Accuracy and stability of an arterial sensor for glucose monitoring in a porcine model using glucose clamp technique.

Intravascular glucose sensors have the potential to improve and facilitate glycemic control in critically ill patients and might overcome measurement delay and accuracy issues. This study investigated the accuracy and stability of a biosensor for arterial glucose monitoring tested in a hypo- and hyperglycemic clamp experiment in pigs. 12 sensors were tested over 5 consecutive days in 6 different pigs. Samples of sensor and reference measurement pairs were obtained every 15 minutes. 1337 pairs of glucose values (range 37-458 mg/dl) were available for analysis. The systems met ISO 15197:2013 criteria in 99.2% in total, 100% for glucose <100 mg/dl (n = 414) and 98.8% for glucose ≥100 mg/dl (n = 923). The mean absolute relative difference (MARD) during the entire glycemic range of all sensors was 4.3%. The MARDs within the hypoglycemic (<70 mg/dl), euglycemic (≥70-180 mg/dl) and hyperglycemic glucose ranges (≥180 mg/dl) were 6.1%, 3.6% and 4.7%, respectively. Sensors indicated comparable performance on all days investigated (day 1, 3 and 5). None of the systems showed premature failures. In a porcine model, the performance of the biosensor revealed a promising performance. The transfer of these results into a human setting is the logical next step.

Novel Single-Site Device for Conjoined Glucose Sensing and Insulin Infusion: Performance Evaluation in Diabetes Patients During Home-Use.

OBJECTIVE: This study evaluated a novel diabetes treatment device that combines commercially available continuous glucose monitoring and insulin infusion technology in such a way as to perform insulin delivery and glucose sensing through a single skin insertion site (single-port device). METHODS: Ten type 1 diabetes patients used the device for up to six days in their home/work environment for open-loop insulin delivery and glucose sensing. On an additional day, the device was used in combination with an algorithm to perform automated closed-loop glucose control under hospital settings. To assess the performance of the device, capillary blood glucose concentrations were frequently determined and a continuous glucose sensor was additionally worn by the patients. RESULTS: The average mean absolute relative deviation from blood glucose concentrations obtained for the sensor of the device was low (median, 13.0%; interquartile range, 10.5-16.7%; n = 10) and did not differ from that of the additionally worn glucose sensor (versus 13.9%; 11.9-15.3%; P = 0.922). Furthermore, insulin delivery with the single-port device was reliable and safe during home use and, when performed in combination with the control algorithm, was adequate to achieve and maintain near normoglycemia. CONCLUSION: Our data show the feasibility of open- and closed-loop glucose control in diabetes patients using a device that combines insulin delivery and glucose sensing at a single tissue site. SIGNIFICANCE: The reduction in device size and invasiveness achieved by this design may largely increase patient convenience and enhance acceptance of diabetes treatment with continuous glucose monitoring and insulin delivery technology.

Development of a Single-Site Device for Conjoined Glucose Sensing and Insulin Delivery in Type-1 Diabetes Patients.

OBJECTIVE: Diabetes patients are increasingly using a continuous glucose sensor to monitor blood glucose and an insulin pump connected to an infusion cannula to administer insulin. Applying these devices requires two separate insertion sites, one for the sensor and one for the cannula. Integrating sensor with cannula to perform glucose sensing and insulin infusion through a single insertion site would significantly simplify and improve diabetes treatment by reducing the overall system size and the number of necessary needle pricks. Presently, several research groups are pursuing the development of combined glucose sensing and insulin infusion devices, termed single-port devices, by integrating sensing and infusion technologies created from scratch. METHODS: Instead of creating the device from scratch, we utilized already existing technologies and introduced three design concepts of integrating commercial glucose sensors and infusion cannulas. We prototyped and evaluated each concept according to design simplicity, ease of insertion, and sensing accuracy. RESULTS: We found that the best single-port device is the one in which a Dexcom sensor is housed inside a Medtronic cannula so that its glucose sensitive part protrudes from the cannula tip. The low degree of component modification required to arrive at this configuration allowed us to test the efficiency and safety of the device in humans. CONCLUSION: Results from these studies indicate the feasibility of combining commercial glucose sensing and insulin delivery technologies to realize a functional single-port device. SIGNIFICANCE: Our development approach may be generally useful to provide patients with innovative medical devices faster and at reduced costs.

