StatPlus Research Articles

Venous, Arterialized-Venous, or Capillary Glucose Reference Measurements for the Accuracy Assessment of a Continuous Glucose Monitoring System.

Different reference methods are used for the accuracy assessment of continuous glucose monitoring (CGM) systems. The effect of using venous, arterialized-venous, or capillary reference measurements on CGM accuracy is unclear. We evaluated 21 individuals with type 1 diabetes using a capillary calibrated CGM system. Venous or arterialized-venous reference glucose samples were taken every 15 min at two separate visits and assessed per YSI 2300 STAT Plus. Arterialization was achieved by heated-hand technique. Capillary samples were collected hourly during the venous reference visit. The investigation sequence (venous or arterialized-venous) was randomized. Effectiveness of arterialization was measured by comparing free venous oxygen pressure (PO2) of both visit days. Primary endpoint was the median absolute relative difference (ARD). Median ARD using arterialized-venous reference samples was not different from venous samples (point estimated difference 0.52%, P = 0.181). When comparing the three reference methods, median ARD was also not different over the full glycemic range (venous 9.0% [n = 681], arterialized-venous 8.3% [n = 684], and capillary 8.1% [n = 205], P = 0.216), nor over the separate glucose ranges. Arterialization was successful (PO2 venous 5.4 kPa vs. arterialized-venous 8.9 kPa, P < 0.001). Arterialized-venous glucose was significantly higher than venous glucose and numerically higher than capillary glucose (arterialized-venous 142 mg/dL vs. venous 129 mg/dL [P < 0.001] and vs. capillary 134 mg/dL [P = 0.231]). Inconvenience related to arterialization included transient mild edema and redness of the hand in 4 out of 21 (19%) patients. The use of venous, arterialized-venous, or capillary reference measurements did not significantly impact CGM accuracy. Venous reference seems preferable due to its ease of operation.

Multicenter Observational Study of the First-Generation Intravenous Blood Glucose Monitoring System in Hospitalized Patients.

Current methods of blood glucose (BG) monitoring and insulin delivery are labor intensive and commonly fail to achieve the desired level of BG control. There is great clinical need in the hospital for a user-friendly bedside device that can automatically monitor the concentration of BG safely, accurately, frequently, and reliably. A 100-patient observation study was conducted at 6 US hospitals to evaluate the first generation of the Intravenous Blood Glucose (IVBG) System (Edwards Lifesciences LLC & Dexcom Inc). Device safety, accuracy, and reliability were assessed. A research nurse sampled blood from a vascular catheter every 4 hours for ≤ 72 hours and BG concentration was measured using the YSI 2300 STAT Plus Analyzer (YSI Life Sciences). The IVBG measurements were compared to YSI measurements to calculate point accuracy. The IVBG systems logged more than 5500 hours of operation in 100 critical care patients without causing infection or inflammation of a vein. A total of 44135 IVBG measurements were performed in 100 patients with 30231 measurements from the subset of 75 patients used for accuracy analysis. In all, 996 IVBG measurements were time-matched with reference YSI measurements. These pairs had a mean absolute difference (MAD) of 11.61 mg/dl, a mean absolute relative difference (MARD) of 8.23%, 93% met 15/20% accuracy defined by International Organization for Standardization 15197:2003 standard, and 93.2% were in zone A of the Clarke error grid. The IVBG sensors were exposed to more than 200 different medications with no observable effect on accuracy. The IVBG system is an automated and user-friendly glucose monitoring system that provides accurate and frequent BG measurements with great potential to improve the safety and efficacy of insulin therapy and BG control in the hospital, potentially leading to improved clinical outcomes.

Evaluation of symphony ® CGM: a non-invasive, transdermal continuous glucose monitoring system for use in the critically ill

Following a 1 hour warm-up period, a calibration was performed. Blood samples were obtained from a radial artery catheter approximately every hour, centrifuged to plasma, and glucose was measured using a YSI 2300 STAT Plus Glucose Analyzer (reference BG). A maximum of 30 reference BG samples were collected for each patient. Samples were collected as frequently as every 15 minutes for trend analysis. CGM was prospectively calibrated every 4 hours.

Performance of blood glucose meters in compliance with current and future clinical ISO15197 accuracy criteria

Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method.While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within ±15 mg/dL for values <100 mg/dL, and within ±15% for values ≥100 mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%).In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting.

