Patch Pumps: Periodic Insulin Delivery Patterns.

Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in the delivered amount of insulin during basal rate and consecutive bolus delivery in some PP, calling for a more systematic characterization of these periodic delivery patterns. Here, it was found that during basal rate delivery of 1 U/h, some devices of OP, OP-D, and A6 showed deviations of up to ±30% from target delivery that consistently repeated every 5 hours, whereas ACS showed no clear periodicity with considerably lower deviations. Similar results were found during consecutive bolus delivery of 1 U, where deviations repeated consistently every five boluses in some devices of OP, OP-D, and A6. However, there was a large variability in the periodic delivery patterns between individual devices of the same PP model. Examining their pumping techniques indicated a connection between the insulin delivery mechanism and observed delivery patterns of the PP. However, the clinical impact of such patterns is unclear.

Time in Specific Glucose Ranges, Glucose Management Indicator, and Glycemic Variability: Impact of Continuous Glucose Monitoring (CGM) System Model and Sensor on CGM Metrics.

BACKGROUND: International consensus recommends a set of continuous glucose monitoring (CGM) metrics to assess quality of diabetes therapy. The impact of individual CGM sensors on these metrics has not been thoroughly studied yet. This post hoc analysis aimed at comparing time in specific glucose ranges, coefficient of variation (CV) of glucose concentrations, and glucose management indicator (GMI) between different CGM systems and different sensors of the same system. METHOD: A total of 20 subjects each wore two Dexcom G5 (G5) sensors and two FreeStyle Libre (FL) sensors for 14 days in parallel. Times in ranges, GMI, and CV were calculated for each 14-day sensor experiment, with up to four sensor experiments per subject. Pairwise differences between different sensors of the same CGM system as well as between sensors of different CGM system were calculated for these metrics. RESULTS: Pairwise differences between sensors of the same model showed larger differences and larger variability for FL than for G5, with some subjects showing considerable differences between the two sensors. When pairwise differences between sensors of different CGM models were calculated, substantial differences were found in some subjects (75th percentiles of differences of time spent <70 mg/dL: 5.0%, time spent >180 mg/dL: 9.2%, and GMI: 0.42%). CONCLUSION: Relevant differences in CGM metrics between different models of CGM systems, and between different sensors of the same model, worn by the same study subjects were found. Such differences should be taken into consideration when these metrics are used in the treatment of diabetes.

Comparative Accuracy Analysis of a Real-time and an Intermittent-Scanning Continuous Glucose Monitoring System.

BACKGROUND: Currently, two different types of continuous glucose monitoring (CGM) systems are available: real time (rt) CGM systems that continuously provide glucose values and intermittent-scanning (is) CGM systems. This study compared accuracy of an rtCGM and an isCGM system when worn in parallel. METHODS: Dexcom G5 Mobile (DG5) and FreeStyle Libre (FL) were worn in parallel by 27 subjects for 14 days including two clinic sessions with induced glucose excursions. The percentage of CGM values within ±20% or ±20 mg/dL of the laboratory comparison method results (YSI 2300 STAT Plus, YSI Inc., Yellow Springs, OH, United States; glucose oxidase based) or blood glucose meter values and mean absolute relative difference (MARD) were calculated. Consensus error grid and continuous glucose error grid analyses were performed to assess clinical accuracy. RESULTS: Both systems displayed clinically accurate readings. Compared to laboratory comparison method results during clinic sessions, DG5 had 91.5% of values within ±20%/20 mg/dL and a MARD of 9.5%; FL had 82.5% of scanned values within ±20%/20 mg/dL and an MARD of 13.6%. Both systems showed a lower level of performance during the home phase and when using the blood glucose meter as reference. CONCLUSION: The two systems tested in this study represent two different principles of CGM. DG5 generally provided higher accordance with laboratory comparison method results than FL.

