Establishing a Continuous Glucose Monitoring Program

Real-time continuous glucose monitoring (RT-CGM) devices provide detailed information on glucose patterns and trends, and alarms that alert the patient to both hyper- and hypoglycemia. This technology can dramatically improve the day-to-day management of patients with diabetes and promises to be a major advance in diabetes care. The safe and effective use of RT-CGM in diabetes management rests on an understanding of several physiological as well as technological issues. This article outlines the key issues that should be addressed in the training curriculum for patients starting on RT-CGM: (1) physiologic lag between interstitial and blood glucose levels and the implications for device calibration, and interpretation and use of data in diabetes management; (2) practical considerations with the use of sensor alarms and caveats in the setting of alarm thresholds; and (3) potential risk for hypoglycemia related to excessive postprandial bolusing by RT-CGM users, and the practical implications for patient training.     

Is it possible to constantly and accurately monitor blood sugar levels,in people with Type 1 diabetes,with a discrete device (non-invasive or invasive)?

Real-time continuous glucose monitors using subcutaneous needle-type sensors continue to develop. The limitations of currently available systems, however, include time lag behind changes in blood glucose, the invasive nature of such systems, and in some cases, their accuracy. Non-invasive techniques have been developed, but, to date, no commercial device has been successful. A key research priority for people with Type 1 diabetes identified by the James Lind Alliance was to identify ways of monitoring blood glucose constantly and accurately using a discrete device, invasive or non-invasive. Integration of such a sensor is important in the development of a closed-loop system and the technology must be rapid, selective and acceptable for continuous use by individuals. The present review provides an update on existing continuous glucose-sensing technologies, and an overview of emergent techniques, including their accuracy and limitations.     

A history of continuous glucose monitors (CGMs) in self-monitoring of diabetes mellitus

Self-monitoring of glucose for individuals afflicted with diabetes mellitus has allowed patients to take control of their disease and thus directly affect the outcomes related to it. It has been almost a century since the first test to monitor one’s sugar was developed; that being a urine test. The most well-known and prominent medical device for monitor blood glucose for individuals with diabetes are the finger-prick devices. This itself is an approximately 50 year old technology. More recently has been the introduction of continuous glucose monitors (CGMs) which entered the market place in the last year of the 20th century. As this technology has been further refined and improved, limitations associated with it have decreased. The scope of this review is to present a brief history of CGMs, both with the development of these medical devices and the challenges/limitations that they have shown.     

Delays in Minimally Invasive Continuous Glucose Monitoring Devices: A Review of Current Technology

Through the use of enzymatic sensors—inserted subcutaneously in the abdomen or ex vivo by means of microdialysis fluid extraction—real-time minimally invasive continuous glucose monitoring (CGM) devices estimate blood glucose by measuring a patient''s interstitial fluid (ISF) glucose concentration. Signals ac-quired from the interstitial space are subsequently calibrated with capillary blood glucose samples, a method that has raised certain questions regarding the effects of physiological time lags and of the duration of processing delays built into these devices. The time delay between a blood glucose reading and the value displayed by a continuous glucose monitor consists of the sum of the time lag between ISF and plasma glucose, in addition to the inherent electro-chemical sensor delay due to the reaction process and any front-end signal-processing delays required to produce smooth traces. Presented is a review of commercially available, minimally invasive continuous glucose monitors with manufacturer-reported device delays. The data acquisition process for the Medtronic MiniMed (Northridge, CA) continuous glucose monitoring system—CGMS® Gold—and the Guardian® RT monitor is described with associated delays incurred for each processing step. Filter responses for each algorithm are examined using in vitro hypoglycemic and hyperglycemic clamps, as well as with an analysis of fast glucose excursions from a typical meal response. Results demonstrate that the digital filters used by each algorithm do not cause adverse effects to fast physiol-ogic glucose excursions, although nonphysiologic signal characteristics can produce greater delays.     

