Inflammatory Response to CSII Catheters in a Tummy Tuck Model

Study Overview
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Brief Summary
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In insulin pump therapy, insulin is continuously infused into the subcutaneous adipose tissue via a continuous subcutaneous insulin infusion (CSII) catheter using a basal/bolus pattern. Unfortunately, insulin absorption from the tissue surrounding a CSII catheter can be slow, variable, and unreliable. It is recommended to replace CSII catheters after 2 to 3 days of use. Frequently changing the injection site can be tedious and moreover leads to scarring, while reusing the same injection site can lead to medical complications such as lipohypertrophy. CSII catheters are manufactured from both steel and Teflon and use of either of these materials is based on personal preference/experience rather than scientific, empirical data. We hypothesize that the inflammatory response to CSII catheters is a major contributor to variable insulin absorption and that this response is significantly different between materials and catheters shapes. In order to develop CSII catheters with an extended life-time up to 7 days, we need to better understand the inflammatory response caused by the introduction and maintenance of a CSII catheter into the subcutaneous adipose tissue. This study is a pilot study in humans scheduled for elective plastic surgery where a large skin flap is removed from the abdominal region. Teflon and steel CSII catheters will be inserted into the abdomen 7, 4, and 3 days prior to surgery. This study design allows for the removal of tissue plugs surrounding CSII catheters without causing additional scarring for the patient.

Detailed Description
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Background: Approximately one million patients worldwide manage their diabetes with an insulin pump. Insulin is continuously infused into the subcutaneous adipose tissue via a Continuous Subcutaneous Insulin Infusion (CSII) catheter using a basal/bolus pattern that can be adjusted by the patient according to meal times, mimicking the natural function of the pancreas. One major advantage of this form of therapy is the improvement of living quality. Compared to multiple daily insulin injections, the catheter has to be inserted only once every 2-3 days where it remains within the subcutaneous tissue. This is especially advantageous for children of young age. Unfortunately, insulin absorption from the tissue surrounding a CSII catheter can be slow, variable, and unreliable. It is recommended to replace infusion sets and CSII catheters after 2 to 3 days of clinical use. After this time, blood glucose control becomes difficult for the patient because insulin absorption from the subcutaneous tissue into the blood stream and lymphatics becomes highly variable. The underlying mechanisms for impaired insulin absorption are poorly understood and the knowledge of rotating the site of injection is based on user experience. Frequently changing the injection site can be tedious and moreover leads to scarring, while reusing the same injection site can lead to medical complications such as lipohypertrophy. In order to develop CSII catheters with an extended life-time up to 7 days, there is a need to better understand the inflammatory response caused by the introduction and maintenance of a CSII catheter into the subcutaneous adipose tissue. The clinical use of a 7-day CSII catheter with low pharmacokinetics (PK) variability will significantly improve blood glucose control, decrease the risk for hypoglycemia, increase compliance, and decrease cost. Since continuous glucose monitoring (CGM) devices are approved for 7-day wear time, the development of a CSII catheter with extended lifetime is also crucial for the development of single-port artificial pancreas (AP) systems where CSII and CGM are combined in one catheter, mimicking pancreatic function. Furthermore, the improvement of catheter longevity will reduce insertion sites and scars. This is especially important for children with a smaller body surface area. The choice of one material over the other is largely based on the patient's personal preference, his or her endocrinologist's or diabetes educator's opinion and therapy costs. There is a trend in both the United States and Europe towards using Teflon sets (90 % and 75 %, respectively) but approximately 40 to 45 % of pump users in Germany use steel catheters. Compared to Teflon, steel catheters are easier to insert and are less prone to kinking, and can be worn by patients allergic to Teflon. Patients using steel catheters report better metabolic control, less variable insulin absorption and less unexplained hyperglycemia (Heinemann 2016; Reichert et al. 2013). However, especially during exercise, steel may cause discomfort and the softer and more flexible Teflon catheter is assumed to be more comfortable to wear. The wear-time of the CSII catheter considerably varies between patients (from 2 to 10 days), although recommendations for the optimal frequency of changing an insulin infusion set (2 days for steel and 3 days for Teflon) exist. In a prior pig study the inflammatory response to commercial CSII catheters comparing steel, Teflon and Teflon with an anti-inflammatory coating was analyzed. There was significant reduction in area of inflammation and macrophage recruitment around the non-coated and coated Teflon catheters. Steel elicited the most severe inflammatory response with significantly higher fibrosis. Although the pig has proven to be an excellent model for the study of human skin and adipose tissue, there is an urgent medical need to confirm these findings in a human model. For the histopathological and molecular analysis of subcutaneous tissue in the vicinity of the catheter, large amounts of tissue need to be excised from the site of interest. This makes a human study almost impossible. Nevertheless, the generation of human data is crucial and a lot of this important information is still lacking in diabetes research and treatment. The possibility to excise extensive amounts of tissue without causing additional scars or pain (except that caused by the abdominoplasty itself) for the patient presents the main benefit of this study setup. Aim: The aim of this study is to compare the inflammatory response to commercially available CSII catheters of two different materials (steel and Teflon) over 1 day, 4 days and 7 days of wear-time in humans scheduled for elective plastic surgery (abdominoplasty). Hypothesis: Conventional steel CSII catheters elicit a more severe acute inflammatory response in the subcutaneous adipose tissue than Teflon CSII catheters. H0 = there is no difference in mean area of fibrin deposition around catheters H1 = there is a significant difference in mean area of fibrin deposition between catheters

