (QC failed) require repeating the test with a fresh container (same lot) of strips. Failure of the repeat testing requires repeat with a new lot of reagent strips (if available). If the results are still unacceptable, the glucose analyzer should be taken out of service until the problem is corrected. Results obtained in the allowable range (QC passed) are subjected to further assessment of daily imprecision of results.

Blood Glucose POCT Quality Assessment/Harmonization

As commercially available control materials usually have only the Bacceptable glucose concentration range[ rather than a defined target mean value, the current glucose POCT QC result should be compared with values obtained from previous testing of the same lot of QC material. From the accumulated data including at least 20 measurements, imprecision could be calculated expressed as coefficient of variation (CV) as follows: I CV % ¼ 100 ð1Þ GM where CV% is coefficient of variation (%), I is standard deviation (SD), and GM is mean glucose concentration calculated from the accumulated measurement results; vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi uN u u ~ ðG i G M Þ2 t I ¼ i¼1 ð2Þ N 1 where I is SD, Gi is the ith result of the measurement of glucose concentration, GM is mean glucose concentration calculated from the accumulated measurement results, and N is the number of the accumulated results. Using the same device and the same lot of sensor strips, it has been recommended that the imprecision should not exceed a CV of 5%.11 Bias (B) should be calculated as the difference between the mean measured glucose concentration (calculated from a minimum of 20 measurements) and the nominal glucose concentration (may be calculated as mean value of the provided range): B ¼ GM GC ð3Þ where B is bias expressed in measurement units, GM is mean glucose concentration calculated from accumulated measurement results, and GC is nominal glucose concentration in the QC material provided by the manufacturer; GM GC or B% ¼ 100 ð4Þ GC where B% is bias expressed in percent, GM is mean glucose concentration calculated from the accumulated measurement results, and GC is nominal glucose concentration in the QC material provided by the manufacturer. Each laboratory should establish its own performance criteria for allowable error within the guidelines of their regulatory requirements. For example, to ensure that more than 95% of the QC results are within 10% of total error (TE), the allowable bias must be less than 1.75% of the nominal value7 using the following equation:12 TE ¼ ð1:65 CV %Þ þ B% ð5Þ where TE is total error, and 1.65 is the probability factor. The calculated TE should not exceed the allowable TE (TEA) as defined by the laboratory or recommended by appropriate professional group. If TE is equal to or less than TEA, the glucose analyzer is authorized for its intended use for the evaluation of glycemia in clinical settings; otherwise, it should be removed from service. For example, with selfYglucose monitoring for concentration between 5.6 and 11.2 mmol/L (100 and 200 mg/dL), the TEA should not exceed 20% using different devices and different sensor systems14 as previously suggested.

Check of Glucose Analyzer Using Control Blood If an adequately prepared control blood is available for use in a particular glucose POCT device, the quality assessment

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procedures are performed as described in the previous two sections except GN (representing the glucose concentration target value as given by the manufacturer) replaces GM in equations 1Y4.

Check of Glucose Analyzer Performance Using Split Patients’ Blood Samples Quality assessment of POCT glucose should be additionally performed by comparison of glucose test results obtained by the glucose POCT analyzer and the central laboratory on at least 40 samples, spanning the analytical measurement range, at a suggested minimum frequency of twice per year. A paired (dependent) t test is applied for estimation of agreement: ; X D pffiffiffiffiffiffi t¼ N ð6Þ SD For this equation, the differences (XD) between all pairs [glucose (POC) j glucose (laboratory)] must be calculated (N = ; number of pairs.) The mean (X D) and SD of those differences are used in the equation. Using tables of the t distribution, the calculated t value is compared with the t value for n degrees of freedom and p (probability) of 0.05. If the calculated t value is less than or equal to the table value, then it can be stated that there is no significant difference in the results of the 2 methods with at least 95% confidence. In addition, 95% of the specimens with laboratory measured glucose concentrations of more than 4.2 mmol/L (76 mg/dL) should not have differences that exceed the defined accuracy limits of your institution.