Accuracy assessment of bolus and basal rate delivery of different insulin pump systems used in insulin pump therapy of children and adolescents.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) is commonly used in patients with diabetes. Accurate and reliable delivery by insulin pumps is essential for a safe and effective therapy, particularly when using small doses. In this study, accuracy of bolus and basal rate delivery of various available insulin pumps was evaluated. METHODS: In total, 13 insulin pump systems were tested: eight durable pumps with different infusion sets and one patch pump. Based on IEC 60601-2-24, insulin delivery was measured by recording weight gain of a beaker into which insulin was infused by the pumps. Bolus accuracy was determined by individually weighing 25 consecutive 0.1 or 1.0 U boluses and basal rate accuracy was determined during basal rate delivery of 0.1 or 1.0 U/h for 72 hours. For analyses, basal rate delivery was divided into 1-hour windows and deviation from target was calculated. RESULTS: Regarding different systems, average 0.1 U bolus delivery was -2% to +9% of the intended volume with 53% to 96% of boluses within ±15% of target. During 0.1 U/h basal rate delivery, most pumps showed an initial over-delivery for the first few hours. Three systems reached a total basal rate error <5%; others showed up to +24%. In general, delivery was more accurate when using larger doses. CONCLUSIONS: Considerable differences in insulin delivery accuracy were observed between the tested pumps. In general, when using very low doses, accuracy of insulin delivery is limited in most insulin pumps. This should be considered for CSII therapy in children.

Measurement accuracy of two professional-use systems for point-of-care testing of blood glucose.

Background The professional-use systems HemoCue® Glucose 201+ (HC201+) and HemoCue® Glucose 201 RT (HC201RT) are widely used for point-of-care testing (POCT) of blood glucose (BG). HC201RT utilizes unit-use microcuvettes which can be stored at room temperature, whereas HC201+ microcuvettes have to be stored at <8 °C. In this study, system accuracy of HC201+ and HC201RT was evaluated using capillary and venous blood samples. Methods For each system, two reagent system lots were evaluated within a period of 2 years based on testing procedures of ISO 15197:2013, a standard applicable for self-monitoring of blood glucose (SMBG) systems. For each reagent system lot, the investigation was performed by using 100 capillary and 95 to 99 venous blood samples. Comparison measurements were performed with a hexokinase laboratory method. Accuracy criteria of ISO 15197:2013 and POCT12-A3 were applied. In addition, bias was analyzed according to Bland and Altman, and error grid analysis was performed. Results When measuring capillary samples, both systems fulfilled accuracy requirements of ISO 15197:2013 and POCT12-A3 with the investigated reagent system lots. When measuring venous samples, only HC201+ fulfilled these requirements. Bias between HC201+ and reference measurements was more consistent over venous and capillary samples and microcuvette lots than for HC201RT. Error grid analysis showed that clinical actions might have been different depending on which system was used. Conclusions In this study, HC201+ showed a high level of accuracy irrespective of the sample type (capillary or venous). In contrast, HC201RT measurement results were markedly affected by the type of sample.

Accuracy of Bolus and Basal Rate Delivery of Different Insulin Pump Systems.

BACKGROUND: Insulin pumps are used for basal rate and bolus insulin delivery in patients with diabetes. In this in vitro study, accuracy of delivery of different commercial insulin pumps was evaluated. MATERIALS AND METHODS: Accuracy of 10 different insulin pump systems (5 durable pumps with different insulin infusion sets and 1 patch pump) was tested with a microgravimetric method. Mean bolus accuracy of 25 successive 1 U boluses and of 12 successive 10 U boluses was assessed, and delivery time for 10 U boluses was measured. Basal rate accuracy at 1.0 U/h was evaluated for 72 h and for individual 1-h windows. RESULTS: Mean bolus delivery was within ±5% of target for both tested bolus sizes, but precision of individual boluses was higher with the larger boluses. Delivery times varied between the different pump models but agreed with the specifications of the respective manufacturers. Regarding basal rate accuracy, the total deviation for 72 h was very small in all pumps; however, larger deviations were observed during the first 12 h. For the patch pump, large variations between individual 1-h windows were observed. CONCLUSIONS: In general, all compared insulin pump systems showed a similar level of accuracy. Differences, especially between durable pumps and the patch pump, were observed when considering each hour of basal rate delivery separately.

Performance and Usability of Three Systems for Continuous Glucose Monitoring in Direct Comparison.

