Preventing hypoglycemia using predictive alarm algorithms and insulin pump suspension.

BACKGROUND: Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures occur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM]) with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to assess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was predicted. METHODS: Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center. On the first admission their basal insulin was increased until their blood glucose level was <60 mg/dL. On the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was prevented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia. RESULTS: Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon, hypoglycemia was prevented 60% of the time. Using a linear prediction algorithm with an 80 mg/dL threshold and a 45-min prediction horizon, hypoglycemia was prevented 80% of the time. There was no rebound hyperglycemia following pump suspension. CONCLUSIONS: Further development of algorithms is needed to prevent all episodes of hypoglycemia from occurring.

The impact of accelerometer use in exercise-associated hypoglycemia prevention in type 1 diabetes.

Exercise-associated hypoglycemia is a common adverse event in people with type 1 diabetes. Previous in silico testing by our group demonstrated superior exercise-associated hypoglycemia mitigation when a predictive low glucose suspend (PLGS) algorithm was augmented to incorporate activity data. The current study investigates the effectiveness of an accelerometer-augmented PLGS algorithm in an outpatient exercise protocol. Subjects with type 1 diabetes on insulin pump therapy participated in two structured soccer sessions, one utilizing the algorithm and the other using the subject's regular basal insulin rate. Each subject wore their own insulin pump and a Dexcom G4™ Platinum continuous glucose monitor (CGM); subjects on-algorithm also wore a Zephyr BioHarness™ 3 accelerometer. The algorithm utilized a Kalman filter with a 30-minute prediction horizon. Activity and CGM readings were manually entered into a spreadsheet and at five-minute intervals, the algorithm indicated whether the basal insulin infusion should be on or suspended; any changes were then implemented by study staff. The rate of hypoglycemia during and after exercise (until the following morning) was compared between groups. Eighteen subjects (mean age 13.4 ± 3.7 years) participated in two separate sessions 7-22 days apart. The difference in meter blood glucose levels between groups at each rest period did not achieve statistical significance at any time point. Hypoglycemia during the session was recorded in three on-algorithm subjects, compared to six off-algorithm subjects. In the postexercise monitoring period, hypoglycemia occurred in two subjects who were on-algorithm during the session and four subjects who were off-algorithm. The accelerometer-augmented algorithm failed to prevent exercise-associated hypoglycemia compared to subjects on their usual basal rates. A larger sample size may have achieved statistical significance. Further research involving an automated system, a larger sample size, and an algorithm design that favors longer periods of pump suspension is necessary.

Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis.

OBJECTIVE: Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS: In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS: Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11-14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4-10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS: In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

A novel method to detect pressure-induced sensor attenuations (PISA) in an artificial pancreas.

Continuous glucose monitors (CGMs) provide real-time interstitial glucose concentrations that are essential for automated treatment of individuals with type 1 diabetes. Miscalibration, noise spikes, dropouts, or pressure applied to the site (e.g., lying on the site while sleeping) can cause inaccurate glucose signals, which could lead to inappropriate insulin dosing decisions. These studies focus on the problem of pressure-induced sensor attenuations (PISAs) that occur overnight and can cause undesirable pump shut-offs in a predictive low glucose suspend system. The algorithm presented here uses real-time CGM readings without knowledge of meals, insulin doses, activity, sensor recalibrations, or fingerstick measurements. The real-time PISA detection technique was tested on outpatient "in-home" data from a predictive low-glucose suspend trial with over 1125 nights of data. A total of 178 sets were created by using different parameters for the PISA detection algorithm to illustrate its range of available performance. The tracings were reviewed via a web-based analysis tool by an engineer with an extensive expertise on analyzing clinical datasets and ~3% of the CGM readings were marked as PISA events which were used as the gold standard. It is shown that 88.34% of the PISAs were successfully detected by the algorithm, and the percentage of false detections could be reduced to 1.70% by altering the algorithm parameters. Use of the proposed PISA detection method can result in a significant decrease in undesirable pump suspensions overnight, and may lead to lower overnight mean glucose levels while still achieving a low risk of hypoglycemia.

Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer.

Inflammation plays a direct role in colorectal cancer (CRC) progression; however the molecular mechanisms responsible for this effect are unclear. The inflammation induced cyclooxygenase 2 (COX-2) enzyme required for the production of Prostaglandin E2 (PGE2), can promote colorectal cancer by decreasing expression of the tumour suppressor gene Programmed Cell Death 4 (PDCD4). As PDCD4 is also a direct target of the oncogene microRNA-21 (miR-21) we investigated the relationship between the COX-2 and miR-21 pathways in colorectal cancer progression. Gene expression profile in tumour and paired normal mucosa from 45 CRC patients demonstrated that up-regulation of COX-2 and miR-21 in tumour tissue correlates with worse Dukes' stage. In vitro studies in colonic adenocarcinoma cells revealed that treatment with the selective COX-2 inhibitor NS398 significantly decreased miR-21 levels (p = 0.0067) and increased PDCD4 protein levels (p<0.001), whilst treatment with PGE2 up-regulated miR-21 expression (p = 0.019) and down-regulated PDCD4 protein (p<0.05). These findings indicate that miR-21 is a component of the COX-2 inflammation pathway and that this pathway promotes worsening of disease stage in colorectal cancer by inducing accumulation of PGE2 and increasing expression of miR-21 with consequent downregulation of the tumour suppressor gene PDCD4.

Inpatient trial of an artificial pancreas based on multiple model probabilistic predictive control with repeated large unannounced meals.

BACKGROUND: Closed-loop control of blood glucose levels in people with type 1 diabetes offers the potential to reduce the incidence of diabetes complications and reduce the patients' burden, particularly if meals do not need to be announced. We therefore tested a closed-loop algorithm that does not require meal announcement. MATERIALS AND METHODS: A multiple model probabilistic predictive controller (MMPPC) was assessed on four patients, revised to improve performance, and then assessed on six additional patients. Each inpatient admission lasted for 32 h with five unannounced meals containing approximately 1 g/kg of carbohydrate per admission. The system used an Abbott Diabetes Care (Alameda, CA) Navigator(®) continuous glucose monitor (CGM) and Insulet (Bedford, MA) Omnipod(®) insulin pump, with the MMPPC implemented through the artificial pancreas system platform. The controller was initialized only with the patient's total daily dose and daily basal pattern. RESULTS: On a 24-h basis, the first cohort had mean reference and CGM readings of 179 and 167 mg/dL, respectively, with 53% and 62%, respectively, of readings between 70 and 180 mg/dL and four treatments for glucose values <70 mg/dL. The second cohort had mean reference and CGM readings of 161 and 142 mg/dL, respectively, with 63% and 78%, respectively, of the time spent euglycemic. There was one controller-induced hypoglycemic episode. For the 30 unannounced meals in the second cohort, the mean reference and CGM premeal, postmeal maximum, and 3-h postmeal values were 139 and 132, 223 and 208, and 168 and 156 mg/dL, respectively. CONCLUSIONS: The MMPPC, tested in-clinic against repeated, large, unannounced meals, maintained reasonable glycemic control with a mean blood glucose level that would equate to a mean glycated hemoglobin value of 7.2%, with only one controller-induced hypoglycemic event occurring in the second cohort.

The Impact of Accelerometer and Heart Rate Data on Hypoglycemia Mitigation in Type 1 Diabetes.

