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Methods are described for simultaneous continuous in vivo monitoring of blood glucose, lactate, alanine and 3-hydroxybutyrate. The methods use dialysis, immobilized enzymes and measure generated reduced pyridine nucleotides fluorimetrically. The methods are accurate, sensitive, stable, and are suitable for use in emergency situations or in clinical investigation.
Ion-selective potentiometry is used more and more in clinical medicine for the determination of electrolytes in various body fluids. With regard to K+, Na+, Ca2+ and Cl- this technique has almost completely displaced flame photometry, atomic absorption spectrophotometry and coulometry. Moreover, reliable automated devices have facilitated routine analyses. Until now there are 6 different types of ion-selective sensors: glass membrane, solid phase, fluid membrane, carrier, gas-sensitive, and enzyme electrodes with immobilized enzymes. The latter are particularly used for in vivo monitoring, especially for continuous blood glucose monitoring. The essential fields of application in the clinical laboratory are the determinations of the cations H+, K+, Na+, Ca2+, Mg2+ and NH3+, and the anions F-, I-, Br-, Cl- and HCO3-. Despite the wide-spread application of ion-selective potentiometry a number of disturbing factors have to be taken into account by the user as well as by the manufacturer in order to get satisfactory results. For instance, there are differences between direct and indirect potentiometry. Moreover, the activities measured cannot be extrapolated readily to the desired concentrations. A careful and accurate calibration, a suitable sample preparation and an adjustment of the measuring conditions to the characteristics of the specimen and the matrix of the sample is necessary before each measurement. Therefore, a consequent internal and external quality control is necessary to achieve an optimal quality of these methods determining vital parameters in medicine. Thus, the technique of ion-selective potentiometry represents an important milestone in clinical chemistry. Moreover, being a very rapid procedure it is indispensable to clinical diagnostics.
The concentration of extracellular glucose in anesthetized rat brain was measured continuously with two types of substrate-specific microelectrodes in a number of physiological and pathological conditions. Extracellular glucose level increased in hyperglycemia and decreased in hypoglycemia, paralleling the changes in blood sugar. Increased neuronal activity and in particular spreading depression, evoked triphasic alterations in extracellular glucose concentration: an initial rapid fall was followed by an equally swift overshoot above the baseline and a subsequent return to it. Limitation in O2 supply led to a decline in extracellular content of glucose: respiration with 5% O2 reduced the level by 7-20% and that with 3% O2 by 75-85%. Decreases to undetectable concentrations were seen in ischemia despite the use of an oxygen-insensitive microglucose sensor. Restoration of oxygen supply to the brain was accompanied by increases in extracellular glucose content above the original normoxic level, which returned to baseline values after 10-15 min. In hyperglycemic animals ischemia-induced leakage of K+ was delayed while the rate of recovery to control levels after restitution of blood flow was enhanced. It is concluded that continuous monitoring of glucose with glucose-specific microelectrodes provides a new and important insight into brain energy metabolism.
A new method for continuous measurement of subcutaneous tissue glucose content is introduced: by combining the microdialysis technique with a wearable amperometric glucose sensor, a device for continuous glucose measurement in the subcutaneous tissue was obtained. This device was applied to healthy volunteers (n = 10) over the period of an oral glucose load and to type I diabetic patients (n = 10) under the conditions of daily life. Glucose profiles in both healthy and diabetic persons were followed in the subcutaneous tissue up to 27 hours. This technique will certainly open new perspectives of monitoring and treating diabetic patients.
AIMS: To compare the efficacy of insulin pump treatment with multiple daily injections in the treatment of poorly controlled obese Type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin. METHODS: Forty obese Type 2 diabetic subjects (using insulin) were randomized to treatment with continuous subcutaneous infusion pump (CSII) (Minimed) or multiple daily insulin injections (MDI). At the end of the first 18-week treatment period, patients underwent a 12-week washout period during which they were treated with MDI plus metformin. They were then crossed-over to the other treatment for an 18-week follow-up period. Patients performed 4-point daily self blood-glucose monitoring (SBGM) on a regular basis and 7-point monitoring prior to visits 2, 8, 10 and 16. A subset of patients underwent continuous glucose monitoring using the Minimed(R) continuous glucose monitoring system (CGMS) at visits 2, 8, 10 and 16. A standard meal test was performed in which serum glucose was tested at fasting and once each hour for 6 h following a test meal. Glucose levels were plotted against time and the area under the curve (AUC) was calculated. HbA(1c), weight, daily insulin dose and hypoglycaemic episodes were recorded. RESULTS: In obese Type 2 diabetic patients already treated with insulin, treatment with CSII significantly reduced HbA(1c) levels compared with treatment with MDI. An additional CSII treatment benefit was demonstrated by reduced meal-test glucose AUC. Initial reduction of daily insulin requirement observed in CSII-treated subjects during the first treatment period was attributable to a period effect and did not persist over time. CONCLUSIONS: In the intent-to-treat analysis, CSII appeared to be superior to MDI in reducing HbA(1c) and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated Type 2 diabetic subjects.