BACKGROUND: To be able to compare continuous glucose monitoring (CGM) systems, they have to be worn in parallel by the same subjects. This study evaluated the performance and usability of three different CGM systems in direct comparison. METHOD: In this open, prospective study at two sites, 54 patients with diabetes wore three CGM systems each (Dexcom G5™ Mobile CGM system [DG5], Guardian™ Connect system [GC], and a Roche CGM system [RCGM]) in parallel for 6 or 7 days in a mixed inpatient and outpatient setting. Capillary comparison measurements were performed using a self-monitoring of blood glucose (SMBG) system. During study site visits, glucose excursions were induced. Performance of the systems was evaluated by calculating mean absolute relative differences (MARD, calculated as absolute differences for glucose concentrations <100 mg/dL and as relative differences for glucose concentrations ≥100 mg/dL), and mean relative differences (MRD, bias) between CGM and SMBG results. In addition, usability of the systems was assessed. RESULTS: Overall MARD was 10.1 ± 2.1 for DG5, 11.5 ± 4.2 for GC, and 11.9 ± 5.6 for RCGM. Performance improved in all systems after the first day of use. All systems showed >99% of values within zones A and B of the consensus error grid. Overall, all CGM systems showed a small negative bias compared to SMBG. Usability of the systems differed regarding patch adhesion rate, failure rate, and patient rating. Most patients preferred GC, but in general all systems were rated positively. CONCLUSION: All three CGM systems showed similar overall accuracy in this direct comparison, but small differences were observed with regard to specific glucose ranges and usability aspects.

Accuracy of five systems for self-monitoring of blood glucose in the hands of adult lay-users and professionals applying ISO 15197:2013 accuracy criteria and potential insulin dosing errors.

OBJECTIVE: In this study, accuracy in the hands of intended users was evaluated for five self-monitoring of blood glucose (SMBG) systems based on ISO 15197:2013, and possibly related insulin dosing errors were calculated. In addition, accuracy was assessed in the hands of study personnel. METHODS: For each system (Accu-Chek 1 Aviva Connect [A], Contour 2 Next One [B], FreeStyle Freedom Lite 3 [C], GlucoMen 4 areo [D] and OneTouch Verio 5 [E]) one test strip lot was evaluated as required by ISO 15197:2013, clause 8. Number and percentage of SMBG measurements within ±15 mg/dl and ±15% of the comparison measurements at glucose concentrations <100 mg/dl and ≥100 mg/dl, respectively, were calculated. In addition, data is presented in surveillance error grids, and insulin dosing errors were modeled. The study was registered at ClinicalTrials.gov (NCT03033849). RESULTS: Four systems (A, B, C, D) fulfilled the tested reagent system lot ISO 15197:2013 accuracy criteria with the tested reagent system lot with at least 95% (lay-users) and 99.5% (study personnel) of results within the defined limits. Measurements with all five systems were within the clinically acceptable zones of the consensus error grid and the surveillance error grid. Median modeled insulin dosing errors were between -0.8 and +0.6 units for measurements performed by lay-users and between -0.7 and +0.8 units for study personnel. Frequent lay-user errors were not checking the test strips' expiry date, applying blood incorrectly and handling the device incorrectly. CONCLUSION: In this study, the systems showed slight differences in the number of results within ISO 15197:2013 accuracy limits. Inaccurate SMBG measurements can result in insulin dosing errors and adversely affect glycemic control.

Reporting Insulin Pump Accuracy: Trumpet Curves According to IEC 60601-2-24 and Beyond.

Accuracy of insulin pump basal rate delivery, if tested according to the standard IEC 60601-2-24 for infusion pumps, shall be presented as a trumpet curve. This way of graphical presentation is common; however, it is often misunderstood and misinterpreted by people. It is often assumed that a trumpet curve shows the error rate as a function of time, thus implying an increasing accuracy in the course of time. On the contrary, the horizontal axis of a trumpet curve shows increasingly long observation windows. In addition, trumpet curves display only extreme values, that is, those windows with minimal and maximal deviation, which might not be representative for the total deviation. This commentary provides information regarding the calculations and the interpretation of trumpet curves and proposes alternative approaches.

Establishing Methods to Determine Clinically Relevant Bolus and Basal Rate Delivery Accuracy of Insulin Pumps.

BACKGROUND: Adequate testing of delivery accuracy of insulin pumps is under discussion. Especially for patch pumps, test settings are challenging. In addition, evaluation and presentation of accuracy results in a way that is reasonable and useful for clinicians, not only for technicians, is important. METHODS: Test setups based on IEC 60601-2-24 were used and, in addition, different setups for patch pumps were compared to identify an adequate alternative for pumps without external infusion set. These setups are applicable for both bolus and basal rate accuracy testing. In addition, evaluation procedures considering clinical relevance were compiled. RESULTS: A setup for patch pumps that provides reliable results could be realized. Evaluation of basal rate accuracy data should also consider the actual clinical use of insulin pumps and thus, deviating from IEC 60601-2-24, compose the whole measurement period without excluding the first 24 hours. In addition to the presentation using trumpet curves, accuracy of 1-hour windows should be evaluated and displayed. CONCLUSIONS: This article proposes an approach on how to test, evaluate, and present bolus and basal rate accuracy of insulin pumps from a clinical perspective.

