Jonas Kildegaard

Sources of Glycemic Variability—What Type of Technology is Needed?

People on insulin therapy are challenged with evaluation of numerous factors affecting the blood glucose in order to select the optimal dose for reaching their glucose target. Following medical recommendations precisely still results in considerable blood glucose unpredictability, often resulting in frustration in the short term due to hypoglycemia and hyperglycemia, and, in the long term, will likely result in complications. The kinetics of insulin do indeed vary significantly and have become an important focus when developing new insulin analogues and delivery systems; however, numerous of other factors impact glycemic variability. These have different dependences and interactions and are therefore difficult to characterize. Some of the factors are highly dependent and influenced by the type of insulin and devices used in therapy. Development of future therapy products is therefore highly focused on how to minimize glycemic variability.

Injection Technique and Pen Needle Design Affect Leakage From Skin After Subcutaneous Injections.

Background: After a subcutaneous injection fluid might leak out of the skin, commonly referred to as leakage or backflow. The objective was to examine the influence of needle design and injection technique on leakage after injections in the subcutaneous tissue of humans and pigs. Method: Leakage data were obtained from a post hoc analysis of clinical trial data and from a pig study. Data from the clinical study were used to determine leakage as a function of injection volume, speed and region. Data from the pig study were used to determine leakage as a function of needle wall thickness, needle taper, injection angle, and wait time from end of injection to withdrawal of needle from skin. Results: Leakage volume was positively related to injection volume. Injections in the abdomen caused less leakage than thigh injections. A 32G needle caused less leakage than a 31G and a 32G tip (tapered) needle, and a “straight in” 90° needle insertion angle caused less leakage than an angled (~45°) insertion. Wait times of minimum 3 seconds caused less leakage than immediate withdrawal of the needle after injection. Needle wall thickness and injection speed did not influence leakage. Conclusions: Leakage will be minimized using a thin needle, using 90° needle insertion in the abdomen, injecting maximum 800 µL at a time, and waiting at least 3 seconds after the injection until the needle is withdrawn from the skin.

Influence of hypodermic needle dimensions on subcutaneous injection delivery--a pig study of injection deposition evaluated by CT scanning, histology, and backflow.

Thinner and shorter needles for subcutaneous administration are continuously developed. Previous studies have shown that a thinner needle causes fewer occurrences of painful needle insertions and that a shorter needle decreases the occurrence of painful intramuscular injections. However, little is known about local drug delivery in relation to needle length and thickness. This study aimed to compare deposition depth and backflow from three hypodermic needles of 3 mm 34G (0.19 mm), 5 mm 32G (0.23 mm), and 8 mm 30G (0.30 mm) in length and thickness.

A Physiological Model of the Effect of Hypoglycemia on Plasma Potassium

Background: Adrenaline release and excess insulin during hypoglycemia stimulate the uptake of potassium from the bloodstream, causing low plasma potassium (hypokalemia). Hypokalemia has a profound effect on the heart and is associated with an increased risk of malignant cardiac arrhythmias. It is the aim of this study to develop a physiological model of potassium changes during hypoglycemia to better understand the effect of hypoglycemia on plasma potassium. Method: Potassium counterregulation to hypokalemia was modeled as a linear function dependent on the absolute potassium level. An insulin-induced uptake of potassium was modeled using a negative exponential function, and an adrenaline-induced uptake of potassium was modeled as a linear function. Functional expressions for the three components were found using published data. Results: The performance of the model was evaluated by simulating plasma potassium from three published studies. Simulations were done using measured levels of adrenaline and insulin. The mean root mean squared error (RMSE) of simulating plasma potassium from the three studies was 0.09 mmol/liter, and the mean normalized RMSE was 14%. The mean difference between nadirs in simulated and measured potassium was 0.12 mmol/liter. Conclusions: The presented model simulated plasma potassium with good accuracy in a wide range of clinical settings. The limited number of hypoglycemic episodes in the test set necessitates further tests to substantiate the ability of the model to simulate potassium during hypoglycemia. In conclusion, the model is a good first step toward better understanding of changes in plasma potassium during hypoglycemia.