Glucose Measurement of Intensive Care Unit Patient Plasma Samples Using a Fixed-Wavelength Mid-Infrared Spectroscopy System

Glycemic control is a rapidly developing field in intensive care medicine with the aim of reducing mortality, morbidity, and cost. Current intensive care unit (ICU) glucose measurement technologies are susceptible to interference from medications, volume expanders, and other substances present in critically ill patients. We hypothesized that a fixed-wavelength mid-infrared (mid-IR) spectroscopy system would be accurate for measuring glucose levels of ICU patients. This is a prospective investigation of plasma samples from two different institutions treating a heterogeneous population of ICU patients. The first 292 samples were collected from 86 patients admitted to Stamford Hospital, and the next 352 samples were collected from 75 patients from three ICUs at the University of Maryland. Plasma samples were measured on a Fourier-transform infrared or a proprietary spectrometer, with a glucose prediction algorithm to correct for spectral interference, which were compared with reference measurements taken using a YSI 2300 glucose analyzer. Glucose values ranged from 24 to 343 mg/dl. Numerous medications and injury/disease states were observed in the patient populations, with metoprolol, fentanyl, and multiple organ failure the most prevalent. Despite these interferents, there was a high correlation (r ≥ 0.94) and low standard error (≤12.8 mg/dl) between the predicted glucose values and those of the YSI 2300 STAT Plus reference instrument in the three studies. A total of 95.1% of the 644 values in the three studies met International Organization for Standardization 15197 criteria. These results suggest that a fixed-wavelength mid-IR spectrometer can measure glucose accurately in the plasma of ICU patients.

Accuracy Evaluation of Five Blood Glucose Monitoring Systems Obtained from the Pharmacy: A European Multicenter Study with 453 Subjects

This multicenter study was conducted to evaluate the performance of five recently introduced blood glucose (BG) monitoring (BGM) devices under daily routine conditions in comparison with the YSI (Yellow Springs, OH) 2300 Stat Plus glucose analyzer. Five hundred one diabetes patients with experience in self-monitoring of BG were randomized to use three of five different BGM devices (FreeStyle Lite® [Abbott Diabetes Care Inc., Alameda, CA], FreeStyle Freedom Lite [Abbott Diabetes Care], OneTouch® UltraEasy® [LifeScan Inc., Milpitas, CA], Accu-Chek® Aviva [Roche Diagnostics, Mannheim, Germany], and Contour® [Bayer Vital GmbH, Leverkusen, Germany]) in a daily routine setting. All devices and strips were purchased from local regular distribution sources (pharmacies, four strip lots per device). The patients performed the finger prick and the glucose measurement on their own. In parallel, a healthcare professional performed the glucose assessment with the reference method (YSI 2300 Stat Plus). The primary objective was the comparison of the mean absolute relative differences (MARD). Secondary objectives were compliance with the International Organization for Standardization (ISO) accuracy criteria under these routine conditions and Clarke and Parkes Error Grid analyses. MARD ranged from 4.9% (FreeStyle Lite) to 9.7% (OneTouch UltraEasy). The ISO 15197:2003 requirements were fulfilled by the FreeStyle Lite (98.8%), FreeStyle Freedom Lite (97.5%), and Accu-Chek Aviva (97.0%), but not by the Contour (92.4%) and OneTouch UltraEasy (91.1%). The number of values in Zone A of the Clarke Error Grid analysis was highest for the FreeStyle Lite (98.8%) and lowest for the OneTouch Ultra Easy (90.4%). FreeStyle Lite, FreeStyle Freedom Lite, and Accu-Chek Aviva performed very well in this study with devices and strips purchased through regular distribution channels, with the FreeStyle Lite achieving the lowest MARD in this investigation.