HARMONIZATION ASSESSMENT OF GLUCOSE POCT RESULTS WITH LABORATORY MEASUREMENTS OF GLUCOSE CONCENTRATION Point-of-care testing glucose measurements in various hospital settings are performed on fresh blood samples, which are subject to more factors affecting sample and result variability than are plasma samples used for glucose measurement in central laboratories. In particular, hematocrit15 influences glucose concentration measurement in undiluted blood and is not a factor in glucose concentration assays performed on plasma.8,16 For this reason, plasma has been chosen as the recommended sample for glucose testing7; glucose measurement systems using different types of samples must be harmonized to this reference. The harmonization assessment procedure uses results of simultaneous glucose concentration measurements in human blood samples using the POCT device and the method used in the central laboratory. The use of QC materials is not acceptable for harmonization assessment, as problems with QC material commutability exist. Samples with both low (hypoglycemic, 2Y3.5 mmol/L [36Y50 mg/dL]) and high (hyperglycemic, 12Y17 mmol/L [216Y310 mg/dL]) glucose concentrations must be included in the harmonization assessment experiment. In addition, the proper sequence of the control procedure must be observed, and the reporting units used for the harmonization assessment should be consistent. The harmonization coefficient (hi) is calculated as the ratio of the laboratory comparative glucose concentration to the glucose concentration obtained by the POCT glucose analyzer: CGr hi ¼ ð7Þ CGe where CGr is the comparative glucose concentration by laboratory method, and CGe is glucose concentration measured

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using the POCT glucose analyzer. The allowable hi should be defined by each institution, for example, 0.9 to 1.1. After accumulating at least 20 hi values based on 20 splitsamples measurements using each instrument within 20 consecutive days, the laboratoryYglucose analyzer mean harmonization coefficient (hm ) should be calculated. If the hm value is higher than 1.075 or lower than 0.925 (inter method bias higher than 7.5%), the glucose analyzer may produce inconsistent results with a TE exceeding 20% and must be removed from service until repaired or replaced. All laboratory assays that generate results that are traceable to the glucose reference system on standards and that fulfill the requirement of maximum imprecision, bias, and TE not exceeding 3.3%, 2.5%, and 7.9%, respectively,7 are suitable for use as a comparative method for glucose POCT measurements.17 Comparison should be based on the results referenced to the glucose concentration in plasma. Point-of-care glucose analyzers should correct capillary blood values to plasma concentration values. Some POC glucose analyzers systems/device automatically make this correction. Otherwise, it may be done by multiplying blood results by a factor of 1.11.8 Before new-lot test strips or cuvettes are used, a comparison of results obtained by the POCT device and the laboratory comparative method should be carried out. Either fresh blood collected for laboratory examination or capillary blood can be used. Capillary blood should be collected by the operator using a standardized lancet (skin prick device). The first drop of blood appearing from the pricked finger should be removed with sterile tissue. The measurement is performed using blood obtained from the second drop. The blood should be applied to the glucose analyzer strip as specified in the manufacturer’s instruction. When the comparative laboratory analyzer can measure glucose concentration directly in blood, the sample for laboratory measurement should be collected from the same puncture by aspiration into a heparinized capillary tube or syringe. The collected sample is placed on ice and immediately transported to the laboratory. Alternatively, the POCT device measures glucose in heparinized venous blood, which is immediately centrifuged to separate plasma for further processing in the central laboratory.

REPORTING POCT GLUCOSE CONTROL MEASUREMENTS Documentation of Glucose Analyzer Quality Assessment Results of all QC procedures used must be recorded and the documentation kept in the site where the glucose analyzer is used. The record must include the date and time, the name of the person performing the test, the results of tests, and confirmation that the glucose analyzer may be used for its intended purpose. Periodically, the data should be transferred to a central laboratory QC unit, where it must be stored in accordance with the requirements imposed by national, regional, or local health care regulations.