Insulin Bolus Administration in Insulin Pump Therapy: Effect of Bolus Delivery Speed on Insulin Absorption from Subcutaneous Tissue.

BACKGROUND: This study assessed subcutaneous absorption kinetics of rapid-acting insulin administered as a bolus using bolus delivery speeds commonly employed in commercially available insulin pumps (i.e., 2 and 40 s for delivering 1 insulin unit). MATERIALS AND METHODS: Twenty C-peptide-negative type 1 diabetic subjects were studied on two occasions, separated by at least 7 days, using the euglycemic clamp procedure. After an overnight fast, subjects were given, in random order, a subcutaneous insulin bolus (15 U of insulin lispro, Eli Lilly) either for 30 s using an Animas IR2020 pump (fast bolus delivery) or for 10 min using a Medtronic Minimed Paradigm 512 pump (slow bolus delivery). RESULTS: Fast bolus delivery resulted in an earlier onset of insulin action as compared with slow bolus delivery (21.0 ± 2.5 vs. 34.3 ± 2.7 min; P < 0.002). Furthermore, time to reach maximum insulin effect was found to be 27 min earlier with fast bolus delivery as compared with slow bolus delivery (98 ± 11 vs. 125 ± 16 min; P < 0.005). In addition, the area under the plasma insulin curve from 0 to 60 min for fast bolus delivery was greater than the one for slow bolus delivery (10,307 ± 1291 vs. 8192 ± 865 min·pmol/L; P = 0.027). CONCLUSIONS: Results suggest that insulin bolus delivery with fast delivery speed may result in more rapid insulin absorption and, thus, may provide a better control of meal-related glucose excursions than that obtained with bolus delivery using slow delivery speeds. Our findings may have important implications for the future design of the bolus delivery unit of insulin pumps.

A prolonged run-in period of standard subcutaneous microdialysis ameliorates quality of interstitial glucose signal in patients after major cardiac surgery.

We evaluated a standard subcutaneous microdialysis technique for glucose monitoring in two critically ill patient populations and tested whether a prolonged run-in period improves the quality of the interstitial glucose signal. 20 surgical patients after major cardiac surgery (APACHE II score: 10.1 ± 3.2) and 10 medical patients with severe sepsis (APACHE II score: 31.1 ± 4.3) were included in this investigation. A microdialysis catheter was inserted in the subcutaneous adipose tissue of the abdominal region. Interstitial fluid and arterial blood were sampled in hourly intervals to analyse glucose concentrations. Subcutaneous adipose tissue glucose was prospectively calibrated to reference arterial blood either at hour 1 or at hour 6. Median absolute relative difference of glucose (MARD), calibrated at hour 6 (6.2 (2.6; 12.4) %) versus hour 1 (9.9 (4.2; 17.9) %) after catheter insertion indicated a significant improvement in signal quality in patients after major cardiac surgery (p < 0.001). Prolonged run-in period revealed no significant improvement in patients with severe sepsis, but the number of extreme deviations from the blood plasma values could be reduced. Improved concurrence of glucose readings via a 6-hour run-in period could only be achieved in patients after major cardiac surgery.

Estimation of human leptin concentration in the subcutaneous adipose and skeletal muscle tissues.

BACKGROUND: Interstitial leptin concentrations in subcutaneous adipose and skeletal muscle tissues were determined by open-flow microperfusion. METHOD: In 12 lean male subjects (age: 25.6 ± 1.1 years), a zero flow rate experiment using different flow rates was applied. Recovery was determined by urea as an internal reference. In the no-net-flux experiments, catheters were perfused with five solutions containing different concentrations of leptin. Concentrations of interstitial leptin were calculated by applying linear regression analysis to perfusate as opposed to sampled leptin concentrations. RESULTS: The zero flow rate protocol showed significantly higher concentrations of leptin in the interstitial fluid of subcutaneous adipose compared to skeletal muscle tissue [36.8 ± 10.32 vs. 7.1 ± 2.5% of the corresponding plasma level (P = 0.018)]. The recovery of urea in the samples was comparable for all catheters [79.4 ± 6.8 vs. 83.0 ± 5.8 of the corresponding plasma level, flow rate of 0.3 µL/min; (P = ns)] and was higher when compared to leptin. In the no-net-flux protocol, the concentration of leptin in subcutaneous adipose tissue was almost identical to plasma [90. 5 ± 7.0%] and the skeletal muscle tissue concentration of leptin was 23.7 ± 2.5% of the corresponding plasma level. CONCLUSION: Open-flow microperfusion enables the estimation of leptin concentrations in subcutaneous adipose and skeletal muscle tissues in humans in vivo. This is the first documentation on the use of open-flow microperfusion to demonstrate that relevant amounts of leptin are also found in skeletal muscle tissue.