Validation and comparison of two methods of measuring lactate in equine plasma

Some methods of lactate (LA) measurement have not been validated appropriately for use in horses. To validate 2 LA analysers (YSI 2300 Stat Plus and TDx Lactic Acid Assay) for use with equine plasma and to compare plasma [LA] determined by the 2 methods. Both instruments were evaluated for linearity, parallelism, recovery and precision using serial dilutions of standard LA solutions and equine plasma and then comparing results with linear regression or paired t tests. Plasma [LA] results were compared in 275 blood samples collected from horses exercising at various intensities using Bland-Altman analysis. Level of significance was P < 0.05. YSI exhibited good linearity for both LA standards and equine plasma (P < 0.05) at 0-30 mmol/l. TDx had good linearity at 0-12 mmol/l (P < 0.05); with LA standard solutions >12 mmol/l and with equine plasma, linearity was decreased. YSI exhibited good parallelism between LA standards and equine plasma LA measurements throughout the 0-30 mmol/l range (P > 0.05). Parallelism was poor with TDx (P < 0.05). Mean ± s.d. % recovery was 101.7 ± 3.4% for YSI (acceptable) and 110.6 ± 8.4% for TDx (unacceptable). Within-run and mean between-run coefficients of variation (CV) for plasma samples tested from 3.3-29.5 mmol/l were 0.4-3.0% for YSI. CVs for samples tested from 2.8-8.0 mmol/l were 17.4-24.1% for TDx. In 275 plasma samples, [LA] ranged from 0.1-42.7 mmol/l and 0.3-50.6 mmol/l for the YSI and TDx methods, respectively. The difference in plasma [LA] determined by the 2 methods was -1.0 ± 3.2 mmol/l, documenting that the TDx overestimated the YSI results by a mean value of 1 mmol/l. It was concluded that the YSI method was a reliable method for measuring equine plasma [LA] from 0-30 mmol/l. The TDx method was found not to be suitable for use with equine plasma due to greater variability in measurements (high CV).

Modeling the Effects of Subcutaneous Insulin Administration and Carbohydrate Consumption on Blood Glucose

Estimation of the magnitude and duration of effects of carbohydrate (CHO) and subcutaneously administered insulin on blood glucose (BG) is required for improved BG regulation in people with type 1 diabetes mellitus (T1DM). The goal of this study was to quantify these effects in people with T1DM using a novel protocol. The protocol duration was 8 hours: a 1-3 U subcutaneous (SC) insulin bolus was administered and a 25-g CHO meal was consumed, with these inputs separated by 3-5 hours. The DexCom SEVEN® PLUS continuous glucose monitor was used to obtain SC glucose measurements every 5 minutes and YSI 2300 Stat Plus was used to obtain intravenous glucose measurements every 15 minutes. The protocol was tested on 11 subjects at Sansum Diabetes Research Institute. The intersubject parameter coefficient of variation for the best identification method was 170%. The mean percentages of output variation explained by the bolus insulin and meal models were 68 and 69%, respectively, with root mean square error of 14 and 10 mg/dl, respectively. Relationships between the model parameters and clinical parameters were observed. Separation of insulin boluses and meals in time allowed unique identification of model parameters. The wide intersubject variation in parameters supports the notion that glucose-insulin models and thus insulin delivery algorithms for people with T1DM should be personalized. This experimental protocol could be used to refine estimates of the correction factor and the insulin-to-carbohydrate ratio used by people with T1DM.

Measurement delay associated with the Guardian RT continuous glucose monitoring system.

AimsUsing compartment modelling, we assessed the time delay between blood glucose and sensor glucose measured by the Guardian® RT continuous glucose monitoring system in young subjects with Type 1 diabetes (T1D).MethodsTwelve children and adolescents with T1D treated by continuous subcutaneous insulin infusion (male/female 7/5; age 13.1 ± 4.2 years; body mass index 21.9 ± 4.3 kg/m2; mean ± sd) were studied over 19 h in a Clinical Research Facility. Guardian® RT was calibrated every 6 h and sensor glucose measured every 5 min. Reference blood glucose was measured every 15 min using a YSI 2300 STAT Plus Analyser. A population compartment model of sensor glucose–blood glucose kinetics was adopted to estimate the time delay, the calibration scale and the calibration shift.ResultsThe population median of the time delay was 15.8 (interquartile range 15.2, 16.5) min, which was corroborated by correlation analysis between blood glucose and 15-min delayed sensor glucose. The delay has a relatively low intersubject variability, with 95% of individuals predicted to have delays between 10.4 and 24.3 min. Population medians (interquartile range) for the scale and shift are 0.800 (0.777, 0.823) (unitless) and 1.66 (1.47, 1.84) mmol/l, respectively.ConclusionsIn young subjects with T1D, the total time delay associated with the Guardian® RT system was approximately 15 min. This is twice that expected on physiological grounds, suggesting a 5- to 10-min delay because of data processing. Delays above 25 min are rarely to be observed.

