Six Sensor CGM Array- Which do you trust? Data from subject D2 Joseph

Non-Closed Loop Insulin Administration Approaches A. Types- MD judgment, paper protocols, order-entry systems, computerized algorithms B. No adjustment for insulin sensitivity (Portland, PID computer protocols)- may take longer to goal # C. Adjusts for Insulin Sensitivity- Yale, U. Wash, Glucommander- faster but > risk hypoglycemia Ideally, want BOTH : faster, without hypoglycemia ; ULTIMATELY ALL SUFFER FROM HUMAN INTERFACE ISSUES SO COMPUTERIZED ALGORITHMS IN CLOSED-LOOP CGMS DATA MAY BE SAFEST, LEAST RESOURCE INTENSIVE, APPROACH Ideally, adjustable goal - ‘dial-in’ to fit sensor issues, different ICU’s, types of patients, different ICU directors! Steil,g., ICY insulin Delivery Algorithms, J. Diabetes Sci Technol 3:125,2009

Efficiency, nurse compliance Computerized Algorithms to Regulate Glucose in ICU- Potential to Compensate for Imperfect Sensors Patient safety Efficiency, nurse compliance Decrease workload, reduce cognitive failure Improve control, decrease hypoglycemia Proportional Integrative Derivative- Proportional- absolute deviation, # vs. goal, Integral – trends- leads to ‘basal’ insulin Derivative- rate of change- leads to ‘correction factor’ Model Predictive Control- uses multiple variables to model the behavior of glu/ ins in ICU- potential for less variability- but if don’t include an important variable, can be ‘off the track’ Hoekstra Critical Care 2009,13:223

Computerized Glucose Regulation in the ICU PID advantage in hospital where multiple variables May apply that are not in MPC model !!! Or use MPC to monitor PID result, to supervise/ detect possible sensor failure/ Detect change in patient condition

Hospital Closed Loop discrete PID algorithm From the Stanford PICU study. Data shows example control achieved using reference blood glucose (BG) readings and discrete PID insulin infusion. Generation 4 sensor performance shown in blue (2006 ADA).

Mathematical Modeling to predict glycemia in ICU in order to Test Insulin Infusion Algorithms eMPC

Methods- Sites of Delivery; (1) multiple daily (subcutaneous) insulin injection (MDII) (2) continuous subcutaneous insulin infusion (CSII) ,better but not rapid enough effects for sudden changes seen in critical care (3) intravenous insulin infusion (IVII), best for critical care Drawbacks = obstruction of insulin infusion catheter, phlebitis, catheter related infection (4) continuous intraperitoneal insulin infusion (CIPII)- physiologic, but too many issues Control is inferior to IVII in cases of high BG variability, eg: critical care Not suitable with abdominal diseases including peritonitis and abdominal surgery. Catheter-related complications (e.g., occlusions, aggregation of insulin, local infections) Production of anti-insulin antibodies. High cost Meds to be delivered Glucose/ Insulin/ Glucagon- ? Incretin, Pramlintide Hoshino, J Artif Organs (2009) 12:141–149

So, Given CGMS in ICU SETTING IS STILL HAMPERED BY 1. Relative Inaccuracy of sensors 2. Site/ Sensor Issues 3. Changing Insulin Sensitivity 4. Human Interface Issues One can have ALGORITHM ADJUST FOR THESE VARIABLES , but, knowing error rates, ADJUST GOAL to AVOID HYPOGLYCEMIA

Hyperinsulinemic-Normoglycemic Clamp Technique in Cardiac Surgery 70 non-DM 40 DM Target 3.5-6.1mM (This is a low range, ~65-110 Insulin 5mu/kg/min; d20, varying rates Hypoglycemia ] <60 [ Sato, Nutrition, 2010

Set algorithm 120mg% (6.6 mM), to avoid Hypoglycemia eg: Compensate for Imperfect Sensors, Clinical variables- ePID, External Closed-Loop Clinical Study 9/12/2018 9:00 PM Aggregate Closed-Loop Results vs. Normal Glucose Tolerant Profile (UCLA Clinical trial, n = 10 T1DM, n = 18 NGT) Dial-up range one wishes!! Diabetes 2006; 55(12): 3344–3350.

JDRF Potential Pathway to an Artificial Pancreas From Safety/ Regulary point of View 1 2 Hypo/Hyper Minimizer 3 Very Low Glucose a Insulin Off Pump Hypoglycemia Minimizer START Fully Automated Insulin + Anti-insulin Closed Loop 6 Fully Automated Insulin Closed Loop 5 Automated Basal / Hybrid Closed Loop 4 END

How to Speed up? 12

Work Forward to Achieve Ideal Process- Where Do We Go From Here? Closed- Loop Continuous Monitoring In Critical Care --Back to the Future-- SAFETY IS OVERRIDING PRINCIPLE- Aim for lowest glucose possible without hypoglycemia (<80 Need Now- ROI exists- Live with what we have now- adjusting algorithms to current sensor limitations- Adjust DESIGN and USAGE of Imperfect Tools until IDEAL available Work Forward to Achieve Ideal

The Ultimate Goal: Full Normalization of Glycemia 9/12/2018 9:00 PM The Ultimate Goal: Full Normalization of Glycemia Medtronic Diabetes has a goal of working toward the development of an artificial pancreas. We have two versions of a closed-loop system under development and clinical testing. An external system using the subcutaneous glucose sensor working in combination with the external pump, and a fully implanted system utilizing a long-term chronically implanted vascular sensor with our implanted insulin pump which provides intraperitoneal insulin delivery. THANK YOU!! Diabetes 2004; 53(5): 1201–1207.