A glucose-controlled insulin and glucose infusion system (Biostator system, Miles Laboratories Inc., Elkhart, Ind.) was used during operation for removal of four suspected insulinomas. In two patients the Biostator system continuously monitored plasma glucose levels and, through a computer-controlled feedback mechanism, automatically infused insulin or glucose as needed. In this way plasma glucose could be kept at approximately 110 mg/dl throughout the procedure. In one patient a rise in insulin infusion rate and a fall in glucose infusion rate followed removal of the tumor. In the other, absence of these findings was consistent with the clinical suspicion that the source of hypoglycemia had not been removed. In two other patients the Biostator system continuously monitored the patient's plasma glucose, without feedback-controlled administration of insulin or glucose. This demonstrated that, in these patients, tumor manipulation and removal did not lead to severe hypoglycemia, and thus eliminated any need to prophylactically infuse large amounts of glucose. Successful tumor removal was followed by a rise in blood glucose levels in both of these individuals. The glucose-controlled insulin and glucose infusion system appears to be a useful instrument for intraoperative management of patients with suspected insulinomas.
The microdialysis technique was used for following the glucose content of the extracellular subcutaneous (SC) fluid under varying blood glucose levels in rats. The glucose content in the microdialysis perfusion fluid was continuously analyzed by means of the measuring flow chamber of an ex vivo glucose monitor. In six ChBB rats blood glucose levels were varied between 40 mg/dl and 575 mg/dl by intravenous (IV) infusion of glucose and by SC injections of insulin, respectively. After a running-in period of about half an hour, the glucose content in the perfusion fluid was closely related to the blood glucose concentration (r > 0.92) up to a time period of 6 hrs. The "relative recovery" rate of glucose by the microdialysis probe in the SC tissue varied within the 6 experimental sessions. The relative recovery rate could be shown to be not dependent on the absolute blood glucose levels in the individual rat within the glucose concentration range tested.
We instructed pregnant women with insulin dependent diabetes mellitus (IDDM) or noninsulin dependent diabetes mellitus (NIDDM) how to monitor their own blood glucose concentrations and evaluated the efficiency and feasibility of continuous subcutaneous insulin infusion (CSII) therapy. Self-monitored glucose concentrations with a reflectance meter correlated with those of hospital laboratory measurements (hexokinase method) with a coefficient of more than 0.9. Glycosylated hemoglobin (HbA1) levels of the patients were normalized with insulin treatment based on the self-monitored glucose concentrations. In pregnant women with NIDDM who monitored their blood glucose concentrations before breakfast, the fasting glucose concentrations could be lowered by insulin administration and the duration of hospitalization could be shortened compared to non-monitored patients. Although diurnal variations were prominent in pregnant women with IDDM and precise control of their blood glucose concentrations was difficult with conventional insulin administration, even if the patients had monitored their glucose concentrations 7 times a day, the mean glucose concentrations and M values could be kept in the optimum range in patients treated with CSII. These methods have contributed to the improvement in maternal and infant complications.
An important question about blood glucose control in diabetes is, Can present and future blood glucose values be predicted from recent blood glucose history? If this is possible, new continuous blood glucose monitoring technologies under development may lead to qualitatively better therapeutic capabilities. Not only could continuous monitoring technologies alert a user when a hypoglycemic episode or other blood glucose excursion is underway, but measurements may also provide sufficient information to predict near-future blood glucose values. A predictive capability based only on recent blood glucose history would be advantageous because there would be no need to involve models of glucose and insulin distribution, with their inherent requirement for detailed accounting of vascular glucose loads and insulin availability. Published data analyzed here indicate that blood glucose dynamics are not random, and that blood glucose values can be predicted, at least for the near future, from frequently sampled previous values. Data useful in further exploring this concept are limited, however, and an appeal is made for collection of more.