Elevated Cerebrospinal Fluid Lactate Concentrations in Patients with Bipolar Disorder and Schizophrenia: Implications for the Mitochondrial Dysfunction Hypothesis

Evidence is accumulating that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder and schizophrenia. Cerebrospinal fluid (CSF) concentration of lactate, a product of extra-mitochondrial glucose metabolism, is commonly elevated in individuals with mitochondrial disorders, especially those with neuropsychiatric symptoms. We tested the hypothesis that patients with bipolar disorder and schizophrenia would, on average, have elevated CSF lactate concentrations compared with healthy control subjects. The CSF lactate and CSF and plasma glucose concentrations were measured with a YSI (YSI, Yellow Springs, Ohio) 2300 STAT Plus Glucose & Lactate Analyzer in 15 samples from each of three groups of subjects: bipolar I disorder patients, schizophrenic patients, and healthy control subjects. Mean CSF lactate concentrations were significantly higher in bipolar (1.76 +/- .38) and schizophrenic subjects (1.61 +/- .31) compared with control subjects (1.31 +/- .21 mmol/L). These differences persisted after adjusting means for CSF glucose concentration, which correlated positively with CSF lactate concentration. This is the first report of increased CSF lactate concentrations in patients with bipolar disorder and schizophrenia. Elevated CSF lactate indicates increased extra-mitochondrial and anaerobic glucose metabolism and is consistent with impaired mitochondrial metabolism. Measuring CSF lactate concentration might help identify bipolar and schizophrenic patients with mitochondrial dysfunction who might benefit from research to elucidate and ultimately rectify possible mitochondrial pathology underlying these disorders.

Performance Evaluation of a New Blood Glucose Monitor That Requires No Coding: The OneTouch® Vita™ System

Improvements to blood glucose monitoring systems aim to simplify the testing process, reduce or eliminate errors, and provide additional information for patients with diabetes. New systems must continue to demonstrate high-quality analytical performance. The new OneTouch Vita System (LifeScan, Inc., Milpitas, CA) offers a no-code testing process and proven technology found in the OneTouch Ultra System. Comparative studies were conducted with the new and established systems to evaluate their precision and accuracy. Within-run precision in blood, total precision with controls, and system accuracy were evaluated using three lots of OneTouch Vita Test Strips and one lot of OneTouch Ultra Test Strips. Accuracy was tested across a wide glucose range (38-520 mg/dl, 2.1-28.9 mmol/liter) using fingertip blood samples from 139 subjects. Reference plasma glucose values were obtained using the YSI 2300 STAT Plus Glucose & Lactate Analyzer (YSI Inc., Yellow Springs, OH). All studies were designed in accordance with requirements published by the International Organization for Standardization (ISO 15197). Precision testing (within-run and total) with both systems produced coefficients of variation (CVs) of <5% for all sample types and glucose levels. Within-run precision testing with blood showed CVs of <3.1% and <4.7% for the OneTouch Vita and OneTouch Ultra Systems respectively. Total precision with control samples gave CVs of <3.0% and <3.6% for the two systems. Consensus error grid analysis showed equivalent clinical accuracy with 98.4% (821/834) and 98.2% (273/278) of results within zone A. Both systems met the ISO acceptability requirements for system accuracy. The OneTouch Vita System provides a simple no-code testing process with performance comparable to the OneTouch Ultra and OneTouch Ultra2 Systems.

Differences in Erythrocyte Sedimentation Rates Using the Westergren Method and a Centrifugation Method

The erythrocyte sedimentation rate (ESR) is a nonspecific screening test to assess elevations of acute phase proteins that occur in various acute and chronic diseases. The recommended method is based on the Westergren method. Other technologies to measure ESR have been developed, including centrifugation-based methods. We compared a centrifugation method (ESR STAT PLUS, Hema Technologies, Lebanon, NJ) with the current Westergren method (Sediplast ESR system, Polymedco, Cortlandt Manor, NY) at 3 ESR levels (0-20, 21-60, and >60 mm/h) in a pediatric population and found correlation coefficients of r=0.63, r=0.83, and r=0.43 respectively. The centrifugation ESR exceeded the Westergren ESR by a small but significant amount in the 0-20 mm/h range, where most normal ranges fall. The 2 methods were also compared in blood samples from patients with sickle cell disease, who tend to have lower ESRs owing to impaired rouleau formation. In the sickle cell group (n=39; r=0.87), the centrifugation ESR consistently exceeded (97% of time) the Westergren ESR. This study identifies the differences in ESR results using 2 methods in general and specific pediatric populations.

Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men

Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin (r = 0.36-0.46, P < 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r = -0.37-0.40, P < 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU (P < 0.05). Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for. We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism.

In Vivo Effects of Uncoupling Protein-3 Gene Disruption on Mitochondrial Energy Metabolism

To clarify the role of uncoupling protein-3 (UCP3) in skeletal muscle, we used NMR and isotopic labeling experiments to evaluate the effect of UCP3 knockout (UCP3KO) in mice on the regulation of energy metabolism in vivo. Whole body energy expenditure was determined from the turnover of doubly labeled body water. Coupling of mitochondrial oxidative phosphorylation in skeletal muscle was evaluated from measurements of rates of ATP synthesis (using (31)P NMR magnetization transfer experiments) and tricarboxylic acid (TCA) cycle flux (calculated from the time course of (13)C enrichment in C-4 and C-2 of glutamate during an infusion of [2-(13)C]acetate). At the whole body level, we observed no change in energy expenditure. However, at the cellular level, skeletal muscle UCP3KO increased the rate of ATP synthesis from P(i) more than 4-fold under fasting conditions (wild type, 2.2 +/- 0.6 versus knockout, 9.1 +/- 1.4 micromol/g of muscle/min, p < 0.001) with no change in TCA cycle flux rate (wild type, 0.74 +/- 0.04 versus knockout, 0.71 +/- 0.03 micromol/g of muscle/min). The increased efficiency of ATP production may account for the significant (p < 0.05) increase in the ratio of ATP to ADP in the muscle of UCP3KO mice (5.9 +/- 0.3) compared with controls (4.5 +/- 0.4). The data presented here provide the first evidence of uncoupling activity by UCP3 in skeletal muscle in vivo.

COMPARISON OF PHYSIOLOGICAL PROFILES OF ELITE OFF-ROAD CYCLISTS AND ELITE ROAD CYCLISTS 935

There are minimal data in the literature describing international caliber off-road cyclists (mountain bikers), particularly as they compare physiologically to international caliber road cyclists. Elite female (n=10) and male (n=10) athletes representing the National Off-Road Bicycle Association (NORBA) National Team were evaluated over a six-month period during the 1994 season. During the same time interval, elite female (n=10) and male (n=10) athletes representing the United States Cycling Federation (USCF) National Road Team were tested. Athletes were evaluated on an electrically braked bicycle ergometer using a standardized protocol (3-min stages, 25W increments). Measurements were made during submaximal and maximal exercise and included heart rate (Polar Vantage XL), blood lactate (YSI 2300 Stat Plus) and oxygen uptake (Sensormedics 2900). Lactate threshold (LT) was identified as an exponential increase in blood lactate concentration in response to progressive submaximal workloads. All laboratory tests were conducted at 1860m (6100 ft). Among the female athletes, physiological responses at LT and during maximal exercise were similar between NORBA and USCF cyclists with one exception: USCF cyclists demonstrated a significantly greater (p<0.05) absolute and relative maximal aerobic capacity (USCF=3.85 ± 0.30, NORBA=3.33± 0.27 L · min-1; USCF=63.8 ± 4.2, NORBA=57.9± 2.8 ml·kg-1·min-1). Among the male athletes, physiological responses at LT and during maximal exercise were similar between NORBA and USCF cyclists with two exceptions: (1) USCF cyclists produced significantly greater absolute and relative power at LT (USCF=321± 17, NORBA=271 ± 29 W; USCF=4.4 ± 0.3, NORBA=3.8± 0.3 W · kg-1), and (2) USCF cyclists produced significantly greater absolute and relative power during maximal exercise(USCF=470 ± 35, NORBA=420 ± 42 W; USCF=6.5 ± 0.3, NORBA=5.9 ± 0.3 W · kg-1). These data suggest that, in general, elite off-road cyclists possess physiological profiles that are similar to elite road cyclists.

Accuracy of the Ysi Stat Plus Analyzer for Glucose and Lactate

Abstract The YSI model 2300 Stat Plus analyzer accurately measures glucose in aqueous solutions with an overall standard error of prediction (SEP) of 0.28 mM and a mean percent error (MPE) of 1.79 %. The absolute and relative errors for glucose measurements are concentration dependent. Initial measurements demonstrate the need to periodically monitor the accuarcy of this analyzer to avoid systematic errors. Lactate is measured with an overall SEP of 0.18 mM and MPE of 5.10 %. Analysis of the residuals indicates a slight negative bias of -0.07 mM for lactate.