Tissue Histology Surrounding Continuous Subcutaneous Insulin Infusion (CSII) Catheters Implanted in Canines for 7 Days

M Wiltshire, A Dinesen, J Hauzenberger, J Vidas , J McGavin , C Loeum, A Ebelin, Y Trimba, T Kaner, M Pate, M Joseph, A Pantoja, M Torjman, and J Joseph.

Jefferson Artificial Pancreas Center, Department of Anesthesiology, Sidney Kimmel Medical College, Thomas Jefferson University

Introduction

§ We are trying to understand the mechanisms that causevariable insulin absorption when infused through acommercial CSII catheter into the subcutaneous tissue.

§ A pilot observational canine study was performed toevaluate the PK-PD of insulin lispro absorption and thetissue histology surrounding CSII catheters implanted for 7days.

§ Insulin absorption into the circulation may be affected byvariable capillary blood flow, insulin transport across theendothelium, lymph flow, insulin sequestration within thewound, degradation by proteases, and transport upwardalong the cannula onto the skin surface.

§ Manufacturers and clinicians recommend insertion of a newCSII catheter at an alternate location every 2 to 3 days tominimize the risk for hyperglycemia, hypoglycemia, DKAand infection.

Methods

§ IACUC approval§ 13 adult mongrel female non-diabetic canine~ 30 kg§ Two Teflon CSII catheters (Quickset, Medtronic MiniMed)

and 3 CGM (Guardian G4, DexCom) were inserted into thesoft underbelly of each canine using general anesthesia.

§ One CSII catheter was continuously infused with insulinlispro (basal rate 0.1 unit/hour), while the other catheter wasfilled with saline and capped.

§ Glucose clamp experiments were performed days 1, 3, 6, &7 after implantation (hyperinsulinemic-euglycemic clamp).

§ Glucose clamps used a bolus of insulin lispro (0.1 unit/kg)only (n= 5), insulin lispro plus tissue plasminogen activator(n=3), insulin lispro plus streptokinase (n=3), insulin lisproplus streptokinase plus mechanical vibration (n=1), andinsulin lispro plus tissue plasminogen activator plusmechanical vibration (n=1).

§ The skin and subcutaneous tissue surrounding the CSIIcatheters were excised, fixed with 10% formalin, sectioned,and stained.

§ A surgical pathologist is currently analyzing the slides todetermine the degree of tissue damage, inflammation, andthrombus in relation to adjacent vascular adipose tissue.

Results

Discussion

References1. Schmid V, Hohberg C, Borchert M, Forst T, Pfützner A. Pilot

study for assessment of optimal frequency for changing catheters in insulin pump therapy-trouble starts on day 3. J diabetes Sci Technol . 2010;4(4):976-982.

2. Clausen TS, Kaastrup P, Stallknecht B. Effect of insulin catheter wear-time on subcutaneous adipose tissue blood flow and insulin absorption in humans. Diabetes Technol Ther. 2009;11(9):575-580. doi:10.1089/dia.2009.0058

3. Onuki, Y, Bhardwaj U, Papadimitrakopoulos F, Burgess D, A Review of the Biocompatibility of Implantable Devices: Current Challenges to Overcome Foreign Body Response, J Diabetes Sci and Technol, Vol. 2, Issue 6; 20081003-13.

4. Richter W, Bhansali S, Morris M, Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration, The AAPS Journal, Vol. 14, No. 3, September 2012, DOI: 10.1208/s12248-012-9367-0

§ CSII catheters implanted for 7 days produced a variableamount of damage to adipose cells, connective tissue,capillaries, lymphatic vessels and skeletal muscle cells.

§ All of the CSII cannulas were parti ally or completelysurrounded by a layer of inflammatory tissue (containingneutrophils, macrophages, cellular debris, and fibrous tissue).

§ Canine subcutaneous tissue had layers of skeletal muscleand mammary tissue mixed within the adipose tissue.

§ The layer of inflammator y tissue surrounding CSII cathetersinfused with insulin lispro only, insulin lispro plusstreptokinase, and insulin lispro plus tPa varied in thickness,composition, density, and continuity

§ The layer of inflammator y tissue surrounding CSII cathetersfilled with saline and capped was similar to layer ofinflammatory tissue infused with insulin.

§ The tissue surrounding the CSII catheters infused withlispro only (control group), tissue plasminogen activator, orstreptokinase had minimal thrombus.

Results

-RI GHT

RA-RI GHT

Figure 2: Lispro Insulin

Figure 4: Lispro Insulin + Streptokinase

Figure 3: Lispro Insulin + tPa

Results

§ The layer of inflammatory tissue that surrounds a CSIIcannula may inhibit or slow the flow of insulin into adjacentvascular subcutaneous tissue.

§ There was a variable degree of tissue damage and variableamount of inflammatory tissue.

§ The layer of inflammatory tissue was variable in thickness,density, composition, and continuity.

§ The tissue histology surrounding the CSII cannula wasgrossly similar when infused with insulin lispro only, lisproplus tPa, lispro plus streptokinase, and filled only with saline.

§ A detailed analysis of the tissue histology is currently beingcompleted by a surgical pathologist.

Figure 1: Cross section of Teflon CSII catheter showing layer of inflammatory tissue and adjacent adipose tissue.

Funded by an Innovation Award from the Juvenile Diabetes Research Foundation