Assessing the effectiveness of 3†months day and night home closed-loop insulin delivery in adults with suboptimally controlled type 1 diabetes: a randomised crossover study protocol.

INTRODUCTION: Despite therapeutic advances, many people with type 1 diabetes are still unable to achieve optimal glycaemic control, limited by the occurrence of hypoglycaemia. The objective of the present study is to determine the effectiveness of day and night home closed-loop over the medium term compared with sensor-augmented pump therapy in adults with type 1 diabetes and suboptimal glycaemic control. METHODS AND ANALYSIS: The study will adopt an open label, three-centre, multinational, randomised, two-period crossover study design comparing automated closed-loop glucose control with sensor augmented insulin pump therapy. The study will aim for 30 completed participants. Eligible participants will be adults (≥18 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c)≥7.5% (58 mmol/mmol) and ≤10% (86 mmol/mmol)). Following a 4-week optimisation period, participants will undergo a 3-month use of automated closed-loop insulin delivery and sensor-augmented pump therapy, with a 4-6 week washout period in between. The order of the interventions will be random. All analysis will be conducted on an intention to treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3 months free living phase. Secondary outcomes include HbA1c changes; mean glucose and time spent above and below target glucose levels. Further, participants will be invited at baseline, midpoint and study end to participate in semistructured interviews and complete questionnaires to explore usability and acceptance of the technology, impact on quality of life and fear of hypoglycaemia. ETHICS AND DISSEMINATION: Ethical approval has been obtained at all sites. Before screening, all participants will be provided with oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT01961622 (ClinicalTrials.gov).

Day and night home closed-loop insulin delivery in adults with type 1 diabetes: three-center randomized crossover study.

OBJECTIVE: To evaluate the feasibility of day and night closed-loop insulin delivery in adults with type 1 diabetes under free-living conditions. RESEARCH DESIGN AND METHODS: Seventeen adults with type 1 diabetes on insulin pump therapy (means ± SD age 34 ± 9 years, HbA1c 7.6 ± 0.8%, and duration of diabetes 19 ± 9 years) participated in an open-label multinational three-center crossover study. In a random order, participants underwent two 8-day periods (first day at the clinical research facility followed by 7 days at home) of sensor-augmented insulin pump therapy (SAP) or automated closed-loop insulin delivery. The primary end point was the time when sensor glucose was in target range between 3.9 and 10.0 mmol/L during the 7-day home phase. RESULTS: During the home phase, the percentage of time when glucose was in target range was significantly higher during closed-loop compared with SAP (median 75% [interquartile range 61-79] vs. 62% [53-70], P = 0.005). Mean glucose (8.1 vs. 8.8 mmol/L, P = 0.027) and time spent above target (P = 0.013) were lower during closed loop, while time spent below target was comparable (P = 0.339). Increased time in target was observed during both daytime (P = 0.017) and nighttime (P = 0.013). CONCLUSIONS: Compared with SAP, 1 week of closed-loop insulin delivery at home reduces mean glucose and increases time in target without increasing the risk of hypoglycemia in adults with relatively well-controlled type 1 diabetes.

Recirculation--a novel approach to quantify interstitial analytes in living tissue by combining a sensor with open-flow microperfusion.

We report a novel approach to quantify interstitial analytes in living tissue by combining open-flow microperfusion (OFM) with a sensor and the re-circulation method. OFM is based on the unrestricted exchange of molecules between the interstitial fluid (ISF) and a perfusion medium through macroscopic perforations that enables direct access to the ISF. By re-circulating the perfusate and monitoring the changes of the analytes' concentration with a sensor, the absolute analyte concentration in the ISF can be calculated. In order to validate the new concept, the absolute electrical conductivity of the ISF was identified in six subjects to be 1.33 ± 0.08 S/m (coefficient of variation CV = 6 %), showing the robustness of this approach. The most striking feature of this procedure is the possibility to monitor several compounds simultaneously by applying different sensors which will allow not only the determination of the concentration of a single substance in vivo but also the simultaneous dynamics of different analytes. This will open new fields in analytical chemistry, pharmacology, as well as clinical experimental research.

Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog.

OBJECTIVE: Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions. METHODS: Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP ) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively). RESULTS: SICLAMP was highly variable (5.9-75.9 dl/min per kg per µU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight-fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT. CONCLUSIONS: These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.

Day and night closed-loop control in adults with type 1 diabetes: a comparison of two closed-loop algorithms driving continuous subcutaneous insulin infusion versus patient self-management.

OBJECTIVE: To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control. RESEARCH DESIGN AND METHODS: This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals). RESULTS: Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms. CONCLUSIONS: Both CAM and iAP algorithms provide safe glycemic control.

Real-time improvement of continuous glucose monitoring accuracy: the smart sensor concept.

OBJECTIVE: Reliability of continuous glucose monitoring (CGM) sensors is key in several applications. In this work we demonstrate that real-time algorithms can render CGM sensors smarter by reducing their uncertainty and inaccuracy and improving their ability to alert for hypo- and hyperglycemic events. RESEARCH DESIGN AND METHODS: The smart CGM (sCGM) sensor concept consists of a commercial CGM sensor whose output enters three software modules, able to work in real time, for denoising, enhancement, and prediction. These three software modules were recently presented in the CGM literature, and here we apply them to the Dexcom SEVEN Plus continuous glucose monitor. We assessed the performance of the sCGM on data collected in two trials, each containing 12 patients with type 1 diabetes. RESULTS: The denoising module improves the smoothness of the CGM time series by an average of ∼57%, the enhancement module reduces the mean absolute relative difference from 15.1 to 10.3%, increases by 12.6% the pairs of values falling in the A-zone of the Clarke error grid, and finally, the prediction module forecasts hypo- and hyperglycemic events an average of 14 min ahead of time. CONCLUSIONS: We have introduced and implemented the sCGM sensor concept. Analysis of data from 24 patients demonstrates that incorporation of suitable real-time signal processing algorithms for denoising, enhancement, and prediction can significantly improve the performance of CGM applications. This can be of great clinical impact for hypo- and hyperglycemic alert generation as well in artificial pancreas devices.

Continuous glucose monitoring accuracy results vary between assessment at home and assessment at the clinical research center.

BACKGROUND: Continuous glucose monitoring system (CGMS) accuracy is of critical importance both in delivering therapeutic value and as a component of a closed-loop system. This study aims at assessing the differences between accuracy assessments of CGMS at home and at the clinical research center (CRC). METHODS: Twelve patients with type 1 diabetes used the Dexcom® SEVEN® PLUS (DexCom, Inc.) CGMS for 7 days. Patients performed ≥6 finger pricks [self-measurement of blood glucose (SMBG)] per day while at home. Reference blood glucose measurements were taken during a 24 h CRC admission (YSI 2300 STAT Plus™). Continuous glucose monitoring system data were compared with YSI and SMBG values. Outcome measures included mean absolute relative difference (MARD) and Clarke error grid analysis (CEGA). RESULTS: During CRC admission, the MARD of CGMS vs YSI glucose values was 19.2% (n = 509)--significantly higher than 16.8% at home (n = 611) (p = .004). In the hypoglycemic range, MARD was 23.9% at CRC (n = 26)--not significantly different from 41.6% at home (n = 39) (p = .269). In the hyperglycemic range, CRC MARD at 20.3% (n = 115) was significantly higher than home MARD at 11.2% (n = 118) (p = .001). Clarke error grid analysis showed no significant difference in distribution of data pairs (overall p = .317). CONCLUSIONS: This study illustrates the importance of the setting used when assessing CGMS accuracy. Continuous glucose monitoring system accuracy at home appeared better than at the CRC. This is probably due to the higher sampling rate of reference measurements, feasible only in the CRC. Testing CGMS accuracy in the CRC provides valuable information over and above home testing.

Efficacy and safety of glucose control with Space GlucoseControl in the medical intensive care unit--an open clinical investigation.