Aerobic exercise can lower blood glucose levels and alter insulin sensitivity both during and several hours after exercise, creating challenges for a closed-loop artificial pancreas. Predictive low glucose suspend (PLGS) algorithms are a first step toward an artificial pancreas, but few of these have been successfully applied to exercise. This study incorporates physical activity measurements from a combined accelerometer/heart rate monitor (HRM) to improve the performance of an existing PLGS algorithm at mitigating exercise-associated hypoglycemia in participants with type 1 diabetes. In all, 22 subjects with type 1 diabetes on insulin pump therapy were provided a combined accelerometer/HRM and (if not already using one) a continuous glucose monitor (CGM), then instructed to go about their everyday lives while wearing the devices. After the monitoring period, each subject's insulin pump, CGM, and accelerometer/HRM were downloaded and the data were used to augment an existing PLGS algorithm to incorporate activity. Using a computer simulator, the accelerometer-augmented algorithm was compared to the HRM-augmented algorithm to determine which was most effective at mitigating hypoglycemia. Mean length of monitoring was 4.9 days. Across all subjects, 11 061 CGM readings were recorded during the monitoring period. In the simulator analysis, the PLGS algorithm reduced hypoglycemia by 62%, compared to 71% and 74% reductions for the HRM-augmented and accelerometer-augmented algorithms, respectively; combined accelerometer and HRM augmentation provided a 76% reduction. In a simulated setting, the accelerometer-augmented pump suspension algorithm decreases the incidence of exercise-related hypoglycemia by a meaningful amount compared to the PLGS algorithm alone. Results also failed to justify the additional user burden of a HRM.

A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1 diabetes.

OBJECTIVE: Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. RESEARCH DESIGN AND METHODS: Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred. RESULTS: Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. CONCLUSIONS: Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

Outpatient safety assessment of an in-home predictive low-glucose suspend system with type 1 diabetes subjects at elevated risk of nocturnal hypoglycemia.

OBJECTIVE: Nocturnal hypoglycemia is a common problem with type 1 diabetes. In the home setting, we conducted a pilot study to evaluate the safety of a system consisting of an insulin pump and continuous glucose monitor communicating wirelessly with a bedside computer running an algorithm that temporarily suspends insulin delivery when hypoglycemia is predicted. RESEARCH DESIGN AND METHODS: After the run-in phase, a 21-night randomized trial was conducted in which each night was randomly assigned 2:1 to have either the predictive low-glucose suspend (PLGS) system active (intervention night) or inactive (control night). Three predictive algorithm versions were studied sequentially during the study for a total of 252 intervention and 123 control nights. The trial included 19 participants 18-56 years old with type 1 diabetes (hemoglobin A1c level of 6.0-7.7%) who were current users of the MiniMed Paradigm® REAL-Time Revel™ System and Sof-sensor® glucose sensor (Medtronic Diabetes, Northridge, CA). RESULTS: With the final algorithm, pump suspension occurred on 53% of 77 intervention nights. Mean morning glucose level was 144±48 mg/dL on the 77 intervention nights versus 133±57 mg/dL on the 37 control nights, with morning blood ketones >0.6 mmol/L following one intervention night. Overnight hypoglycemia was lower on intervention than control nights, with at least one value ≤70 mg/dL occurring on 16% versus 30% of nights, respectively, with the final algorithm. CONCLUSIONS: This study demonstrated that the PLGS system in the home setting is safe and feasible. The preliminary efficacy data appear promising with the final algorithm reducing nocturnal hypoglycemia by almost 50%.

Inpatient studies of a Kalman-filter-based predictive pump shutoff algorithm.

BACKGROUND: An insulin pump shutoff system can prevent nocturnal hypoglycemia and is a first step on the pathway toward a closed-loop artificial pancreas. In previous pump shutoff studies using a voting algorithm and a 1 min continuous glucose monitor (CGM), 80% of induced hypoglycemic events were prevented. METHODS: The pump shutoff algorithm used in previous studies was revised to a single Kalman filter to reduce complexity, incorporate CGMs with different sample times, handle sensor signal dropouts, and enforce safety constraints on the allowable pump shutoff time. RESULTS: Retrospective testing of the new algorithm on previous clinical data sets indicated that, for the four cases where the previous algorithm failed (minimum reference glucose less than 60 mg/dl), the mean suspension start time was 30 min earlier than the previous algorithm. Inpatient studies of the new algorithm have been conducted on 16 subjects. The algorithm prevented hypoglycemia in 73% of subjects. Suspension-induced hyperglycemia is not assessed, because this study forced excessive basal insulin infusion rates. CONCLUSIONS: The new algorithm functioned well and is flexible enough to handle variable sensor sample times and sensor dropouts. It also provides a framework for handling sensor signal attenuations, which can be challenging, particularly when they occur overnight.