Prediction Quality of Glucose Trend Indicators in Two Continuous Tissue Glucose Monitoring Systems.

BACKGROUND: Continuous interstitial glucose monitoring (CGM) systems often provide glucose trend indicators (e.g., arrows) in addition to current glucose values. These indicators are recommended to be used in therapeutic decisions, because they are ascribed predictive qualities by CGM system manufacturers and expert committees. This study assessed how reliably trend indicators match future glucose change, because such information is missing. METHODS: In a clinical trial, two different CGM systems were used by 20 participants, with two sensors of each system per patient. Participants used the systems for 14 days with three study site visits (48 h each). During study site visits, glucose trend indicators, as displayed by the CGM systems, were recorded at least once per hour during daytime and once at night in a diary. In addition, CGM data were downloaded from the devices. Trend indicators were compared with glucose change calculated from CGM data >30 min after recording the trend indicator. RESULTS: Approximately 60% of trend indicators matched the glucose change calculated from CGM data. More than 10% of trend indicators differed by at least two trend indicator categories. Focusing on trend indicators recorded around carbohydrate (CHO) intake and insulin deliveries resulted in approximately half of trend indicators matching the calculated glucose change. CONCLUSIONS: Trend indicators do not always match future glucose change, especially within the first few hours after CHO intake and insulin deliveries. Manufacturers' labeling and recommendations should reflect this, so that CGM users can make informed decisions.

Measurement Performance of Two Continuous Tissue Glucose Monitoring Systems Intended for Replacement of Blood Glucose Monitoring.

BACKGROUND: Currently, two systems for continuous tissue glucose monitoring (CGM) (Dexcom® G5 [DG5] and FreeStyle Libre [FL]) are intended to replace blood glucose monitoring (BGM) and, according to manufacturer labeling, are distributed as such in some jurisdictions, including the United States and the European Union. METHODS: The measurement performance of these two systems in comparison with a BGM system was analyzed in a 14-day study with 20 participants comprising study site visits, which included phases of induced rapid glucose changes, and home use phases. Performance analysis was mainly based on deviations between CGM readings and BGM results. Sensor-to-sensor precision was also analyzed. RESULTS: Approximately 25% of DG5 and FL results showed differences from BGM results exceeding 15 mg/dL or 15% (at glucose concentration below or above 100 mg/dL, respectively) at times of therapeutic decisions, and ∼5% of differences exceeded 30 mg/dL or 30%. Performance was different depending on the setting (study site visits, home use phases, and phases of induced rapid glucose changes). In consensus error grid (CEG) analysis, both systems showed >99.5% of results within the clinically acceptable zones A and B. CONCLUSIONS: In this study, both systems showed deviations from blood glucose (BG) measurements, the current standard approach in diabetes therapy. Although a large percentage of results was found in CEG zones A and B, for approximately one in four therapeutic decisions, CGM and BG readings differed by at least 15 mg/dL or 15%. Such deviations should be taken into account when using CGM systems.

Occlusion Detection Time in Insulin Pumps at Two Different Basal Rates.

BACKGROUND: The detection of insulin infusion set (IIS) occlusions is an important feature of insulin pumps with regard to patient safety. However, there are no requirements for a time limit until an alarm has to be triggered after an occlusion occurred. The standard IEC 60601-2-24 is applicable for insulin pumps and describes test settings and procedures to determine occlusion detection time (ODT). METHODS: In this study, ODT of six different insulin pump models with different IIS (in total 10 different insulin pump systems) was tested for two basal rates (1.0 U/h and 0.1 U/h). RESULTS: Differences were seen between the tested pump systems. At a basal rate of 1.0 U/h all insulin pump systems showed an acceptable ODT of less than 5 hours. However, at a basal rate of 0.1 U/h, as often used in children, the median ODT ranged from approximately 4 hours to more than 40 hours. With the lower basal rate, median ODT was longer than 6-8 hours for 9 of the 10 systems. CONCLUSIONS: Insulin pump users should not blindly rely on occlusion alarms but perform regular glucose monitoring and manufacturers should develop mechanisms that allow an earlier detection at low basal rates.

