A Patient Safety Initiative For Insulin Pumps

A Patient Safety Initiative For Insulin Pumps Manufacturing Standards to improve insulin pump safety and medical outcomes Suggestions for improvements and editorial changes are welcome. Send comments to: John Walsh, PA, CDE at jwalsh@diabetesnet.com and Ruth Roberts, MA rroberts@diabetesnet.com (619) 497-0900 Version 2: 09/28/09Version 1: 12/07/08

Definitions • TDD – total daily dose of insulin (all basals and boluses) • Basal –background insulin pumped slowly through the day to keep BG flat • Bolus – a quick surge of insulin as • Carb boluses to cover carbs • Correction boluses to lower high readings that arise from too little basal insulin delivery or insufficient carb boluses • Bolus On Board (BOB) – the units of bolus insulin with glucose-lowering activity still working from recent boluses • Duration of Insulin Action (DIA) – time that a bolus will lower the BG. This is used to calculate BOB.

Background • Although insulin pumps * were first designed to improve insulin delivery, new technology has transformed them into data collection centers. Additional data from continuous glucose monitoring devices increases the data’s value. • Data necessary for monitoring and clinical decisions is now directly accessible in the pump itself. With regular glucose testing and data analysis, a pump can provide important clinical information to users and clinicians regarding glucose and insulin dosing patterns with recommendations for improvement. * “Pump” collectively refers to the pump body, PDA, cell phone, and other devices that control insulin delivery and store data.

Over 500,000 insulin pumps are in use around the world, yet there are no formal guidelines regarding manufacturing standards and medical practice in the diabetes clinical community and pump manufacturing industry. These suggested standards are intended as imprements for future insulin pumps and in current pumps where software changes allow. They are designed to: Provide safer dosing increments and problem solving to pump users Allow clinicians to make safer and more informed dosing decisions when managing a variety of pumps Facilitate the training of adjunctive medical and accessory personnel (ER, surgical, school nurses, etc.) to improve their familiarity and interactions with insulin pumps Introduction

Benefits Of Insulin Pump Standards These mechanical standards are designed for: • Consistent use of pump settings between pump manufacturers • Accuracy and safety of carb and correction factor increments • Safety of DIA defaults and consistent use of DIA increments • Consistent handling of BOB and insulin stacking • Improved monitoring for hypoglycemia & hyperglycemia • Direct entry of glucose values into bolus calculations • Notification when use of correction boluses is excessive • Faster identification of control issues caused by infusion sets

# Topic Carb Factor Increments Correction Factor Increments Carb Factor Accuracy Correction Factor Accuracy DIA Default Times DIA Time Increments Handling Of BOB Overview Slides are numbered by topic for easy reference. # Topic 8. Multi-Linear And Curvilinear DIA 9. Hypoglycemia Alert 10. Hyperglycemia Alert 11. Correction Bolus Alert 12. Insulin Stacking Alert 13. Automatic Entry Of BG Values 14. Infusion Set Monitoring

Increments and Accuracy Carb factor Correction factor DIA Defaults DIA Handling Of BOB Hypo Manager Safety # Topic • Alerts • Hypo frequency • Hyper frequency • Unusual highs • Correction Bolus Excess • Insulin Stacking • Overview table of alert frequency 13. Infusion Set Monitor

BOB TDD Correction bolus % Carb bolus % Basal % Avg glucose SD Carbs/day with approximate calorie equivalent Accurate carb and correction factors Automatic basal and factor testing How often bolus recommendation is overridden and direction Frequency of occlusions and stops (and length of stops) Easy Data Access

ReviewChange in TDD Changes The BG For some later slides, it helps to know how a change in the TDD affects the glucose levels. Using a modified Davidson Rule for the carb factor and a 2000 Rule for the correction factor: • 1.25% change in the TDD changes glucose levels about 25 mg/dl when given as a single dose • A 5% change in the TDD is equivalent to about a 25 mg/dl rise or fall in the glucose through the day • A 5 to 6% change in the carb factor (approx. 2.5% to 3% of the TDD) changes the glucose about 20 mg/dl per meal.

1 Carb Factor Increments Carb Factor (CarbF): the number of grams of carb covered by 1 u of insulin for an individual The smaller the carb factor, the larger a carb bolus

1 Standard For: Carb Factor Increments Carb factor increments shall be less than or equal to 5% of the next larger whole number so that each single step adjustment causes subsequent carb boluses to change by no more than 5% from previous doses. Recommended minimum carb factor increments: 5 1.0 g/u above 20 g/u 0.5 g/u for 10 to 20 g/u 0.2 g/u for 5 to 9.8 g/u 0.1 g/u for 3 to 4.9 g/u 0.05 g/u for 0.1 to 2.95 g/u 5 Improved carb factor increments recommended by Gary Scheiner, MS, CDE

Carb Factor (CarbF) Increments 1 Issue: Existing carb factor increments are too large. Current carb factors are a safety concern because they lack the precision required to avoid excessive hyperglycemia and hypoglycemia, especially for smaller carb factor numbers.