The Need for Performance Standards for Continuous Glucose Monitors

Self-monitoring blood glucose (SMBG) devices or glucose meters currently provide a means for patients to manage insulin dosing through intermittent monitoring of blood glucose levels several times a day, but newer continuous glucose monitor devices (CGM) offer the potential of real-time glucose monitoring with less pain and lower cost. Unlike SMBG devices that sample glucose levels in circulating blood, CGM samples from the interstitial fluid. CGM devices generate not only a single level, but through averaging with past glucose results, can predict future trends. While consensus guidelines exist for evaluating the agreement of SMBG devices to other glucose and laboratory methods, no guidelines currently exists for CGM devices. Standards are needed to define the performance of CGM devices, both in terms of spot accuracy and trend information, as well as the level of performance required for clinical management. The Diabetes Technology Society (DTS) has been in close communication on the development of CGM guidelines with the Food and Drug Administration (FDA) and the Clinical and Laboratory Standards Institute (CLSI). Development of standards for CGM devices if adopted by the FDA would set minimum requirements of performance for manufacturers to meet in producing CGM devices and define common terminology for the display and clinical utilization of CGM data. It is expected that CGM performance standards will advance over time as technology improves and consumer demands change. The development of CGM standards will also play an important role in accelerating the development of an artificial pancreas, which relies on CGM technology.     

Applications and pitfalls of hemoglobin A1C and alternative methods of glycemic monitoring

IntroductionIntensive glycemic control minimizes the risks of microvascular complications in diabetes. A1C is a convenient estimate of mean blood glucose, but is not the only marker available. The practical use and limitations of alternative markers and continuous glucose monitors are the focus of this review.MethodsPubMed and the Cochrane Library were searched for studies concerning applications or limitations of A1C, fructosamine, glycated albumin, 1,5-anhydroglucitol, skin autofluorescence, and continuous glucose monitoring. Papers reporting on strengths, limitations, or comparisons of these methods were reviewed for inclusion.ResultsA1C reflects three months of glycemic control and is not an ideal marker in all patient populations. Fructosamine and glycated albumin reflect mean blood glucose over three weeks. 1,5-Anhydroglucitol can measure hyperglycemic excursions in days to weeks. Continuous glucose monitors provide immediate feedback for timely intervention to reduce glycemic excursions and can assess glycemic variability. Current barriers to continuous glucose monitor use include inexperience, cost, discomfort, and medication interference.ConclusionsMany promising alternative glycemic markers exist. The main limitations for all alternative methods of glycemic monitoring are a lack of standardization for clinically useful cut-offs or guidelines, and a lack of long-term data on their association with complications, particularly in varied patient populations.     

动态血糖仪的工作原理和误差评估

动态血糖监测可以提供24h连续血糖图谱,适合各种糖尿病患者使用,尤其适合易发低血糖、血糖控制不稳定的患者。目前国际上动态血糖仪主要有以下几种：CGMS Gold、GW2B、Guardian RT、GlucoDay、Pendra、FreeStyle Navigator、STS System。动态血糖仪共同的缺点是单点血糖值准确性不够,其误差产生的原因可能与仪器延迟、生理状态、校准偏差、植入部位等有关。评价动态血糖仪准确性的指标很多,包括相对误差中位数、平均绝对误差、误差删格分析方法等。但各型动态血糖仪之间没有统一的评价指标,且评价方法本身也有缺陷。     

Automated Inpatient Blood Sampling for Glucose Measurement: Glucose Monitoring in Acute Care: Technologies on the Horizon

Current glucose monitoring technology appears inadequate for the management of diabetic surgical and in critically ill patients requiring intensive insulin therapy. Subcutaneous sensors measure interstitial fluid glucose, and this technology has not yet been shown to provide the timely and accurate measurements necessary for intravenous insulin administration in surgical and critical care patients on intensive insulin therapy. Technologies under development that may be more suitable for surgical and intensive care unit patients are the automated intermittent type glucose monitors and central catheter glucose monitors. Improved accuracy, patient safety, incorporation of control algorithms, and alleviation of added nursing labor are important factors for consideration with future acute care glucose monitors. Hospital costs for these monitors are difficult to estimate but may be relatively low if their use can be related to better patient outcome, reduced labor costs, and increased job satisfaction for the nursing staff.     