BACKGROUND: We aimed to investigate the performance of the Space GlucoseControl system (SGC) (B. Braun, Melsungen, Germany) in medical critically ill patients. The SGC is a nurse-driven, computer-assisted device for glycemic control combining infusion pumps with the enhanced Model Predictive Control algorithm. SUBJECTS AND METHODS: The trial was designed as a single-center, open clinical investigation in a nine-bed medical intensive care unit in a tertiary center in Graz, Austria. Efficacy was assessed by percentage of time within the target range (4.4-8.3 mmol/L; primary end point), mean blood glucose, and sampling interval. Safety was assessed by the number of hypoglycemic episodes (≤2.2 mmol/L). RESULTS: Twenty mechanically ventilated patients (age, 63±16 years; body mass index, 31.0±10.7 kg/m(2); Acute Physiology and Chronic Health Evaluation II score, 25.4±6.3; 14 males; six with diabetes) were included for a period of 7.0±3.6 days. Time within target range was 83.4±8.9% (mean±SD), and mean arterial blood glucose was 6.8±0.4 mmol/L. No severe hypoglycemic episodes (<2.2 mmol/L) occurred, and the percentage of time within 2.2 and 3.3 mmol/L was low (0.03±0.07%). The sampling interval was 2.0±0.4 h. The mean insulin dose was 93.5±80.1 IU/day, and the adherence to the given insulin dose advice was high (98.3%). A total of 11 unintended therapy interruptions (0.08 events/treatment day) caused by software problems occurred in four patients. CONCLUSIONS: SGC is a safe and efficient method to control blood glucose in critically ill patients in the medical intensive care unit.

Development and validation of a low cost blood filtration element separating plasma from undiluted whole blood.

Clinical point of care testing often needs plasma instead of whole blood. As centrifugation is labor intensive and not always accessible, filtration is a more appropriate separation technique. The complexity of whole blood is such that there is still no commercially available filtration system capable of separating small sample volumes (10-100 µl) at the point of care. The microfluidics research in blood filtration is very active but to date nobody has validated a low cost device that simultaneously filtrates small samples of whole blood and reproducibly recovers clinically relevant biomarkers, and all this in a limited amount of time with undiluted raw samples. In this paper, we show first that plasma filtration from undiluted whole blood is feasible and reproducible in a low-cost microfluidic device. This novel microfluidic blood filtration element (BFE) extracts 12 µl of plasma from 100 µl of whole blood in less than 10 min. Then, we demonstrate that our device is valid for clinical studies by measuring the adsorption of interleukins through our system. This adsorption is reproducible for interleukins IL6, IL8, and IL10 but not for TNFα. Hence, our BFE is valid for clinical diagnostics with simple calibration prior to performing any measurement.

Microdialysis--a versatile technology to perform metabolic monitoring in diabetes and critically ill patients.

Continuous subcutaneous glucose monitoring has been tested in type 1 diabetes (T1D). Since in critically ill patients vascular access is granted vascular microdialysis may be preferential. To test this hypothesis comparative accuracy data for microdialysis applied for peripheral venous and subcutaneous glucose monitoring was obtained in experiments in T1D patients. Twelve T1D patients were investigated for up to 30 h. Extracorporeal vascular (MDv) and subcutaneous microdialysis (MDs) was performed. Microdialysis samples were collected in 15-60 min intervals, analyzed for glucose and calibrated to reference. MDv and MDs glucose levels were compared against reference. Median absolute relative difference was 14.0 (5.0; 28.0)% (MDv) and 9.2 (4.4; 18.4)% (MDs). Clarke Error Grid analysis showed that 100% (MDv) and 98.8% (MDv) were within zones A and B. Extracorporeal vascular and standard subcutaneous microdialysis indicated similar performance in T1D. We suggest microdialysis as a versatile technology for metabolite monitoring in subcutaneous tissue and whole blood.

A stepwise approach toward closed-loop blood glucose control for intensive care unit patients: results from a feasibility study in type 1 diabetic subjects using vascular microdialysis with infrared spectrometry and a model predictive control algorithm.

