A Randomized Controlled Trial Testing the Influence of Three- and Seven-days Insulin Infusions and Two Types of Insulin on Hyperechogenicity in Subcutis and Glycemic Variables in Children and Adolescents With Type 1 Diabetes

Background An increasing proportion of patients with diabetes mellitus type 1 (T1D) is using diabetes devices in order to achieve better glycemic control, improved quality of life and more flexible lifestyle. Continuous subcutaneous insulin infusion (CSII) or insulin pumps are infusing small doses of insulin by a catheter fastened to the skin by an infusion set. Modern systems with automated insulin delivery as the precursor to the completely automated artificial pancreas, give algorithm-based corrections on basis of the interstitial fluid glucose measurement from the continuous glucose monitor (CGM). The first studies on these new more automated closed loop systems show improvements in time-in-range (TIR) but still with room for improvement. Several studies have observed better outcome in those treated with Medtronic 780g using the most aggressive targets (blood glucose target of 5.5 mmol/l and insulin action time of 2 hours). The ability of change in settings to predict future outcomes is though not explored and the importance of settings versus behavior is unknown. One type of behavior is timing of shift of insulin infu-sions set, prolonged use is associated with higher blood glucose, probably caused by decrease in absorption. Other studies indicate that the depth of subcutaneous tissue may also be important, since buttocks seems to be better than abdomen in small children The absorption of insulin is a very important measure that potentially could vary a lot in relation to both age, sex, timing, exercise, blood flow and a whole range of other aspects, but especially also according to the tissue that insulin is infused into. The skin site used for the infusion set is therefore increasingly im-portant, and this could therefore account for at least some of the glycemic variability seen even in pa-tients using these highly automated systems. New infusions set with extended wear time have been developed and tested in adults showing good results although tendency to increase in sensor glucose after 6 days. The extended wear time have not been tested in children and none have examined the extend of lipohypertrophy with extended wear time or the importance of skin depth.

Ultrasound have shown promising results to investigate the skin depth as well as subcutaneous areas by means of both density and vascularity. Regarding the density of tissue, hyper- and hypo- echogenicity are important measures that might reflect different grades of lipohypertrophy. Lipodystrophy (lipo-hypertrophy and lipoatrophy) are a well-known complications to insulin infusion. The importance of type of insulin has only been investigated in cross-sectional designs finding no differences related to insulin type. Just one old study showed a positive effect of changing from fast-acting to rapid-acting insulin on lipohypertrophy. Similar there is low evidence for the importance of insulin type on lipoatrophy which is also a rare condition. Current guideline recommend change in type of insulin with lipoatrophy whereas if experiencing lipohypertrophy patients are asked to find new areas for infusion. Another newly study have also shed light on the subcutis and the findings of lipohypertrophy or pre-clinical lipohypertrophy by ultrasound. A study similarly found proportions of hyperechogenicity among 60%-75% of all insulin pump users, with as well neovascularization in about 10% of the users. These findings that may reflect fibrosis, inflammation, or lipohypertrophy seems im-portant to investigate and test how to prevent them from arising.

The attachment of infusions sets to the skin provoke allergenic or toxic eczema and prolonged wear time seems to increase the risk of this complication. On the other site fewer skin stripping episodes with longer wear time may be beneficial for the skin, therefore comparing the occurrence of eczema and the skin barrier in users of 3 and 7 days infusions set is highly relevant. The subtle nonvisible changes in the skin could be level of natural moisturizing factor (NMF) which can be investigated by tape strips. The skin barrier can also be studied by electric impedance spectroscopy (EIS) a new method that have been shown to detect skin barrier dysfunction in normal looking non-lesional skin of children and predict who is more likely to develop atopic dermatitis. It is able to discriminate between skin without visible changes and healthy skin as well as show a significant increase in EIS that correlated with healing. EIS has also been used to study irritancy from detergents which may be a good surrogate for skin irritation at diabetes treatment sites. Recent studies have been in animal models but historically irritation ( e.g. from sodium laural sulfate has been studied quite extensively with EIS in humans. The microcirculation may be an important marker of skin recovery and skin inflammation seen as hyperemia. Tissue Viability Imaging (TiVI) uses polarization light spectroscopy to study micro vascularization by esti-mating the red blood cell (RBC) concentration in the skin. The method is very robust and offers instantaneous capturing of data and low variability, though normal values for children and different areas are scarce. The non-invasive properties make EIS and TiVi promising new tools for detecting early signs of skin impairment and changes that could reveal if skin have been impaired by the infusions set and guide when to reuse a site.

4. Aim The primary aim of present study is to investigate if the use of three days insulin infusion set is superior to seven days in preventing the occurrence of hyperechogenicity in areas recently used for insulin infusion and if the type of insulin matter comparing insulin aspart - Novo Rapid, or insulin lispro - Humalog. Second-ly, to estimate the glycemic variables/day of using the infusions set within the recommended period or outside recommendations (> 72 hours for three-days set and > 168 hours for seven-days set). Thirdly, to investigate occurrence of eczema and skin barrier changes depending on the use of three- or seven-days infusions set.

5. Study design Study type and design: Randomized controlled intervention study with crossover between 3 and 7-days infusions set and randomised to Novorapid or humalog