In Vivo Study of the Inflammatory Tissue Response Surrounding a Novel Extended-Wear Kink-Resistant Insulin Infusion Set Prototype Compared With a Commercial Control Over Two Weeks of Wear Time.

BACKGROUND: Infusion set function remains the limiting factor of insulin pump therapy due to nonmetabolic complications. Here, we tested an investigational extended-wear infusion set prototype with a soft, angled, wire-reinforced cannula with three additional side holes, and compared failure mechanisms and tissue response with a commercial Teflon control. METHODS: A total of 48 Teflon and 48 prototype infusion sets were inserted subcutaneously every other day for 14 days in 12 swine and infused with dilute insulin. After two weeks, tissue around cannulas was excised, and occlusions, leaks, and kinks were determined. Tissue was processed and stained to assess the total area of inflammation (TAI) and the inflammatory layer thickness (ILT) around the cannulas. Data were analyzed using Fisher's exact, analysis of variance-general linear model, Kruskal-Wallis, and post hoc tests. RESULTS: On average, the TAI surrounding the investigational cannula was 52.6% smaller than around the commercial control. The ILT was 66.3% smaller around investigational cannulas. Kinks occurred in 2.1% (investigational) vs 32.4% (commercial) cannulas (P < .001). There was no difference in occlusion alarms and leaks onto skin. CONCLUSIONS: The data suggest that the infusion set prototype elicits less inflammation over an extended wear time and is resistant to kinking, compared with a commercial Teflon device. This is consistent with previously published data on the impact of cannula material/angle on the inflammatory tissue response. We highlight the following important aspects of infusion set design: (1) secure skin adhesion, (2) reliable cannula insertion, (3) automatic removal of the stylet, (4) cannula material/design that resists kinking, and (5) minimization of local tissue inflammation.

Progressive Acceleration of Insulin Exposure Over 7 Days of Infusion Set Wear.

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report insulin pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide <0.6 nmol/L, ≥6 months pump use) were enrolled in a crossover euglycemic clamp pilot study comparing conventional Teflon angled IISs with an investigational extended-wear IIS. PK/PD data from six participants were obtained for 5 h postbolus. Although PD data were unstable, PK profiles (pooled data from both groups) of insulin lispro (0.15 U/kg bolus) showed statistically significant progressive decreases from days 0 to 7 for tmax (P < 0.001), Cmax (P < 0.05), and mean residence time (P < 0.0001). Area under the insulin concentration curve (AUC0-300) declined by ∼24% from days 0 to 7 (P < 0.05). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. The study was registered in clinicaltrials.gov (NCT04398030).

Feasibility study of a prototype extended-wear insulin infusion set in adults with type 1 diabetes.

AIM: To assess the feasibility of a prototype insulin infusion set (IIS) for extended wear in adults with type 1 diabetes. MATERIALS AND METHODS: The prototype Capillary Biomedical investigational extended-wear IIS (CBX IIS) incorporates a soft, flexible, reinforced kink-resistant angled nylon-derivative cannula with one distal and three proximal ports to optimize insulin delivery. Twenty adult participants with type 1 diabetes established on insulin pump therapy used the CBX IIS for two 7-day test periods while wearing a Dexcom G5 continuous glucose monitor. RESULTS: Participants were able to wear the CBX IIS for an average of 6.6 ± 1.4 days. Eighty-eight percent (36 of 41) of sets were worn for 7 days. No serious adverse events were reported. Five infusion sets failed prematurely because of: unresolvable hyperglycaemia (three); hyperglycaemia with elevated ketones (one); or infection (one). Median time in range (3.9-10.0 mmol/L) was 62% (54-76). Average glucose levels per day of infusion set wear showed a statistically significant increase over time (p < .001). CONCLUSIONS: Our preliminary observations confirm the tolerability of the prototype CBX IIS for extended wear, albeit with a deterioration in glucose control after the third day.

In vivo investigation of the tissue response to commercial Teflon insulin infusion sets in large swine for 14 days: the effect of angle of insertion on tissue histology and insulin spread within the subcutaneous tissue.