Raman Spectroscopy as a Promising Tool for Noninvasive Point-of-Care Glucose Monitoring

Self-monitoring of glucose is important for managing diabetes. Noninvasive glucose monitors are not yet available, but patients would benefit highly from such a device. We present results that may lead to a novel, point-of-care noninvasive system to measure blood glucose based on Raman spectroscopy. A hospitalized cohort of 111 subjects was measured using a custom-made Raman spectrometer system. Blood glucose reference samples were used to correlate Raman data to glucose levels, using advanced preprocessing and analysis algorithms. A correlation coefficient (R ²) of .83 was found correlating independent Raman-based predictions on reference blood glucose for the full cohort. Stratification of the cohort in gender-specific groups raised correlation levels to .88 (females) and .94 (males). Glucose could be measured noninvasively with average errors as low as 0.9 mM. We conclude that this novel system shows promising results for the advance of noninvasive, point-of-care glucose monitoring.     

Pilot Studies of Transdermal Continuous Glucose Measurement in Outpatient Diabetic Patients and in Patients during and after Cardiac Surgery

Background

We tested the hypothesis that glucose can be measured continuously and reliably in patients in diverse settings using a transdermal biosensor coupled to a permeated skin site. In addition, we compared a novel, abrasion-based skin permeation method to an ultrasound-based method for transdermal continuous glucose monitoring.

Method

Transdermal continuous glucose monitors were applied to patients with diabetes (study I), patients undergoing cardiac surgery (study II), and healthy volunteers (study III). Reference blood glucose measurements were performed with glucometers or standard blood glucose analyzers. At the conclusion of the 24-hour study, data were postprocessed for comparison with the reference blood glucose values collected during the study period.

Results

Data were validated for 10 subjects for 12 hours in study I, 8 subjects for 24 hours in study II, and 6 subjects in study III. The transdermal continuous glucose monitors usually required 1 hour of warm up. Depending on the study setting, single or multiple calibrations were applied to the datasets. Comparing predicted glucose versus reference blood glucose values, we found that study I yielded 89.6% in zone A and 9.0% in zone B in the Clarke error grid (222 data points), study II yielded 86.4% in zone A and 13.6% in zone B (147 data points), and study III yielded 89.9% in zone A and 10.1% in zone B (378 data points).

Conclusions

Continuous transdermal glucose monitoring was demonstrated successfully in diverse clinical settings. The performance of abrasion was equivalent to ultrasound skin permeation methodology for transdermal glucose monitoring.     

Glucose measurement in body fluids: A ready reckoner for clinicians

Background and aimsBlood glucose measurement is central to the diagnosis and management of patients with diabetes. Considering that a clinician relies heavily on blood (or rarely other body fluid) glucose values for decision making, an understanding of the basic aspects of glucose measurement in body fluids is necessary.MethodsA literature search was conducted in PubMed for articles in English on measurement of glucose in body fluids.ResultsGlucose can be measured in several body fluids, namely blood, interstitial fluid, urine, cerebrospinal fluid, pleural fluid and ascitic fluid in appropriate clinical settings. For blood glucose measurement, the present-day enzymatic methods have replaced the older reducing and condensation methods on account of their better accuracy. It is important to consider preanalytical factors such as sample collection, storage and transport when analyzing a laboratory blood glucose report. The measurement of glucose in interstitial fluid using continuous glucose monitoring system (CGMS) enables better understanding of glucose trends and fluctuations. The CGMS data should be reported using standard metrics which include parameters such as mean 24-h glucose, glycemic variability and time-in, below and above range. The measurement of glucose in urine sample is rarely ever used these days and should be reserved for exceptional circumstances.ConclusionThis review provides a detailed account of various aspects of glucose measurement including their evolution, pitfalls, and their utility in current clinical practice.     

Pendra goes Dutch: lessons for the CE mark in Europe

The development of a truly non-invasive continuous glucose sensor is an elusive goal. We describe the rise and fall of the Pendra device. In 2000 the company Pendragon Medical introduced a truly non-invasive continuous glucose-monitoring device. This system was supposed to work through so-called impedance spectroscopy. Pendra was Conformité Européenne (CE) approved in May 2003. For a short time the Pendra was available on the Dutch direct-to-consumer market. A post-marketing reliability study was performed in six type 1 diabetes patients. Mean absolute difference between Pendra glucose values and values obtained through self-monitoring of blood glucose was 52%; the Pearson's correlation coefficient was 35.1%; and a Clarke error grid showed 4.3% of the Pendra readings in the potentially dangerous zone E. We argue that the CE certification process for continuous glucose sensors should be made more transparent, and that a consensus on specific requirements for continuous glucose sensors is needed to prevent patient exposure to potentially dangerous situations.     

