Lipohypertrophy and Insulin: An Old Dog That Needs New Tricks.

OBJECTIVE: To review the current status of practical knowledge related to insulin-associated lipohypertrophy (LH) - an accumulation of fatty subcutaneous nodules commonly caused by repeated injections and/or infusions of insulin into the same site. METHODS: Review of published literature with additional contributions from leading multidisciplinary experts with the emphasis on clinical aspects including pathophysiology, clinical and economic consequences, diagnosis, prevention and treatment. RESULTS: LH is the most common dermatologic complication of insulin therapy. Risk factors for the development of lipohypertrophy include repeated delivery of large amounts of insulin into the same location over time, repeated injection trauma to the skin and subcutaneous tissue, and multiple injections using the same needle. Subcutaneous insulin injection in skin areas with lipohypertrophy is associated with reduced pain; however, this problem can interfere with insulin absorption, thereby increasing the likelihood of glucose variability, hypo- and hyperglycemia when a site is changed. Modern visualization technology of the subcutaneous space with ultrasound can demonstrate lipohypertrophy early in the course of its development. CONCLUSIONS: The physiological and psychological consequences of developing insulin lipohypertrophy can be prevented and treated with education focusing on insulin injection techniques.

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).

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.

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.

Review of the Long-Term Implantable Senseonics Continuous Glucose Monitoring System and Other Continuous Glucose Monitoring Systems.

The article published by Kevin Cowart in this issue of the Journal of Diabetes Science and Technology (JDST) is a detailed overview of the clinical trial data and analysis used to demonstrate the safety and effectiveness of the Eversense continuous glucose monitoring (CGM) System for regulatory approval and clinical acceptance. The article describes the published study results for safety, accuracy, reliability, ease of insertion/removal, adverse events, and ease of diabetes patient-use for controlling their glucose levels short and long term. The author nicely compares Eversense CGM System safety and performance with the short-term subcutaneous tissue CGM systems being commercialized by Dexcom, Medtronic Diabetes, and Abbott Diabetes. This comparison may help the clinician define which type of patient with diabetes might benefit the most from the long-term implantable CGM system. The majority of studied patients describe a positive experience managing their diabetes with the Eversense CGM System and request implantation of a new sensor 90 or 180 days later.

Accuracy of Vital Signs Measurements by a Smartwatch and a Portable Health Device: Validation Study.

BACKGROUND: New consumer health devices are being developed to easily monitor multiple physiological parameters on a regular basis. Many of these vital sign measurement devices have yet to be formally studied in a clinical setting but have already spread widely throughout the consumer market. OBJECTIVE: The aim of this study was to investigate the accuracy and precision of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and oxygen saturation (SpO2) measurements of 2 novel all-in-one monitoring devices, the BodiMetrics Performance Monitor and the Everlast smartwatch. METHODS: We enrolled 127 patients (>18 years) from the Thomas Jefferson University Hospital Preadmission Testing Center. SBP and HR were measured by both investigational devices. In addition, the Everlast watch was utilized to measure DBP, and the BodiMetrics Performance Monitor was utilized to measure SpO2. After 5 min of quiet sitting, four hospital-grade standard and three investigational vital sign measurements were taken, with 60 seconds in between each measurement. The reference vital sign measurements were calculated by determining the average of the two standard measurements that bounded each investigational measurement. Using this method, we determined three comparison pairs for each investigational device in each subject. After excluding data from 42 individuals because of excessive variation in sequential standard measurements per prespecified dropping rules, data from 85 subjects were used for final analysis. RESULTS: Of 85 participants, 36 (42%) were women, and the mean age was 53 (SD 21) years. The accuracy guidelines were only met for the HR measurements in both devices. SBP measurements deviated 16.9 (SD 13.5) mm Hg and 5.3 (SD 4.7) mm Hg from the reference values for the Everlast and BodiMetrics devices, respectively. The mean absolute difference in DBP measurements for the Everlast smartwatch was 8.3 (SD 6.1) mm Hg. The mean absolute difference between BodiMetrics and reference SpO2 measurements was 3.02%. CONCLUSIONS: Both devices we investigated met accuracy guidelines for HR measurements, but they failed to meet the predefined accuracy guidelines for other vital sign measurements. Continued sale of consumer physiological monitors without prior validation and approval procedures is a public health concern.

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.

The accuracy of blood pressure measurement by a smartwatch and a portable health device.