Objective: This study investigated the effects of the inflammatory tissue response (ITR) to an insulin infusion set (IIS) on insulin bolus spread over wear time, as well as the effect of cannula insertion angle on the ITR, bolus shape, and pump tubing pressure. Research design and methods: Angled or straight IISs were inserted every other day for 14 days into the subcutaneous tissue of 11 swine and insulin was delivered continuously. Prior to euthanasia, a 70 µL bolus of insulin/X-ray contrast agent was infused while recording a pressure profile (peak tubing pressure, pmax; area under the pressure curve, AUC), followed by the excision of the tissue-catheter specimen. Bolus surface area (SA) and volume (V) were assessed via micro-CT. Tissue was stained to analyze total area of inflammation (TAI) and inflammatory layer thickness (ILT) surrounding the cannula. Results: A bolus delivered through an angled IIS had a larger mean SA than a bolus delivered through a straight cannula (314.0±84.2 mm2 vs 229.0±99.7 mm2, p<0.001) and a larger volume (198.7±66.9 mm3 vs 145.0±65.9 mm3, p=0.001). Both decreased significantly over wear time, independent of angle. There was a significant difference in TAI (angled, 9.1±4.0 mm2 vs straight, 14.3±8.6 mm2, p<0.001) and ILT (angled, 0.7±0.4 vs straight, 1.2±0.7 mm, p<0.001). pmax (p=0.005) and AUC (p=0.014) were lower using angled IIS. As ILT increased, pmax increased, while SA and V decreased. Conclusions: The progression of the ITR directly affected bolus shape and tubing pressure. Although straight insertion is clinically preferred, our data suggest that an angled IIS elicits lower grades of ITR and delivers a bolus with lower tubing pressure and greater SA and V. The subcutaneous environment plays a crucial role in IIS longevity, and the insertion angle needs to be considered in future IIS designs and clinical trials.

Continuous intra-arterial blood glucose monitoring using quenched fluorescence sensing in intensive care patients after cardiac surgery: phase II of a product development study.

PURPOSE: Variations in blood glucose (BG), hyperglycaemia and hypoglycaemia are associated with adverse clinical outcomes in intensive care unit patients. Continuous glucose monitoring (CGM) offers the potential to improve BG control, leading to improved patient outcomes. In our product development study, we determined the safety and performance of the GluCath Intravascular CGM System for up to 48 hours in 20 patients admitted to the ICU after cardiac surgery. METHODS: The GluCath system uses a quenched chemical fluorescence mechanism to optically measure glucose in blood. After undergoing elective cardiac surgery, 20 patients had a GluCath sensor inserted through a preexisting radial artery (RA) catheter, and BG was monitored for up to 48 hours. Qualitative measures included effects on patient care, blood pressure monitoring, and ease of blood sampling through the arterial catheter. Safety assessment of the sensor involved ultrasound (US) monitoring for intra-arterial thrombi. Quantitative measures were the accuracy of the sensor in comparison with the reference analyser, and the proportion of paired BG measurements that were compliant with the ISO15197:2003 and CLSI POCT 12-A3 accuracy reference standards. BG was managed according to usual protocols. RESULTS: Twenty sensors were successfully deployed through pre-existing RA catheters and stayed in the RA of the 20 patients for between 6 and 48 hours, with a median time of 45.0 hours (interquartile range, 42.0-47.3 hours). Sixteen of the inserted sensors (80%) remained in situ for more than 40 hours. Three catheters were removed due to clinically significant sampling difficulty or waveform dampening. Two patients had US evidence of a thrombus; in neither patient was the sensor removed early, and there were no significant sequelae or adverse effects detected. For the 758 paired measurements available for performance analysis, reference BG values ranged between 5.3 mmol/L and 12.8 mmol/L. Of the 758 paired sensor measurements, 735 (97.0%) met the ISO15197:2003 criteria (within 20% of a reference measurement when BG is ≥ 4.2 mmol/L [75 mg/dL]), and 648 (85.5%) met the CLSI POCT 12-A3 criteria (within 12.5% of a reference measurement when the BG level is ≥ 5.6 mmol/L [100mg/dL] and within 0.67 mmol/L [12 mg/dL] when the BG level is < 5.6mmol/L [100 mg/dL]). The aggregate mean absolute relative difference (MARD) between the sensor and the reference BG was 6.4%, with individual sensor MARDs ranging from 3.6% to 12.4%. CONCLUSIONS: The GluCath system, using quenched fluorescence sensing, was safe and showed acceptable accuracy when deployed for up to 48 hours in ICU patients after elective cardiac surgery.

Vascular Glucose Sensor Symposium: Continuous Glucose Monitoring Systems (CGMS) for Hospitalized and Ambulatory Patients at Risk for Hyperglycemia, Hypoglycemia, and Glycemic Variability.

Hyperglycemia, hypoglycemia, and glycemic variability have been associated with increased morbidity, mortality, length of stay, and cost in a variety of critical care and non-critical care patient populations in the hospital. The results from prospective randomized clinical trials designed to determine the risks and benefits of intensive insulin therapy and tight glycemic control have been confusing; and at times conflicting. The limitations of point-of-care blood glucose (BG) monitoring in the hospital highlight the great clinical need for an automated real-time continuous glucose monitoring system (CGMS) that can accurately measure the concentration of glucose every few minutes. Automation and standardization of the glucose measurement process have the potential to significantly improve BG control, clinical outcome, safety and cost.