Documentation of QC Test Results Results of glucose POCT control testing, expressed as plasma glucose concentration, should be separately recorded for each glucose measuring device in BControl Data Files,[ either paper or electronic. The data forms should indicate whether the results were harmonized with local clinical laboratory. Systematic (daily) glucose control measurements should be recorded using a control chart, for example, Levey-Jennings plot, to express variation of each examined glucose analyzer. The * 2009 Lippincott Williams & Wilkins


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midline of the chart graph should represent the mean glucose concentration value calculated using 20 consecutive control measurements. Limits should represent the acceptable glucose concentration range, usually expressed as GM T 2 times the SD.

Documentation of POCT Performance Using Patient Blood Samples Results of glucose POCT harmonization assessment testing using patients’ blood samples (Bsplit-sample[ measurements) should be reported separately. Results obtained from the laboratory should be considered as reference values. Data should be referred to American Diabetes Association recommendations that specify an allowable glucose measurement TE of less than 10% if Bnonprofessional[ staffs operate clinical glucose analyzers.7,13 However, although TEs of 10% or less are desired, they are not possible with current technology.14

ADDITIONAL ISSUES Matching Glucose POCT With the Intended Medical Purpose Quality assessment practices should evaluate glucose POCT results relative to their intended clinical use. Point-ofcare testing glucose measurements are sufficient to monitor glycemia in hospitalized patients to detect critical changes in their blood glucose concentrations (both in the range of hyperglycemia and hypoglycemia). However, because of their current analytical performance, most POCT glucose meters are not recommended for diagnostic purposes.7,17

Linearity Assessment of POCT Glucose Analyzer Before Release for use in Clinical Situations Before a glucose analyzer is released for POCT use, its performance must be verified using manufacturer’s recommended materials. Linearity testing of response over the operational glucose concentration range of the glucose meter is required. This testing should be performed using material recommended by the manufacturer or approved by regulatory agencies. Alternatively, the linearity check can be performed over the range of 1.83 to 18.3 mmol/L (30Y300 mg/dL) using patients’ blood samples. Patient sample selection is based on glucose concentrations determined by the laboratory comparative method. If there is a failure in reproducing comparative glucose concentrations, for example, the slope of the regression line deviates more than T0.1 from 1.00 and patient samples differ more than 10%, the linearity check should be repeated using new materials, including a new lot of glucose sensor strips where possible. If the linearity test fails again, and the operator is confident about the reliability of the materials used, the device should be considered defective and should be removed from service.

FINAL COMMENTS The maintenance of traceability of the POC glucose analyzer results depends on proper calibration and continuous harmonization with the central laboratory. However, differences between the response of individual POC glucose analyzers, even of the same type and model, pose challenges to instrument validations, comparisons, and harmonization assessment.18Y20 Moreover, the quality of the glucose POCT results also depends on factors such as operator skill, the amount of specimen applied, and capillary blood dilution of capillary blood by interstitial fluid.20,21 Therefore, optimal results require profes-