Flash Glucose Monitoring: Differences Between Intermittently Scanned and Continuously Stored Data.

The flash glucose monitoring system FreeStyle Libre (Abbott Diabetes Care Ltd., Witney, UK) measures interstitial glucose concentrations and continuously stores measurement values every 15 minutes. To obtain a current glucose reading, users have to scan the sensor with the reader. In a clinical trial, 5% of the scanned data showed relative differences of more than ±10% compared with continuously stored data points (median -0.5%). Such differences might impact results of studies using this system. It should be indicated whether scanned or continuously stored data were used for analyses. Health care professionals might have to differentiate between data reports from clinical software and the scanned data their patients are provided with. Additional information on these differences and their potential impact on therapeutic decisions would be helpful.

TheClinical Research Tool: a high-performance microdialysis-based system for reliably measuring interstitial fluid glucose concentration.

BACKGROUND: A novel microdialysis-based continuous glucose monitoring system, the so-called Clinical Research Tool (CRT), is presented. The CRT was designed exclusively for investigational use to offer high analytical accuracy and reliability. The CRT was built to avoid signal artifacts due to catheter clogging, flow obstruction by air bubbles, and flow variation caused by inconstant pumping. For differentiation between physiological events and system artifacts, the sensor current, counter electrode and polarization voltage, battery voltage, sensor temperature, and flow rate are recorded at a rate of 1 Hz. METHOD: In vitro characterization with buffered glucose solutions (c(glucose) = 0 - 26 x 10(-3) mol liter(-1)) over 120 h yielded a mean absolute relative error (MARE) of 2.9 +/- 0.9% and a recorded mean flow rate of 330 +/- 48 nl/min with periodic flow rate variation amounting to 24 +/- 7%. The first 120 h in vivo testing was conducted with five type 1 diabetes subjects wearing two systems each. A mean flow rate of 350 +/- 59 nl/min and a periodic variation of 22 +/- 6% were recorded. RESULTS: Utilizing 3 blood glucose measurements per day and a physical lag time of 1980 s, retrospective calibration of the 10 in vivo experiments yielded a MARE value of 12.4 +/- 5.7. Clarke error grid analysis resulted in 81.0%, 16.6%, 0.8%, 1.6%, and 0% in regions A, B, C, D, and E, respectively. CONCLUSION: The CRT demonstrates exceptional reliability of system operation and very good measurement performance. The ability to differentiate between artifacts and physiological effects suggests the use of the CRT as a reference tool in clinical investigations.

Continuous glucose monitoring in interstitial fluid using glucose oxidase-based sensor compared to established blood glucose measurement in rats.

Glucose monitoring is of importance for success of complex therapeutic interventions in diabetic patients. Its impact on treatment and glycemic control is demonstrated in large clinical trials. Up to eight blood glucose measurements per day are recommended. Notwithstanding, a substantial number of diabetic patients cannot or will not monitor their blood glucose appropriately. Considerable progress in control of disturbed metabolism in diabetic patients can be expected by continuous glucose monitoring. The aim of the study was to evaluate the performance of a new amperometric glucose oxidase-based glucose sensor in vitro and in vivo after subcutaneous implantation into rats. For in vitro testing current output of sensors was measured by exposure to increasing and decreasing glucose concentrations up to 472 mg dL(-1) over a time period of 7 days. After subcutaneous implantation of sensors into interscapular region of male rats glucose in interstitial fluid was evaluated and compared to glucose in arterial blood up to 7 days. Hyper- and hypoglycaemia were induced by intravenous application of glucose and insulin, respectively. Current of each implanted sensor was converted into glucose concentration using the first blood glucose measurement only. A change of current with glucose of 0.35 nA mg(-1)dL(-1) indicates high sensitivity of the sensor in vitro. The response time (90% of steady state) was calculated by approximately 60s. Test strips for blood glucose measurement as reference for sensor readings was found as an appropriate and rapidly available method in rats by comparison with established hexokinase method in an automated lab analyzer with limits of agreement of +32.8 and -25.7 mg dL(-1) in Bland-Altman analysis. In normo- and hypoglycaemic range sensor readings in interstitial fluid correlated well with blood glucose measurements whereas hyperglycaemia was not reflected by the sensor completely when blood glucose was changing rapidly. The data given characterize a sensor with high sensitivity, long term stability and short response time. A single calibration of the sensor is required only in measurement periods up to 7 days. The findings demonstrate that the sensor is a highly promising candidate for assessment in humans.