Use of an Intravascular Fluorescent Continuous Glucose Sensor in ICU Patients.

BACKGROUND: Hyperglycemia and hypoglycemia are associated with adverse clinical outcomes in intensive care patients. In product development studies at 4 ICUs, the safety and performance of an intravascular continuous glucose monitoring (IV-CGM) system was evaluated in 70 postsurgical patients. METHODS: The GluCath System (GluMetrics, Inc) used a quenched chemical fluorescence mechanism to optically measure blood glucose when deployed via a radial artery catheter or directly into a peripheral vein. Periodic ultrasound assessed blood flow and thrombus formation. Patient glucose levels were managed according to the standard of care and existing protocols at each site. Reference blood samples were acquired hourly and compared against prospectively calibrated sensor results. RESULTS: In all, 63 arterial sensors and 9 venous sensors were deployed in 70 patients. Arterial sensors did not interfere with invasive blood pressure monitoring, sampling or other aspects of patient care. A majority of venous sensors (66%) exhibited thrombus on ultrasound. In all, 89.4% (1383/1547) of arterial and 72.2% (182/252) of venous measurements met ISO15197:2003 criteria (within 20%), and 72.7% (1124/1547) of arterial and 56.3% (142/252) of venous measurements met CLSI POCT 12-A3 criteria (within 12.5%). The aggregate mean absolute relative difference (MARD) between the sensors and the reference was 9.6% for arterial and 14.2% for venous sensors. CONCLUSIONS: The GluCath System exhibited acceptable accuracy when deployed in a radial artery for up to 48 hours in ICU patients after elective cardiac surgery. Accuracy of venous deployment was substantially lower with significant rates of intravascular thrombus observed using ultrasound.

Accuracy of Intra-arterial and Subcutaneous Continuous Glucose Monitoring in Postoperative Cardiac Surgery Patients in the ICU.

BACKGROUND: The GluCath® intra-arterial continuous glucose monitoring (IA-CGM) system uses a novel quenched chemical fluorescence sensing mechanism to optically measure blood glucose when deployed in the radial artery. The aim of this study was to compare the accuracy of the IA-CGM and the FreeStyle Navigator® subcutaneous continuous glucose monitoring (SC-CGM) system with standard care. METHODS: After admission to the intensive care unit (ICU), the IA-CGM was inserted via a 20 gauge radial arterial study catheter and the SC-CGM was placed at the abdominal wall of postoperative cardiac surgery patients with an expected ICU length of stay > 24 hours. Each device was calibrated according to manufacturer instructions. Glucose values of both CGM systems were blinded for the clinical staff. Reference blood glucose samples were collected from the study catheter every 1-2 hours for at least 24 hours and analyzed on a Radiometer ABL blood gas analyzer. RESULTS: The IA-CGM and SC-CGM sensors were successfully inserted in 8 subjects. Accuracy assessment was performed with 183 paired points: 85.8% of the IA-CGM measurements and 84.2% of the SC-CGM measurements met ISO 15197:2003 glucometer criteria (within 20%) across a 79-248 mg/dl (4.4-13.8 mmol/L) glucose range. Overall ± SD mean absolute relative difference was 12.3 ± 11.3% for IA-CGM and 11.1 ± 8.3% for SC-CGM (difference -1.2%, 95% CI -3.3 to 0.8; P = .24). CONCLUSIONS: The IA-CGM system directly measured arterial blood glucose and did not interfere with clinical care. However, accuracy was similar to that of the less invasive SC-CGM device.

Continuous intra-arterial blood glucose monitoring using quenched fluorescence sensing: a product development study.