Pen needle design influences ease of insertion, pain, and skin trauma in subjects with type 2 diabetes

Objective Pen needles used for subcutaneous injections have gradually become shorter, thinner and more thin walled, and thereby less robust to patient reuse. Thus, different needle sizes, alternative tip designs and needles resembling reuse were tested to explore how needle design influences ease of insertion, pain and skin trauma. Research design and methods 30 subjects with injection-treated type 2 diabetes and body mass index 25–35 kg/m2 were included in the single-blinded study. Each subject received abdominal insertions with 18 different types of needles. All needles were tested twice per subject and in random order. Penetration force (PF) through the skin, pain perception on 100 mm visual analog scale, and change in skin blood perfusion (SBP) were quantified after the insertions. Results Needle diameter was positively related to PF and SBP (p<0.05) and with a positive pain trend relation. Lack of needle lubrication and small ‘needle hooks’ increased PF and SBP (p<0.05) but did not affect pain. Short-tip, obtuse needle grinds affected PF and SBP, but pain was only significantly affected in extreme cases. PF in skin and in polyurethane rubber were linearly related, and pain outcome was dependent of SBP increase. Conclusions The shape and design of a needle and the needle tip affect ease of insertion, pain and skin trauma. Relations are seen across different data acquisition methods and across species, enabling needle performance testing outside of clinical trials. Trial registration number NCT02531776; results.

A Study of Trained Clinicians’ Blood Glucose Predictions Based on Diaries of People with Type 1 Diabetes

OBJECTIVES How accurate can trained clinicians predict blood glucose concentrations? Good clinical treatment is, among other things, related to understanding the factors influencing blood glucose level. We analyze trained clinicians prediction accuracy in comparison with selected computer-implemented prediction algorithms and models. METHODS We have in this study included diaries of 12 people with type 1 diabetes. This test group consists of seven males and five females, ages 24 to 60, HbA1c 6.0 to 8.9 and a BMI between 20 and 28 kg/m2. Eight experienced clinicians tried to predict the blood glucose measurements based on minimum three days of diary history. Selected prediction algorithms and models were used for comparison. The reason we focus on type 1 diabetes is that it has the most critical insulin requirement, so accurate prediction can be more critical than for type 2. RESULTS An accuracy of 28.5% and an error of 26.7% were found from predictions made by the clinicians. A physiological model and an artificial intelligence model showed higher accuracy of 32.2% and 34.2% in comparison with the clinicians (p<0.05). A simple predictor algorithm based on the mean blood glucose history showed significant (p<0.05) lower total root mean square error compared to predictions made by the clinicians. CONCLUSION To predict blood glucose level from diaries has shown to be profoundly difficult even for experienced clinicians in comparison with predictions from computer algorithms and models. This suggests that computer-based systems incorporating predicting algorithms and models are likely to contribute positively to the day-to-day treatment of people with diabetes.

Skin blood perfusion and cellular response to insertion of insulin pen needles with different diameters.

Background: Today most research on pen needle design revolves around pain perception statements through clinical trials, but these are both costly, timely, and require high sample sizes. The purpose of this study was to test if tissue damage, caused by different types of needles, can be assessed by evaluating skin blood perfusion response around needle insertion sites. Method: Three common sized pen needles of 28G, 30G, and 32G as well as hooked 32G needles, were inserted into the neck skin of pigs and then removed. Laser Speckle Contrast Analysis was used to measure skin blood perfusion for 20 minutes after the insertions. Seven pigs were included in the study and a total of 118 randomized needle insertions were conducted. Histology was made of tissue samples inserted with 18G, 28G, and 32G needles, and stained to quantify red and white blood cell response. Results: Based on area under curve, calculated for each individual blood perfusion recording and grouped according to needle type, skin blood perfusion response relates to needle diameter. The response was significantly higher after insertions with 28G and hooked 32G needles than with 30G (P < .05) and 32G (P < .01) needles. Histology results were not significant, but there was a trend of an increased response with increasing needle diameter. Conclusions: Skin blood perfusion response to pen needle insertions rank according to needle diameter, and the tissue response caused by hooked 32G needles corresponds to that of 28G needles. The relation between needle diameter and trauma when analyzing histology was also suggested.