Continuous glucose monitoring in normal mice and mice with prediabetes and diabetes

It is well established that the key to minimizing diabetes-associated complications, in both type 1 and type 2 diabetes, is tight regulation of blood glucose levels. Currently the major approach to regulating blood glucose levels in patients with diabetes relies on external blood glucose monitors. However, poor patient compliance usually results in limited insights into the dynamic range of blood glucose levels (i.e., hyperglycemia vs. hypoglycemia), and inadequate prediction and control of blood glucose levels in these patients. Implantable glucose sensors hold promise for controlling blood glucose levels, but currently these sensors have only limited in vivo life span. Recently we have developed an extremely robust murine model for implantable glucose sensors. In the present study, we have extended this model by developing a complete system for real-time continuous glucose monitoring in normal mice and mice with prediabetes and diabetes (type 1). These studies demonstrated that (1) glucose sensors can be implanted and maintained subcutaneously in the mice; (2) continuous glucose sensor data can be obtained for at least 5 days; and (3) subcutaneous blood glucose sensing paralleled blood glucose levels in normal mice and mice with prediabetes and diabetes. Subcutaneous blood glucose sensing also successfully tracked changes in blood glucose levels induced in the mice with diabetes by administration of oral glucose or insulin. These results mirror the results for subcutaneous blood glucose sensing seen in both normal subjects and patients with diabetes, and therefore validate both our continuous glucose monitoring system in the mouse, and the use of the mouse as a model for implantable glucose sensing in vivo.     

In vitro assessment of infant pulmonary function equipment

Commercially available automated pulmonary monitors are used increasingly in neonatal intensive care units. However, detailed information regarding the static and dynamic accuracy of these monitors is rarely available. Collaboration between scientists, clinicians, and manufacturers is essential to establish improved technical standards and protocols for testing of equipment and for the development of more reliable neonatal pulmonary monitors. The aim of this study was to develop a protocol for the in vitro assessment of commercial infant pulmonary function equipment which could be applied within the laboratory to provide rapid feedback to the manufacturer. A recently released neonatal pulmonary monitor, the Bicore CP100 (software version 3.3), was selected for the development of this protocol. The deadspace and resistance of the measuring device were determined. The flow and airway pressure measuring systems were evaluated alone and connected to a tracheal tube for both static accuracy and frequency response. The pressure— volume relationship of the esophageal balloon was determined and its static accuracy and frequency response were assessed. The algorithms for on-line calculations were checked and their correct application confirmed by examination of an ASCII data print out. Finally, the pulmonary monitor was tested during intermittent positive pressure ventilation of a neonatal lung model of known compliance and resistance. © 1995 Wiley-Liss, Inc.     

Continuous glucose monitors: the long-awaited watch dogs?

To date, several continuous glucose sensors have been developed and launched in the U.S. and European markets, though large-scale application in standard diabetes care still awaits its breakthrough. This report offers an overview of the current applications and clinically relevant aspects of continuous glucose monitors (CGMs), e.g., the calibration procedure, interpretation of continuous glucose data, and some important limitations. It is still difficult to state with certainty that CGMs allow effective improvement in glycemic control for the majority of patients with type 1 diabetes, in view of the paucity of controlled studies showing an impact on hemoglobin A1c or frequency of hypoglycemia, even if such a tendency seems to emerge from most non-controlled intervention trials. Future controlled trials should also take into account patient-related outcomes, to evaluate the effect of CGMs on health status, treatment satisfaction, and fear of hypoglycemia. Increased accuracy and reimbursement are key to further implementation of CGMs.     

Recommendations for self-monitoring in pediatric diabetes: a consensus statement by the ISPED

A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally.     