BACKGROUND: Continuous glucose monitoring (CGM) has the potential to improve the management of blood glucose (BG) and so improve patient safety and outcomes in intensive care units. The GluCath Intravascular CGM (IV-CGM) System (GluMetrics) uses a novel quenched chemical fluorescence sensing mechanism to measure BG. OBJECTIVE: We aimed to assess the safety and performance of the GluCath IV-CGM for a 24-hour period in 20 patients admitted to an ICU after cardiac surgery. METHODS: Heparin-bonded sensors were deployed via a standard 20-gauge radial arterial catheter inserted for routine care in 21 participants after cardiac surgery. Sensors were inserted shortly after ICU admission and BG was monitored for up to 24 hours. After an in vivo calibration, the system recorded BG every minute. Ultrasound examinations checked for sensor position and the presence of thrombus. Outcome measures were qualitative (ease of use, interference with clinical care, blood pressure monitoring and blood sampling) and quantitative (accuracy in comparison with hourly measurements from a reference analyser). BG was managed according to usual protocols. RESULTS: Of 21 sensors deployed, one failed and one was malpositioned due to operator error. A total of 488 reference samples were collected, with BG concentrations ranging from 4.7mmol/L to 13.4 mmol/L. Calibration samples, samples from the malpositioned sensor and six samples affected by technical errors were excluded. Of 437 paired sensor and reference measurements used to assess accuracy, 353 (80.8%) met International Organization for Standardization standard 15197: 2003 criteria (within 20% of reference when BG≥4.2mmol/L). The aggregate mean absolute relative difference (MARD) was 13.0%, with the MARD for individual sensors ranging from 4.7% to 33.5%. Preremoval ultrasounds detected clinically insignificant intravascular thrombus in five of 21 patients (23.8%). No sensor interfered with clinical care, haemodynamic monitoring or blood sampling. There were no device related serious adverse events. CONCLUSIONS: In this product development study, use of the GluCath system for 24 hours after cardiac surgery had no adverse effect on haemodynamic monitoring, arterial blood sampling or clinical care. Overall accuracy was acceptable in the context of the first phase of a product development study.

Use of an intravascular fluorescent continuous glucose sensor in subjects with type 1 diabetes mellitus.

BACKGROUND: Stress hyperglycemia in the critically ill is associated with increased morbidity and mortality. Continuous glucose monitoring offers a solution to the difficulties of dosing intravenous insulin properly to maintain glycemic control. The purpose of this study was to evaluate an intravascular continuous glucose monitoring (IV-CGM) system with a sensing element based on the concept of quenched fluorescence. METHOD: A second-generation intravascular continuous glucose sensor was evaluated in 13 volunteer subjects with type 1 diabetes mellitus. There were 21 study sessions of up to 24 h in duration. Sensors were inserted into peripheral veins of the upper extremity, up to two sensors per subject per study session. Sensor output was compared with temporally correlated reference measurements obtained from venous samples on a laboratory glucose analyzer. RESULTS: Data were obtained from 23 sensors in 13 study sessions with 942 paired reference values. Fourteen out of 23 sensors (60.9%) had a mean absolute relative difference ≤ 10%. Eighty-nine percent of paired points were in the clinically accurate A zone of the Clarke error grid and met ISO 15197 performance criteria. Adequate venous blood flow was identified as a necessary condition for accuracy when local sensor readings are compared with venous blood glucose. CONCLUSIONS: The IV-CGM system was capable of achieving a high level of glucose measurement accuracy. However, superficial peripheral veins may not provide adequate blood flow for reliable indwelling blood glucose monitoring.

Use of a novel fluorescent glucose sensor in volunteer subjects with type 1 diabetes mellitus.

BACKGROUND: Stress hyperglycemia in the critically ill has been found to be associated with increased morbidity and mortality. Studies have found significant improvements in morbidity and mortality in postsurgical patients whose glucose levels were closely maintained in the euglycemic range. However, subsequent studies, in particular the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, found no improvement in subjects with tight glycemic control. In addition to differences in protocol design, patients in the tight glycemic control arm of the NICE-SUGAR study experienced high rates of hypoglycemia compared with other studies. One interpretation of the NICE-SUGAR study results is that it is difficult to achieve normal glycemia in critically ill patients with existing glucose monitoring technology. The purpose of the study reported here was to evaluate the safety and performance of a continuous intravascular glucose sensor that could be used in the future in critically ill patients. METHODS: A first-generation prototype of an intravascular continuous glucose sensor was evaluated in 29 volunteer subjects with type 1 diabetes mellitus. The sensor operates on the principle of quenched fluorescence. The fluorescent emission from the sensor chemistry is nonlinear, resulting in improved accuracy in the hypoglycemic range. The duration of each study was 8 hours. Sensor output was compared with temporally correlated reference measurements made from venous samples on a laboratory glucose analyzer. RESULTS: Data were obtained from 18 of the 29 subjects in the study. Data were analyzed retrospectively using a factory calibration plus a one-point in vivo calibration. The mean absolute relative difference was 7.97%, and 95.1% of all the points were in zone A of the Clarke error grid. CONCLUSIONS: This pilot study was the first use in human subjects of a prototype of the GluCath Intravascular Continuous Glucose Monitoring System (GluCath System). The GluCath System is based on a novel fluorescent sensor chemistry. The study found the GluCath System had a high level of accuracy as compared with a laboratory reference analyzer.