Objectives: Handheld medical devices and smartwatches that measure BP without a cuff have recently become available. Since these measurements are relatively more user-friendly than conventional cuff-based measurements they may aid in more frequent BP monitoring. We investigated the accuracy and precision of two popular cuff-less devices: the Everlast smartwatch and the BodiMetrics Performance Monitor.Methods: We enrolled 127 patients from the Thomas Jefferson University Hospital Preadmission Testing Center. Research staff were trained to measure BP according to manufacturer guidelines for the investigational devices. The Everlast smartwatch provides measurements of systolic (SBP) and diastolic (DBP) BP, whereas the Bodimetrics only provides SBP. Reference BP measurements were obtained using a hospital-grade automated sphygmomanometer. After 5 minutes of quiet sitting, four standard and three investigational BP measurements were taken with sixty seconds in between each measurement. The reference BP value was calculated by determining the average of the 2 standard BP measurements that bounded the investigational measurements. We thus determined 3 comparison pairs for each investigational device in each subject. We calculated the mean (SD) of the absolute difference between the respective investigational devices and the reference for SBP and DBP.Results: Data from 42 individuals was excluded because of variation in standard BP measurements per prespecified rules. Of 85 participants used for analysis, 36 (42%) were women, the mean (SD) age was 53 (21) years, 32 (38%) self-reported hypertension, and 97% of these (n = 31) reported taking antihypertensive medications. The average differences between the Everlast watch and reference were 16.9 (13.5) mm Hg for SBP and 8.3 (6.1) mm Hg for DBP. The average difference between the Bodimetrics performance monitor and the reference was 5.3 (4.7) mm Hg for SBP.Conclusions: The Everlast smartwatch and the BodiMetrics Performance Monitor we tested are not accurate enough to be used as BP measurement devices.

Cuff-Less Methods for Blood Pressure Telemonitoring.

Blood pressure telemonitoring (BPT) is a telemedicine strategy that uses a patient's self-measured blood pressure (BP) and transmits this information to healthcare providers, typically over the internet. BPT has been shown to improve BP control compared to usual care without remote monitoring. Traditionally, a cuff-based monitor with data communication capabilities has been used for BPT; however, cuff-based measurements are inconvenient and cause discomfort, which has prevented the widespread use of cuff-based monitors for BPT. The development of new technologies which allow for remote BP monitoring without the use of a cuff may aid in more extensive adoption of BPT. This would enhance patient autonomy while providing physicians with a more complete picture of their patient's BP profile, potentially leading to improved BP control and better long-term clinical outcomes. This mini-review article aims to: (1) describe the fundamentals of current techniques in cuff-less BP measurement; (2) present examples of commercially available cuff-less technologies for BPT; (3) outline challenges with current methodologies; and (4) describe potential future directions in cuff-less BPT development.

Author Correction: Systematic in vivo evaluation of the time-dependent inflammatory response to steel and Teflon insulin infusion catheters.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Comment on 'New photoplethysmogram indicators for improving cuffless and continuous blood pressure estimation accuracy'.

OBJECTIVE: A recent study investigated the potential utility of new photoplethysmogram (PPG) indicators to improve cuffless continuous blood pressure (BP) measurement. APPROACH: In this Comment we provide additional discussion of the physiology underlying PPG- and pulse arrival time (PAT)-based BP measurement. We also discuss validation of these measurements. MAIN RESULTS: Changes in PPG features and PAT can occur independently of BP. Any study validating BP measurement based on PPG features or PAT should include a variety of calibration independent physiological challenges affecting BP. SIGNIFICANCE: PPG/PAT-based BP measurement has been investigated extensively as an alternative to cuff-based BP measurement. We feel the inherent physiological confounding in PPG/PAT-based measurement makes it unlikely that it will be of clinical value.

Systematic in vivo evaluation of the time-dependent inflammatory response to steel and Teflon insulin infusion catheters.

Continuous subcutaneous insulin infusion (CSII) catheters are considered the weak link of insulin pump therapy. Wear-time considerably varies between patients and the choice of catheter material is based on personal preferences rather than scientific facts. Therefore, we systematically assessed and quantified the inflammatory tissue response to steel versus Teflon CSII catheters over a maximum wear-time of 7 days in swine. Tissue surrounding catheters was analysed using histopathology and quantitative real-time PCR. The area of inflammation increased significantly over time independent of material which was confirmed by an increase in CD68 expression and an increase in mononuclear and neutrophil cell infiltrate around the catheters. We observed substantially higher fibrin deposition (p < 0.05) around steel on day 4 of wear-time. IL-6 gene expression increased within 24 hours after insertion, returned to normal levels around Teflon (p < 0.05) but remained high around steel (p < 0.05). IL-10 and TGF-ß levels did not resolve over time, indicating impaired wound healing. In conclusion, there was a major temporal effect in the acute inflammatory response to CSII catheters but we found little difference between materials. This study setup presents a robust tool for the systematic analysis of the tissue response to CSII catheters.

