Insulin, Not the Preservative m-cresol, Instigates Loss of Infusion Site Patency Over Extended Durations of CSII in Diabetic Swine

Insulin induces a progressive increase in the resistance of subcutaneous tissue to fluid flow: Implications for insulin pump therapy

“… 19 , 20 Furthermore, a study comparing subcutaneous tissue responses to infusion cannulas delivering various infusion fluids to diabetic swine found that, 7 to 10 days after cannula insertion, the cell density in the tissue surrounding the cannulas for insulin infusion was substantially higher than that in the tissue surrounding the cannulas for saline infusion. 21 In view of these findings, it seems very likely that collagen fibrils and cells, such as macrophages and fibroblasts, progressively accumulated in the tissue adjacent to the insulin infusion site and thus may have diminished the available area for fluid flow and increased the path length for fluid flow by imposing a tortuous pathway. This, in turn, may have increased the resistance to fluid flow.…”

“…Since the power required for pumps to drive the fluid flow is proportional to the flow resistance, 10 an increase in TFR after prolonged use of an infusion site will also be accompanied by an increase in the power consumption of the pump. Thus, pumps used for administering insulin into the same tissue site over extended durations of time (ie, beyond the recommended duration of 2‐3 days 3 , 21 ) will draw more power from their batteries, resulting in decreased battery life. Consequently, to maintain a sufficient battery life, the batteries of such pumps may have to be enlarged or their energy density increased.…”

Improving the Patient Experience With Longer Wear Infusion Sets Symposium Report

“…Preservatives play a crucial role in insulin stability by preventing insulin aggregation and subsequently, local inflammation. 16 Dynamic light scattering has shown greater formation of insulin aggregates with infused insulin containing reduced preservative concentrations compared to normal preservative concentrations. Furthermore, an in-vitro macrophage cell culture study has observed an increased amount of associated cytokine production from insulin containing reduced preservative concentrations compared to normal concentrations.…”

Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia

“…It is well-established that removal of PP from the insulin solution can lead to protein aggregation. ,,, Thus, we further hypothesize that development of real-time in-line devices that can remove PP immediately prior to insulin infusion in vivo would maintain insulin stability during storage while minimizing PP toxicity and inflammation during infusion, thus ensuring effective blood glucose control in vivo . Despite convincing data demonstrating the chemotoxicity of PP used in insulin formulations, , Swinney et al recently reported that insulin itself and not the insulin phenolic preservatives are responsible for inflammation at the site of infusion pump sets . In these studies, regular insulin with and without 2.5 mg/mL m -cresol was infused into subcutaneous swine tissue for up to 10 days.…”

“…Despite convincing data demonstrating the chemotoxicity of PP used in insulin formulations, 34,35 Swinney et al recently reported that insulin itself and not the insulin phenolic preservatives are responsible for inflammation at the site of infusion pump sets. 38 In these studies, regular insulin with and without 2.5 mg/mL m-cresol was infused into subcutaneous swine tissue for up to 10 days. Subsequently, the tissue responses to these agents were compared.…”