A closed-loop artificial pancreas based on risk management.

BACKGROUND: Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges. METHOD: Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance. RESULTS: We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl. CONCLUSION: The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population.

Real-Time hypoglycemia prediction suite using continuous glucose monitoring: a safety net for the artificial pancreas.

OBJECTIVE: The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes. RESEARCH DESIGN AND METHODS: This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject's own baseline infusion rate. RESULTS Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted. CONCLUSIONS: The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.

Prevention of nocturnal hypoglycemia using predictive alarm algorithms and insulin pump suspension.

OBJECTIVE: The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. RESEARCH DESIGN AND METHODS: Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). RESULTS: The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. CONCLUSIONS: Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

Probabilistic evolving meal detection and estimation of meal total glucose appearance.

BACKGROUND: Automatic compensation of meals for type 1 diabetes patients will require meal detection from continuous glucose monitor (CGM) readings. This is challenged by the uncertainty and variability inherent to the digestion process and glucose dynamics as well as the lag and noise associated with CGM sensors. Thus any estimation of meal start time, size, and shape is fundamentally uncertain. This uncertainty can be reduced, but not eliminated, by estimating total glucose appearance and using new readings as they become available. METHOD: In this article, we propose a probabilistic, evolving method to detect the presence and estimate the shape and total glucose appearance of a meal. The method is unique in continually evolving its estimates and simultaneously providing uncertainty measures to monitor their convergence. The algorithm operates in three phases. First, it compares the CGM signal to no-meal predictions made by a simple insulin-glucose model. Second, it fits the residuals to potential, assumed meal shapes. Finally, it compares and combines these fits to detect any meals and estimate the meal total glucose appearance, shape, and total glucose appearance uncertainty. RESULTS: We validate the performance of this meal detection and total glucose appearance estimation algorithm both separately and in cooperation with a controller on the Food and Drug Administration-approved University of Virginia/Padova Type I Diabetes Simulator. In cooperation with a controller, the algorithm reduced the mean blood glucose from 137 to 132 mg/dl over 1.5 days of control without any increased hypoglycemia. CONCLUSION: This novel, extensible meal detection and total glucose appearance estimation method shows the feasibility, relevance, and performance of evolving estimates with explicit uncertainty measures for use in closed-loop control of type 1 diabetes.

Statistical hypoglycemia prediction.

BACKGROUND: Hypoglycemia presents a significant risk for patients with insulin-dependent diabetes mellitus. We propose a predictive hypoglycemia detection algorithm that uses continuous glucose monitor (CGM) data with explicit certainty measures to enable early corrective action. METHOD: The algorithm uses multiple statistical linear predictions with regression windows between 5 and 75 minutes and prediction horizons of 0 to 20 minutes. The regressions provide standard deviations, which are mapped to predictive error distributions using their averaged statistical correlation. These error distributions give confidence levels that the CGM reading will drop below a hypoglycemic threshold. An alarm is generated if the resultant probability of hypoglycemia from our predictions rises above an appropriate, user-settable value. This level trades off the positive predictive value against lead time and missed events. RESULTS: The algorithm was evaluated using data from 26 inpatient admissions of Navigator(R) 1-minute readings obtained as part of a DirecNet study. CGM readings were postprocessed to remove dropouts and calibrate against finger stick measurements. With a confidence threshold set to provide alarms that correspond to hypoglycemic events 60% of the time, our results were (1) a 23-minute mean lead time, (2) false positives averaging a lowest blood glucose value of 97 mg/dl, and (3) no missed hypoglycemic events, as defined by CGM readings. Using linearly interpolated FreeStyle capillary glucose readings to define hypoglycemic events provided (1) the lead time was 17 minutes, (2) the lowest mean glucose with false alarms was 100 mg/dl, and (3) no hypoglycemic events were missed. CONCLUSION: Statistical linear prediction gives significant lead time before hypoglycemic events with an explicit, tunable trade-off between longer lead times and fewer missed events versus fewer false alarms.