ExampleCarb Factor Increments 1 • 1 gram per unit is the smallest CarbF increment in most pumps. This increment is relatively large for CarbFs lower than 15 or 20 g/u. • For instance, when the carb factor is reduced from 10 to 9 g/u, all subsequent carb boluses are increased by 11.1%. A shift in the carb factor from 1u/5g to 1u/4g causes each subsequent carb bolus to increase by 25%. • For most pump users, a change in carb factor of 5 to 6% causes the average glucose to rise or fall by at least 20 mg/dl after all meals.

ExampleImpact On BG From CarbF Adjustment 1 Table shows average additional fall in glucose when a carb factor is reduced from 10 gram/u to 9 gram/u. ** More carbs = greater glucose fall * Calculated as carbs in meal – carbs in meal X 1900 new carb factor old carb factor TDD

ReviewMedian Carb Factor 1 In unpublished data from the Cozmo Data Analysis Study for 135 pump users in good control* (avg BG = 144.0 mg/dl with 4.92 tests/day): • The average carb factor was 10.4 g/u • Nearly all use a carb factor below 20 g/u • Almost 50% of carb factors are 10.0 g/u or less. • The smaller the carb factor, the more vulnerable the pumper is to error when an increment is changed * Authors’ unpublished data from subset of over 1,000 complaint-free insulin pumps turned in for software upgrade in 2007.

What Current Changes In CarbFs Do 1 Table shows how subsequent carb boluses are affected by a one-step reduction in the CarbF using different CarbF increments. Yellow area shows values for most current pumps. Green areas show safer increments that impact subsequent boluses less than 5%.

2 Correction Factor Increments Corr Factor (CorrF): the number of mg/dl (mmol) drop in glucose that is produced by 1 u of insulin for an individual The smaller the corr. factor, the larger a corr. bolus

2 Standard For: Correction Factor Increments For similar reasons, correction factor increments shall be 5% or less of the next larger whole number so that each single step adjustment causes subsequent correction boluses to change by no more than 5% from previous doses. Recommended minimum correction factor increments: 5.0 mg/dl per u above 80 mg/dl per u 2.0 mg/dl per u for 40 to 78 mg/dl per u 1.0 mg/dl per u for 20 to 39 mg/dl per u 0.5 mg/dl per u for 10 to 19.5 mg/dl per u 0.2 mg/dl per u for 5 to 9.8 mg/dl per u 0.1 mg/dl per u for 3 to 4.9 mg/dl per u 0.05 mg/dl per u for 0.1 to 2.95 mg/dl per u

3 Carb Factor Accuracy Carb Factors are often not physiologically appropriate

3 Standard For: Verification Of Carb Factor Accuracy Insulin pump companies shall record and publish each year the carb factors used in insulin pumps returned for upgrade or repair. This report will include sufficient numbers of pumps to ensure statistical significance for commonly used carb factors between 5 and 20 grams per unit. This data is designed to ensure that pump training and clinical followup are assisting in the selection of accurate carb factors. To improve accuracy of carb factors, efforts shall be taken to better train clinicians and users in appropriate selection of physiologic carb factors.

Personal Carb Factors 3 Issue: Many carb factor settings in today’s insulin pumps today are physiologically inappropriate. Inappropriate carb factors introduce a significant source for error in carb bolus calculations.

Review Carb Factors In Use 1 3 Carb factor settings from 405 Cozmo pumps do NOT have a bell-shaped (physiologic) distribution. “Easy” numbers – 5, 10, 15, and 20 g/unit – are preferred. 10 7 115 20 1

4 Correction Factor Accuracy

4 Standard For: Verification Of Corr Factor Accuracy Insulin pump companies shall record and publish each year the correction factors used in insulin pumps returned for upgrade or repair. This report will include sufficient numbers of pumps to ensure statistical significance for commonly used correction factors between 20 and 80 mg/dl per unit. This data is designed to ensure that pump training and clinical followup are assisting in the selection of accurate correction factors. For more accurate selection of corr. factors, efforts shall be taken to improve corr. factor selection and to automate corr. factor testing.

Personal Correction Factors 4 Issue: Many correction factors used in insulin pumps today are poorly tuned to the user’s need. This inaccuracy significantly magnifies other sources of error in correction bolus calculations.