The aim of this work was to evaluate the performance of a novel non-invasive continuous glucose-monitoring system based on impedance spectroscopy (IS) in patients with diabetes. Ten patients with type 1 diabetes (mean+/-S.D., age 28+/-8 years, BMI 24.2+/-3.2 kg/m(2) and HbA(1C) 7.3+/-1.6%) and five with type 2 diabetes (age 61+/-8 years, BMI 27.5+/-3.2 kg/m(2) and HbA(1C) 8.3+/-1.8%) took part in this study, which comprised a glucose clamp experiment followed by a 7-day outpatient evaluation. The measurements obtained by the NI-CGMD and the reference blood glucose-measuring techniques were evaluated using retrospective data evaluation procedures. Under less controlled outpatient conditions a correlation coefficient of r=0.640 and a standard error of prediction (SEP) of 45 mg dl(-1) with a total of 590 paired glucose measurements was found (versus r=0.926 and a SEP of 26 mg dl(-1) under controlled conditions). Clark error grid analyses (EGA) showed 56% of all values in zone A, 37% in B and 7% in C-E. In conclusion, these results indicate that IS in the used technical setting allows retrospective, continuous and truly non-invasive glucose monitoring under defined conditions for patients with diabetes. Technical advances and developments are needed to expand on this concept to bring the results from the outpatient study closer to those in the experimental section of the study. Further studies will not only help to evaluate the performance and limitations of using such a technique for non non-invasive glucose monitoring but also help to verify technical extensions towards a IS-based concept that offers improved performance under real life operating conditions.
Clearly, continuous blood glucose monitoring by portable instruments is the only and absolute prerequisite for unprejudiced evaluation of the various strategies for substitution of insulin deficiency in any form of diabetes mellitus. Continuous blood or tissue glucose monitoring remain the prerequisite for reestablishing a satisfactory feedback control mechanism between insulin secretion and blood glucose concentration in any nondiabetic patient. Loss of first-phase insulin secretion produces defects in regulation of carbohydrate metabolism, as in type II diabetic human subjects. All efforts to solve this important problem are justified.
Continuous Quality Improvement techniques developed in industry are increasingly being applied to the medical field. Statistical process control charts are a CQI technique aimed at monitoring a process and its variability. At our hospital, statistical quality control charts are being constructed from laboratory blood glucose measurements of patients receiving enteral or parenteral nutrition. The charts will be used to monitor glucose levels, reveal variations, and illustrate the effects of new protocols designed to manage glucose levels.
A device providing frequent, automatic, and non-invasive glucose measurements for persons with diabetes has been developed: the GlucoWatch biographer. This device extracts glucose through intact skin via reverse iontophoresis where it is detected by an amperometric biosensor. The biographer can provide glucose readings every 20 min for 12 h. The performance of this device was evaluated in two large clinical studies in a controlled clinical environment (n=231), and the home environment (n=124). Accuracy of the biographer was evaluated by comparing the automatic biographer readings to serial finger-stick blood glucose (BG) measurements. Biographer performance was comparable in both environments. Mean difference between biographer and finger-stick measurements was -0.01 and 0.26 mmol l(-1) for the clinical and home environments, respectively. The mean absolute value of the relative difference was 1.06 and 1.18 mmol l(-1) for the same studies. Correlation coefficient (r) between biographer and finger-stick measurements was 0.85 and 0.80 for the two studies. In both studies, over 94% of the biographer readings were in the clinically acceptable A+B region of the Clarke Error Grid. A slight positive bias is observed for the biographer readings at low BG levels. Biographer accuracy is relatively constant over all rates of BG changes, except when BG decreases more than 10 mmol l(-1) h(-1), which occurred for only 0.2% of points in the home environment study. Biographer precision, as measured by CV%, is approx. 10%. Skin irritation, characterized by erythema and edema, was either non-existent or mild in >90% of subjects and resolved in virtually all subjects without treatment in several days.
Glucose or lactate biosensors are very useful for monitoring metabolism. Continuous monitoring of glucose is for example very important in diabetic patients. The measurement of lactate, a marker for oxygen deficiency, is used in the intensive care unit to monitor the patients' condition. In our laboratory we have developed two types of on-line biosensors to measure in vivo glucose and lactate: a sandwich-type biosensor and, very recently, a miniaturized flow-through biosensor. These biosensors are not placed in the body itself, but are connected to implanted microdialysis or ultrafiltration probes. Both types of biosensors are based on the oxidation of substrate using glucose oxidase or lactate oxidase and electrochemical detection. In the sandwich-type sensor, the enzymes are physically immobilized between two cellulose nitrate filters, and operate with ferrocene as a mediator. In the miniaturized biosensor, with an internal volume of 10-20 nanolitres, the enzymes are immobilized on the electrode via in situ encapsulation in poly(1,3-phenylenediamine). In this review we shall explain the working of these biosensors, and describe their application in clinical monitoring and experimental research.