Review of measurement methods and clinical validation studies of noninvasive blood pressure monitors: accuracy requirements and protocol considerations for devices that require patient-specific calibration by a secondary method or device before use

Existing standardized protocols for clinical validation of noninvasive blood pressure (BP) monitors do not have specific provisions for monitors that require patient-specific calibration by a secondary method or device before use. This article seeks to identify accuracy requirements and protocol considerations for such monitors. Measurement methods that require patient-specific calibration were reviewed to identify their clinical accuracy requirements. Validation studies of monitors that use these methods were reviewed to identify limitations in their protocols. For a monitor that requires patient-specific calibration, inadequate adaptation of existing protocols can fail to validate the accuracy of the monitor for its intended use. A protocol for such a monitor must have provisions to assess the monitor's accuracy in tracking intrapatient BP changes, from the calibrated level, after a calibration or between calibrations. Performing a patient-specific calibration with a patient at rest and immediately evaluating the monitor against a reference method with the patient also at rest will not assess this accuracy, because changes in BP at rest and over a short time are generally small compared with those that occur over 24 h. For validation purposes, intrapatient BP changes can be achieved by validating the monitor over an extended period or induced by means of physical maneuvers or pharmacological interventions. The secondary method or device used for the calibration must be accurate. The protocol must also have provisions to assess the monitor's ability to correct for changes in hydrostatic pressure, reject or correct for motion artefacts, and correct for other factors that affect measurement accuracy during use. There is a need to establish protocol provisions to ensure that noninvasive BP monitors that require patient-specific calibration are properly validated for their intended use before they are placed on the market or introduced into clinical use.     

Continuous glucose monitoring: long-term implantable sensor approach

Problems with existing glucose monitoring technology have resulted in poor compliance with recommended monitoring guidelines by patients with diabetes. To achieve the goal of tight glucose control by patients with diabetes, a long-term implantable glucose sensor should meet the following functional requirements: it should be a one-time minimally invasive implantable with a wireless external unit; provide on-demand real-time glucose levels and trends; operate for up to 12 months after implantation with infrequent recalibration; contain built-in hypoglycemic and hyperglycemic alarms; and have an ergonomically designed, external, wearable user interface. Measurements of glucose in interstitial fluid (ISF) can be used for long-term monitoring. A novel approach to continuous and long-term glucose sensing could be based on measuring the changes in fluorescence of glucose-sensitive indicator molecules. To measure these changes in fluorescence a miniature optoelectronic device with a glucose sensitive indicator could be implanted subcutaneously for long-term remote operation. The fluorescence-based glucose sensing process is reversible and does not consume glucose. The combination of fluorescence-based glucose detection, sensor miniaturization and the use of biomaterials, inducing neovascularization at the implant site, opens the opportunity for achieving the requirements for long-term, continuous and convenient glucose monitoring.     

Performance of Cleared Blood Glucose Monitors

Cleared blood glucose monitor (BGM) systems do not always perform as accurately for users as they did to become cleared. We performed a literature review of recent publications between 2010 and 2014 that present data about the frequency of inaccurate performance using ISO 15197 2003 and ISO 15197 2013 as target standards. We performed an additional literature review of publications that present data about the clinical and economic risks of inaccurate BGMs for making treatment decisions or calibrating continuous glucose monitors (CGMs). We found 11 publications describing performance of 98 unique BGM systems. 53 of these 98 (54%) systems met ISO 15197 2003 and 31 of the 98 (32%) tested systems met ISO 15197 2013 analytical accuracy standards in all studies in which they were evaluated. Of the tested systems, 33 were identified by us as FDA-cleared. Among these FDA-cleared BGM systems, 24 out of 32 (75%) met ISO 15197 2003 and 15 out of 31 (48.3%) met ISO 15197 2013 in all studies in which they were evaluated. Among the non-FDA-cleared BGM systems, 29 of 65 (45%) met ISO 15197 2003 and 15 out of 65 (23%) met ISO 15197 2013 in all studies in which they were evaluated. It is more likely that an FDA-cleared BGM system, compared to a non-FDA-cleared BGM system, will perform according to ISO 15197 2003 (χ² = 6.2, df = 3, P = 0.04) and ISO 15197 2013 (χ² = 11.4, df = 3, P = 0.003). We identified 7 articles about clinical risks and 3 articles about economic risks of inaccurate BGMs. We conclude that a significant proportion of cleared BGMs do not perform at the level for which they were cleared or according to international standards of accuracy. Such poor performance leads to adverse clinical and economic consequences.