Review Correction Factors In Use 1 4 Avg. correction factors in use for 452 consecutive Cozmo insulin pump downloads Like carb factors, correction factors in use are NOT bell-shaped or physiologic. A more accurate choice of correction factors would create a bell-shaped curve. Users or clinicians appear to frequently select “magic” numbers for correction factors. 10 7 115 20 1

5 DIA Default Times

5 Standard For:DIA Default Times Default duration of insulin action (DIA) times in current pumps vary between 3 and 6 hours. In bolus calculations, a short DIA time shall be set no shorter than 4.5 hours in pumps that determine DIA in a linear fashion and no shorter than 5 hours in pumps that determine DIA in a curvilinear or multi-linear fashion for fast insulins (lispro, aspart, and glulisine) in use at this time.

DIA Default Time Settings 5 Issue: DIA measures the glucose-lowering activity of a carb or correction bolus over time. Current default times for DIA range from 3 to 6 hours in different pumps. • The DIA is often considered another tool to “improve control” rather than being set at an appropriate value and focusing on more appropriate changes in basal rates or carb and correction factors to improve control. • A DIA that is too short allows excess unrecognized bolus insulin to accumulate, usually in the afternoon and evening hours. • Example: for a DIA of 2.5 hrs, a bolus given at 9 am appears to have no activity after 11:30 am. If a high BG occurs at 11:45 am, more bolus than needed will be given. At lunch, the bolus will be excessive, regardless of the BG at that time, creating stacking and a high likelihood of hypoglycemia.

ReviewHow Long Do Boluses Lower The BG? 5 • Numerous GIR studies show rapid insulins lower the glucose for 5 hours or more. • With Novolog (aspart) at 0.2 u/kg (0.091 u/lb), 23% of glucose lowering activity remained after 4 hours.12 • Another study found Novolog (0.2 u/kg) lowered the glucose for 5 hours and 43 min. +/- 1 hour.13 • After 0.3 u/kg or 0.136 u/lb of Humalog (lispro), peak glucose-lowering activity was seen at 2.4 hours and 30% of activity remained after 4 hours. 11 These times would be longer if the unmeasured basal suppression in pharmacodynamic studies were accounted for. 11 From Table 1 in Humalog Mix50/50 product information, PA 6872AMP, Eli Lilly and Company, issued January 15, 2007. 12 Mudaliar S, et al: Insulin aspart (B28 Asp-insulin): a fast-acting analog of human insulin. Diabetes Care 1999; 22:1501-1506. 13 L Heinemann, et al: Time-action profile of the insulin analogue B28Asp. Diabetic Med 1996;13:683-684.

ReviewShort DIAs Hide Bolus Insulin Activity 5 A short DIA time hides true BOB level and its glucose-lowering activity. This can be a safety issue in that it: • Leads to “unexplained” lows • Leads to incorrect adjustments in basal rates, carb factors, and correction factors • Causes users to start ignoring their “smart” pump’s advice An inappropriately long DIA time overestimates bolus insulin activity – this leads to underdosing rather than overdosing on subsequent boluses. DIA should be based on an insulin’s real action time. Do NOT modify the DIA time to fix a control problem

ReviewDuration Of Insulin Action (DIA) 5 Accurate bolus estimates require an accurate DIA. DIA times shorter than 4.5 to 7 hrs may hide BOB and its glucose lowering activity Glucose-lowering Activity 0 6 hrs 2 hrs 4 hrs

ReviewDIA 5 Large doses (0.3 u/kg = 30 u for 220 lb. person) of “rapid” insulin in 18 non-diabetic, obese people Med. doses (0.2 u/kg = 20 u for 220 lb. person) This shows a glucose lowering activity for 7-8 hours Regular Apidra product handout, Rev. April 2004a

ReviewDoes Dose Size Affect DIA? 5 This graphic suggests that smaller boluses do not lower the BG as long as larger boluses. However, this may not be true – see next 2 slides. Size of the injected Humalog dose for a 154 lb or 70 kg person: 0.05 u/kg = 3.5 u 0.1 u/kg = 7 u 0.2 u/kg = 14 u 0.3 u/kg = 21 u Woodworth et al. Diabetes. 1993;42(Suppl. 1):54A

ReviewPharmacodynamics Is Not DIA 5 • The DIA time entered into an insulin pump is based on studies of insulin pharmacodynamics. • However, the traditional method used to determine insulin pharmacodynamics may underestimate insulin’s true duration of action, as shown in the next two slides.