Blood Glucose POCT Quality Assessment/Harmonization

sional knowledge and experience in maintaining analytical quality. Operators have the obligation to perform daily checks of the glucose analyzer before patient testing, and they must use the manufacturer’s recommended control materials and proper technique. Because QC procedures are typically in the scope of routine obligations of the clinical laboratory, extending the laboratory’s oversight of control to glucose POCT should fulfill the requirements for validation and harmonization assessment of glycemia monitoring in various hospital settings using POCT.8,18,20,22 Laboratory involvement in executing a glucose POCT control program requires the participation of qualified laboratory personnel in these programs at the site of testing. The presence of qualified laboratory staff is important for maintaining QC measures and providing training to nonlaboratory medical staff, who are often the routine operators of the POC glucose meters in the ward. Because reliability of POCT strongly depends on the skill of the operators,2,5,22,23 regular professional contact of nurses and other POCT operators with qualified laboratory staff will contribute to enhancing the consistency of POCT results with the local laboratory. REFERENCES 1. Bachner P. Alternate site testing. The old and new paradigm or the past is prologue. Arch Pathol Lab Med. 1995;119:881Y885. 2. Collier CP, Houlder RL, Gleason KJ, et al. A survey to identify potential outcome indicators for a hospital blood glucose monitoring program. Clin Biochem. 1980;31:263Y268. 3. Peet AC, Kennedy DM, Hocking MD, et al. Near patient testing of blood glucose using the Bayer Rapid 860 analyzer in regional neonatal unit. Ann Clin Biochem. 2002;39:502Y508. 4. Freedman DB. Clinical governance: implications for point of care testing. Ann Clin Biochem. 2002;39:421Y423. 5. The National Steering Committee for Quality Assurance in Capillary Blood Glucose Monitoring. Proposed strategies for reducing user error in capillary blood glucose monitoring. Diabetes Care. 1993;16:493Y495. 6. Friedman BA, Mitchel W. Integrating information from decentralized laboratory testing sites: the creation of value added network. Am J Clin Pathol. 1993;99:637Y642. 7. Sacks DB, Bruns DE, Goldstein DE, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2002;48:436Y472. 8. International Federation of Clinical Chemistry and Laboratory Medicine, Scientific Division, Working Group on Selective electrodes and Point-of Care Testing (IFCC-SD-WG-SEPOCT). Approved IFCC recommendation on reporting results for blood glucose. Clin Chem Lab Med. 2006;44:1486Y1490. 9. Johnson RN, Baker JR. Error detection and measurement in glucose monitors. Clin Chim Acta. 2001;307:61Y67. 10. Wood WG, Hanke R, Meissner D, et al. Experience with an external quality assessment programme for point of care testing (POCT) devices for determination of blood glucose. Clin Lab. 2003;49:151Y159. 11. Skeie S, Thue G, Sandberg S. Patient derived quality specifications for instruments used in self-monitoring of blood glucose. Clin Chem. 2001;47:67Y73. 12. Westgard JO. Quality planning modelsVmathematical description of laboratory error budgets. Available at: http://www.westgard.com/ lesson72.htm. Accessed December 11, 2008. 13. American Diabetes Association. Consensus statement: self monitoring of blood glucose. Diabetes Care. 1994;17:81Y86. 14. ISO 15197:2003 In vitro diagnostic test systems - Requirements for



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blood glucose monitoring systems for self-testing in managing diabetes mellitus. International Organization for Standards (ISO). 15. Tang Z, Lee JH, Louie RF, et al. Effects of different hematocrit levels on glucose measurements with handheld meters for point-of-care testing. Arch Pathol Lab Med. 2000;124:1135Y1140. 16. Stahl M, Brandslund I, Joergensen LG, et al. Can capillary whole blood and venous plasma glucose measurements be used interchangeably in diagnosis of diabetes mellitus? Scand J Lab Invest. 2002;62:159Y166.

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analyzers with respect to clinical and analytical approaches. Diabetes Care. 1998;21(4):585Y590. 20. Wehmeier M, Arndt BT, Schumann G, et al. Evaluation of quality assessment of glucose concentration measurement in blood by point of care testing devices. Clin Chem Lab Med. 2006;44: 888Y893. 21. Skeie S, Thue G, Nerhus K, et al. Instruments for self-monitoring of blood glucose: comparisons of testing quality achieved by patients and a technician. Clin Chem. 2002;48:994Y1003.

17. Kuwa K, Nakayama T, Hoshino T, et al. Relationships of glucose concentrations in capillary whole blood, venous whole blood and venous plasma. Clin Chim Acta. 2001;307:187Y192.

22. Kristensen GBB, Nerhus K, Thuie G, et al. Results and feasibility of an external quality assessment scheme for self monitoring of blood glucose. Clin Chem. 2006;52:1311Y1317.

18. Solnica B, Naskalski JW. Quality control of SMBG in clinical practice. Scand J Clin Invest Suppl. 2005;240:80Y86.

23. Kristensen GBB, Nerhus K, Thue G, et al. Standardized evaluation of instruments for self-monitoring of blood glucose by patients and a technologist. Clin Chem. 2004;50:1068Y1071.

19. Franz MSC, Wach P, Krejs GJ, et al. Validation of home blood glucose

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