We have applied a new methodology for noninvasive continuous blood glucose monitoring, proposed in our previous paper, to patients in ICU (intensive care unit), where strict controls of blood glucose levels are required. The new methodology can build calibration models essentially from numerical simulation, while the conventional methodology requires pre-experiments such as sugar tolerance tests, which are impossible to perform on ICU patients in most cases. The in vivo experiments in this study consisted of two stages, the first stage conducted on healthy subjects as preliminary experiments, and the second stage on ICU patients. The prediction performance of the first stage was obtained as a correlation coefficient (r) of 0.71 and standard error of prediction (SEP) of 28.7 mg/dL. Of the 323 total data, 71.5% were in the A zone, 28.5% were in the B zone, and none were in the C, D, and E zones for the Clarke error-grid analysis. The prediction performance of the second stage was obtained as an r of 0.97 and SEP of 27.2 mg/dL. Of the 304 total data, 80.3% were in the A zone, 19.7% were in the B zone, and none were in the C, D, and E zones. These prediction results suggest that the new methodology has the potential to realize a noninvasive blood glucose monitoring system using near-infrared spectroscopy (NIRS) in ICUs. Although the total performance of the present monitoring system has not yet reached a satisfactory level as a stand-alone system, it can be developed as a complementary system to the conventional one used in ICUs for routine blood glucose management, which checks the blood glucose levels of patients every few hours.
OBJECTIVE: The aim of this study was to compare oxidative stress status (OSS) with blood glucose and lipid changes during the fasting, postprandial and postabsorptive phases in type 1 diabetes mellitus. METHODS: Twenty-three patients on intensive insulin treatment received a standard fat-rich breakfast and lunch. OSS was monitored at fasting (F), just after the post-breakfast glycemia peak (BP) (identified by continuous subcutaneous glucose monitoring), 3.5-h post-breakfast (B3.5), just after the post-lunch peak (LP), just after the post-lunch dale (LD) and 5 hours after lunch (L5). RESULTS: Whereas whole blood glutathione and plasma protein thiols increased in the postprandial period (from 6.52 +/- 1.20 (F) to 7.08 +/- 1.45 micromol/g Hb (BP), p = 0.005), ascorbate decreased gradually from 44 +/- 17 (F) to 39 +/- 19 micromol/L (LD), p = 0.015. Retinol and alpha-tocopherol also decreased from 27.1 +/- 7.0 (F) to 25.3 +/- 5.2 micromol/L (BP), p = 0.005. Uric acid decreased later, from 213 +/- 77 (BP) to 204 +/- 68 micromol/L (B3.5), p = 0.01, but then increased in LP (231 +/- 70 micromol/L) and LD to values higher than F (215 +/- 64, micromol/L, p = 0.01). Malondialdehyde increased gradually from 1.02 +/- 0.36 (F) to a maximum of 1.14 +/- 0.40 micromol/L (LP). In the postabsorptive phase (L5) all parameters except for thiols reverted to fasting concentrations. CONCLUSIONS: In type 1 diabetes lipid peroxidation increases during the postprandial phase in parallel to glucose and triglyceride changes. Blood antioxidants, however, followed diverse patterns of change.
BACKGROUND: We sought to review the literature describing the benefits of tight glycemic control in critically ill patients, comparing outcome differences in subgroup populations. METHODS: We searched PubMed for relevant literature on the topic of hyperglycemia and its management in the intensive care unit. RESULTS: Overwhelming evidence in both surgical and medical patients conclusively demonstrates that hyperglycemia is a marker of severity of illness and is also an independent determinant of bad outcome, largely from infectious complications. Randomized trial evidence, in conjunction with historically controlled trials, supports the use of intensive insulin therapy and euglycemic control in critically ill patients, with nondiabetics possibly benefiting even more than diabetic patients. Euglycemia is best achieved, and hypoglycemia attenuated, through use of a protocolized approach. Further elaboration as to what threshold range defines euglycemia in patient subpopulations is needed and what pitfalls must be avoided in this practice. Development of continuous blood glucose monitoring has started and will someday be incorporated into routine practice in the same way that continuous electrocardiographic monitoring and pulse oximetry are standards of care in the intensive care unit. CONCLUSIONS: Hyperglycemia is a predictor of death and complications in critically ill patients. Early aggregated study results show that control of hyperglycemia improves outcomes. Well-designed studies involving thousands of patients have started to better elucidate the concomitant promoters of hyperglycemia and to better quantify the benefits from tight glycemic control.
A method to monitor glucose in whole blood is presented. The aim of the project was to develop a prototype for a bedside monitor system for semi-continuous monitoring of the blood glucose concentration, requiring only one calibration. This was made possible by using the special advantage of the thermal sensor technique in combination with the adjustment of flow. The glucose concentration was determined from the difference between the sensor response and an estimated background signal. Using standard addition technique, calibration factors for background and sensitivity were set and remained unchanged during the monitoring. The background signal was 45 +/- 8 mV (mean +/- S.D., n = 8) and the sensitivity was 28 +/- 1 mV/mmol (mean +/- S.D., n = 4). Recovery in whole blood was 90-98% (mean 94%, n = 12). With an injection interval of 3 min the precision with the sensor was < 3% over more than 100 blood samples. Response time was about 60 s. The calculated glucose values correlated, r = 0.98, with the values obtained with an YSI glucose analyser (Yellow Springs Instruments. Yellow Springs, OH, USA), over the range 2-20 mmol/l.