ReviewPharmacodynamics Underestimates DIA And Overestimates Impact Of Bolus Size 5 • To measure pharmaco-dynamics, glucose clamp studies are done in healthy individuals who receive an injection of fast insulin (0.05 to 0.3 u/kg) • Because there is no basal insulin replacement, the injected insulin dose ALSO SUPPRESSES normal basal release from the pancreas (grey area in figure)

ReviewPharmacodynamic Time Does Not Equal DIA 5 After accounting for the lack of basal insulin replacement, • True DIA times become longer than the PD times derived in traditional research • If basal suppression activity is accounted for, small boluses may be found to have a longer DIA than it currently appears, erasingsome of the apparent variation in DIA related to bolus size • Some of the apparent inter-individual variation in pharmacodynamics may also disappear

6 DIA Time Increments

6 Standard For: DIA Time Increments For safe and accurate estimates of residual BOB, DIA time increments shall be no greater than 15 minutes.

DIA Time Increments 6 Issue: Current DIA time increments vary from 15 minutes to 1 hour in different pumps • When a pump’s DIA time is adjusted, large time increments, such as 1 hr, can introduce large changes in subsequent estimates of BOB. • For example, when the DIA is reduced from 5 hours to 4 hours, subsequent BOB estimates are decreased and recommendations for carb boluses are increased by about 25%.

ReviewGlucose Infusion Rate (GIR) Studies 6 Most GIR studies suggest that pharmacodynamic action of insulin varies only about 25% to 40% between individuals. For a DIA time of 5 hr and 15 min, a 25% range is equivalent to 1 hr and 20 min, such as from 4 hrs and 30 min to 5hr and 50 min. A pump that has 1 hr DIA increments would enable the user to select only 1 or 2 settings within this physiologic range, while a 30 min increment would allow only 2 or 3 choices that are close to a physiologic range.

7 Handling Of BOB Bolus On Board (BOB) aka: insulin on board, active insulin, unused insulin* * Introduced as Unused Insulin in 1st ed of Pumping Insulin (1989)

7 Standard For:Handling Of BOB For safe and accurate BOB measurement: BOB measurements shall include all carb and correction boluses given within the selected DIA When residual BOB is present at the time of a bolus, the BOB shall be subtracted from both carb and correction bolus recommendations. When BOB exceeds the current correction bolus need or the current carb plus correction need, the user will be alerted to how many grams of carb they need to eat to avert a low.[(BOB – correction & carb bolus need) X carb factor]

Handling Of BOB 7 Issue: Current pumps differ significantly in what is counted as BOB and in whether or not BOB is subtracted from subsequent carb boluses. Most insulin pumps assume that excess BOB does not need to be taken into account when determining the next carb bolus. Though commonly determined in this way, the resulting bolus dose recommendations can cause unexplained and unnecessary insulin stacking and hypoglycemia.

ExampleInsulin Stacking 7 With a bedtime BG of 173 mg/dl, is there an insulin deficit or a carb deficit? Bedtime BG = 173 mg/dl Correction Dessert Dinner 6 pm 8 pm 10 pm 12 am

ReviewFrequency Of Insulin Stacking 7 CDA1 Study Results Of 201,538 boluses, 64.8% were given within 4.5 hrs of a previous bolus Although 4.5 hours may underestimate true DIA, use of this minimal DIA time shows that some BOB is present for MOST boluses 4.5 hrs

ReviewBolus On Board (BOB) 7 An accurate measurement of the glucose-lowering activity that remains from recent boluses: • Prevents insulin stacking • Improves bolus accuracy • Allows the current carb or insulin deficit to be determined

ReviewHow Current Pumps Handle BOB 7 * Except when BG is below target BG *A “Yes” response is generally considered safer

ExampleUnsafe BOB1 Handling 7 If a pump user gets frustrated with a high BG and they overdose to speed its fall, or they exercise longer or more intensely than anticipated, they can acquire a significant excess in BOB. In these situations, most current pumps recommend that a bolus be given for all carb intake regardless of how much BOB is actually present. When the BOB is larger than the correction bolus required at the time, the pump’s bolus recommendation introduces an unnecessary risk of hypoglycemia. 1 Pumping Insulin, 1st ed, 1989, Chap 12, pgs 70-73: The Unused Insulin Rule

ExampleDifferences In Bolus Recommendations 7 The graphic shows how widely bolus recommendations vary from one pump to another for the same situation. Situation: BOB = 3.0 u and 30 gr. of carb will be eaten at these glucose levels Carb factor = 1u / 10 gr Corr. Factor = 1 u / 40 mg/dl over 100 Target BG = 100 TDD = ~50 u units mg/dl Omnipod bolus cannot be determined - it counts only correction bolus insulin as BOB

A Patient Safety Initiative For Insulin Pumps