BACKGROUND: Glycemic control can reduce the mortality and morbidity of intensive care patients. The CLINICIP (closed-loop insulin infusion for critically ill patients) project aimed to develop a closed-loop control system for this patient group. Following a stepwise approach, we combined three independently tested subparts to form a semiautomatic closed-loop system and evaluated it with respect to safety and performance aspects by testing it in subjects with type 1 diabetes mellitus (T1DM) in a first feasibility trial. METHODS: Vascular microdialysis, a multianalyte infrared spectroscopic glucose sensor, and a standard insulin infusion pump controlled by an adaptive model predictive control (MPC) algorithm were combined to form a closed-loop device, which was evaluated in four T1DM subjects during 30-hour feasibility studies. The aim was to maintain blood glucose concentration in the target range between 80 and 110 mg/dl. RESULTS: Mean plasma glucose concentration was 110.5 ± 29.7 mg/dl. The MPC managed to establish normoglycemia within 105 ± 78 minutes after trial start and managed to maintain glucose concentration within the target range for 47% of the time. The hyperglycemic index averaged to 11.9 ± 5.3 mg/dl. CONCLUSION: Data of the feasibility trial illustrate the device being effective in controlling glycemia in T1DM subjects. However, the monitoring part of the loop must be improved with respect to accuracy and precision before testing the system in the target population.

Evaluating glycemic control algorithms by computer simulations.

BACKGROUND: Numerous guidelines and algorithms exist to achieve glycemic control. Their strengths and weaknesses are difficult to assess without head-to-head comparison in time-consuming clinical trials. We hypothesized that computer simulations may be useful. METHODS: Two open-label randomized clinical trials were replicated using computer simulations. One study compared performance of the enhanced model predictive control (eMPC) algorithm at two intensive care units in the United Kingdom and Belgium. The other study compared three glucose control algorithms-eMPC, Matias (the absolute glucose protocol), and Bath (the relative glucose change protocol)-in a single intensive care unit. Computer simulations utilized a virtual population of 56 critically ill subjects derived from routine data collected at four European surgical and medical intensive care units. RESULTS: In agreement with the first clinical study, computer simulations reproduced the main finding and discriminated between the two intensive care units in terms of the sampling interval (1.3 h vs. 1.8 h, United Kingdom vs. Belgium; P < 0.01). Other glucose control metrics were comparable between simulations and clinical results. The principal outcome of the second study was also reproduced. The eMPC demonstrated better performance compared with the Matias and Bath algorithms as assessed by the time when plasma glucose was in the target range between 4.4 and 6.1 mmol/L (65% vs. 43% vs. 42% [P < 0.001], eMPC vs. Matias vs. Bath) without increasing the risk of severe hypoglycemia. CONCLUSIONS: Computer simulations may provide resource-efficient means for preclinical evaluation of algorithms for glycemic control in the critically ill.

Prediction of glucose concentration in post-cardiothoracic surgery patients using continuous glucose monitoring.

OBJECTIVE: This study evaluated the predictive capability of simple linear extrapolation of continuous glucose data in postsurgical patients undergoing intensive care. METHODS: Twenty patients, both with or without an established diagnosis of diabetes mellitus, scheduled to undergo cardiothoracic surgery were included. Glucose was continuously monitored in the intensive care unit with a microdialysis-based subcutaneous glucose monitoring system. The prediction horizon (PH) with respect to a given glucose reading was calculated by extrapolating the linear trend of the glucose signal and subjected to both analytical and clinical assessment (by calculation of the average duration of consecutive positive and negative glucose signal trends, the root mean squared error [RMSE], and by insulin titration error grid [ITEG] analysis, respectively). RESULTS: In total, 609 h of continuous glucose data from 17 patients were analyzed. The average duration of consecutive positive and negative glucose signal trends was 7.97 (3.99-19.98) min (median, interquartile range). An increase in the RMSE of 0.5 mmol/L (9 mg/dL) was associated with a PH of 37 min. A strong increase in the number of data points in the unacceptable violation zone of the ITEG was associated with a PH of approximately 20 min. CONCLUSIONS: Our data provide evidence that simple linear extrapolation of glucose trend information obtained by continuous glucose monitoring can be used to predict the course of glycemia in critically ill patients for up to 20-30 min. This "glimpse into the future" can be used to proactively prevent the occurrence of adverse events.

Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans.

An imbalance between pro- and anti-inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low-grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18-gauge open-flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid-heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) levels increased during the study period but were not affected by lipid-heparin infusion. In contrast, the level of IL-10, an anti-inflammatory cytokine, was significantly reduced during the final hour of lipid-heparin infusion (saline: 449.2 ± 105.9 vs. lipid-heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.