Detailed Analysis of Insulin Absorption Variability and the Tissue Response to Continuous Subcutaneous Insulin Infusion Catheter Implantation in Swine.

BACKGROUND: Worldwide, ∼1 million people manage their type 1 diabetes with an insulin pump and a continuous subcutaneous insulin infusion (CSII) catheter. Patients routinely insert a new catheter every 2-3 days due to increasing variability of insulin absorption over time. Catheter insertion and maintenance damage capillaries, lymphatics, cells, and connective tissue leading to an acute inflammatory response. METHODS: We compared an investigational CSII catheter (IC) and a commercial CSII catheter (CC) regarding insulin absorption pharmacokinetics (PK) and tissue inflammation. The two different catheter designs were implanted into the subcutaneous tissue of six swine for 5 days. Insulin boluses were given on days 1, 3, and 5 of wear-time to assess PK. Tissue around catheters was excised and stained to visualize inflammation and morphological changes of adjacent tissue. RESULTS: Insulin absorption was better when infused through a CC with highest Cmax and fastest tmax values on day 5 of catheter wear-time. Both catheter types produced high intra- and intersubject day-to-day insulin absorption variability. The IC caused significantly more tissue disruption and lead to irregular changes in tissue morphology. Both catheter types were surrounded by a layer of inflammatory tissue that varied in composition, thickness, and density over time. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion. CONCLUSIONS: Insulin absorption variability could be attributed to the layer of inflammatory tissue, which may function as a mechanical barrier to insulin flow into adjacent vascular tissue. The impact of the acute inflammatory tissue response on insulin absorption has to be considered in future catheter designs. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion.

Evaluation of an investigational wearable injector in healthy human volunteers.

OBJECTIVES: Introduction of a wearable device for subcutaneous delivery of larger volume bolus injections would encourage patient compliance and reduce the burden on healthcare services. With one such wearable device commercially available, this study examined the safety and functionality of an investigational device in volunteers. METHODS: Four devices were applied to the subject's abdomen: 1) Investigational Device, 2) Investigational Device: subject movement, 3) Control Device: FDA-cleared syringe driver with FDA-cleared infusion set, 4) Control Device: FDA-cleared syringe driver attached to investigational device. Three milliliters of saline were infused through the four devices over 3 minutes. RESULTS: 84 devices were applied to 21 subjects. Three milliliters of saline were safely delivered subcutaneously from the investigational and control devices. Two control devices had occlusions and in each case the pump reached its high pressure limit of 12 psi. VAS pain measurements showed minimal pain for all subjects. Pain scores were significantly (p < 0.001) higher than baseline at the end of injection: mean pain level ranged from 2.0-22.0 mm. CONCLUSIONS: The investigational device performed as intended with minimal pain during needle insertion and infusion, and no leaking of fluid at the skin puncture site. Two occlusions occurred with the control devices.

Glucose Control in the ICU: A Continuing Story.

In the present era of near-continuous glucose monitoring (CGM) and automated therapeutic closed-loop systems, measures of accuracy and of quality of glucose control need to be standardized for licensing authorities and to enable comparisons across studies and devices. Adequately powered, good quality, randomized, controlled studies are needed to assess the impact of different CGM devices on the quality of glucose control, workload, and costs. The additional effects of continuing glucose control on the general floor after the ICU stay also need to be investigated. Current algorithms need to be adapted and validated for CGM, including effects on glucose variability and workload. Improved collaboration within the industry needs to be encouraged because no single company produces all the necessary components for an automated closed-loop system. Combining glucose measurement with measurement of other variables in 1 sensor may help make this approach more financially viable.

Assessing the Accuracy of Continuous Glucose Monitoring (CGM) Calibrated With Capillary Values Using Capillary or Venous Glucose Levels as a Reference.

BACKGROUND: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM. METHODS: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples. RESULTS: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P < .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P < .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P < .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82. CONCLUSION: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.

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.