Official Title
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A Pilot Study for the Systematic Evaluation of the Inflammatory Response to Commercially Available Insulin Infusion Catheters in Subcutaneous Adipose Tissue

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Device: Continous Subcutaneous Insulin Infusion Catheter


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, age 18 years or older Scheduled elective abdominoplasty at the Dpt. of Plastic Surgery, Medical University of Graz Signed informed consent form Exclusion Criteria: Allergy to Teflon or steel Known skin diseases (atopic dermatitis, psoriasis) History of immunodeficiency diseases Patients on glucocorticoid or other immunomodulating therapy History of bleeding disorder Pregnancy or planned pregnancy Unable to fully understand study procedures and to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Non-diabetic patients scheduled for selective plastic surgery (abdominoplasty).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insertion of Insulin Infusion Catheters<br>Non-diabetic patients scheduled for abdominoplasty will be inserted continuous subcutaneous insulin infusion (CSII) catheters of two different materials into the part of the abdomen which will be removed during surgery. | Device: Continous Subcutaneous Insulin Infusion Catheter<br>* Catheters will be inserted into the abdomen of each patient using aseptic technique according to the following schedule: (1) 8 days before surgery, (2) 4 days before surgery and (3) 1 day before surgery (Table 1). At each time point 2 steel (Medtronic Sure-T, 9 mm) and 2 Teflon (Medtronic Quick-set®, 9 mm) CSII catheters will be inserted into the subcutaneous abdominal tissue. In total, 12 catheters will be inserted into each patient's abdomen using only the area predefined by the plastic surgeon for removal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area of inflammation (mm2) | Assessed by microscopy; area of inflamed tissue, including cell infiltration, necrosis, fibrin/collagen deposition | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area of fibrin deposition (mm2) | Assessed by microscopy; area of fibrin | 7 days | 
| Area of fat necrosis (mm2) | assessed by microscopy; area of necrosed adipocytes | 7 days | 
| Inflammation distance (mm) | assessed by microscopy; distance from skin surface to lowest point of microscopically assessed inflammation | 7 days | 
| Cytokine gene expression (fold change) | Assessed by qPCR; relative fold change in gene expression compared to non-traumatized tissue (IL-1b, TNFa, TGFb, IL-6, IL-8, IL-10) | 7 days | 
| Macrophage marker gene expression (fold change) | Assessed by qPCR; relative fold change in CD68 gene expression compared to non-traumatized tissue | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Insulin Pump Therapy, Continuous Subcutaneous Insulin Infusion