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1
IV Insulin Infusion Therapy Indications,
Thresholds and Target Range Glucose, Protocols
and Methodology Transition to Subcutaneous
Insulin,
Bruce W. Bode, MD FACE Susan S. Braithwaite, MD
FACE R. Dennis Steed, MD Paul C. Davidson, MD
FACE December 15, 2003
2
Indications for IV Insulin Infusion

• Diabetic ketoacidosis
• Non-ketotic hyperosmolar state
• Critical care illness (surgical)
• Myocardial infarction or cardiogenic shock
• Post-operative period following heart surgery

3
Indications for IV Insulin Infusion

• Critical care illness (medical)
• NPO status in type 1 diabetes
• General pre-, intra- and post- operative care
• Organ transplantation
• TPN
• Exacerbated hyperglycemia
  during
  high dose glucocorticoid therapy

4
Indications for IV Insulin Infusion

• Stroke
• Dose finding strategy, anticipatory to initiation
  or re-initiation of SC insulin in type 1 or type
  2 diabetes
• Labor and delivery
• Other acute illness requiring prompt glycemic
  control

5
Thresholds for Initiation and Targets of IV
Insulin Infusion Therapy
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Mortality of DM Patients Undergoing CABG
Furnary et al J Thorac Cardiovasc Surg
20031231007-21
7
Glycemic Threshold in CABG

• Portland data suggest BG
• lt 150 mg/dl for mortality
• lt 175 mg/dl for infection
• lt 125 mg/dl for atrial fibrillation

Furnary et al J Thorac Cardiovasc Surg
20031231007-21
8
Surgical ICU Mortality Effect of Average BG Van
den Berghe et al (Crit Care Med 2003 31359-366)
P0.0009
BGgt150
110ltBGlt150
P0.026
BGlt110
9
Reduction of mortality below threshold glucose of
144- 200 mg/dL, with speculative upper limit of
target range at about 145 mg/dL
In this observational study of 531 ICU patients,
glucose results were time- weighted for
analysis. Shown as proportions of the whole
admission, are percentages of admissions spent
in bands of glucose.
Finney SJ et al JAMA 2003290(15)2041-47
Survivors
Nonsurvivors
111-144
? 200
10
Glycemic threshold in Surgical ICU

• BG lt 110 mg/dl or lt 145 mg/dl

Van den Berghe et al Crit Care Med 2003
31(2)359-66 Finney SJ et al JAMA
2003290(15)2041-47
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What About Medical Patients?
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Glycemic Threshold in Acute MI and Intervention
(PTCA)

• DIGAMI supports BG lt 180 mg/dl
• Minimal other data
• - PTCA reflow better with BG 159 than 209
  mg/dl

Malmberg BMJ 19973141512
Iwakura K JACC 2003 411-7
13
Other Medical Conditions

• Infection data supports BG lt 130 mg/dl
• Hartford ICU study 125 mg/dl vs 179 mg/dl
  10X decrease in infections
• Stroke data supports BG lt 140 mg/dl
• Pregnancy data supports BG lt 100 mg/dl

14
Stamford CT ICU Study (Retrospective)
Description of Patient Subgroups (N 1826)

• Cardiac (medical) 28.6 (540)
• Pulmonary 15.8 (289)
• Septic Shock 5.0 (92)
• Other Medical 14.9 (272)
• Neurological 13.2 (241)
• Surgical 7.1 (313)
• Trauma 4.3 (79)

Krinsley JS Mayo Clin Proc 2003 78 1471-1478
15
Hyperglycemia and Hospital Mortality 1826
consecutive ICU patients 10/99 thru 4/02,
Stamford CT
Krinsley JS Mayo Clin Proc 78 1471-1478, 2003
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Glycemic Threshold for Medical Patients

• lt 140 mg/dl if IV Insulin is mandated by
  condition
• Acute MI, NPO, Gastroparesis, etc
• lt 180 mg/dl for patients failing SC therapy

17
Threshold blood glucose in mg/dL
for starting IV insulin
infusion

• Peri-operative care gt 140
• Surgical ICU care gt 110 - 140
• Non-surgical illness gt 140 - 180
• Pregnancy gt 100

Van den Berghes study supports 110
Finneys study supports 145 If drip
indication is failure of SQ therapy, use 180
if indication is specific condition ( DM 1/
NPO, MI, etc ), use 140
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Target blood glucose in mg/dL
during IV insulin infusion

• 80 110 in Surgical ICU patients
• 90 140 in other Surgical and Medical Patients
• 70 100 in Pregnancy

19
Methods For Managing Hospitalized Persons with
Diabetes

• Take Diabetes out of the equation.
• Control glucose!!!

20
Diabetes in Hospitalized Patients
.

Psychology

• Patients expect good glycemic control as part of
  hospital care
• They strive for recommended goals at home
• Difficult to understand staffs casual approach
  to BGs gt150

21
Methods For Managing Hospitalized Persons with
Diabetes

• Continuous Variable Rate IV Insulin Drip
• Major Surgery, NPO, ICU, Unstable, MI, DKA,
  Hyperglycemia, Steroids, Gastroparesis, Delivery,
  etc
• Basal / Bolus Therapy (MDI)
• GIK (Reserved for euglycemic patients)

22
The Ideal IV Insulin Protocol

• Easily ordered (signature only)
• Effective (Gets to goal quickly)
• Safe (Minimal risk of hypoglycemia)
• Easily implemented
• Able to be used hospital wide

23
Components of IV Insulin Therapy

• IV line with minimal flow (gt 40 ml/l)
• Glucose inflow kept constant
• Potassium must be given
• Regular insulin in a 1 U/ml or 0.5 U/ml
  concentration
• Infusion controller adjustable in 0.1 U doses
• Accurate bedside BG monitoring done hourly
  (and if stable, every 2 hours)

24
Essentials of a good IV Insulin Algorithm

• Easily implemented by nursing staff
• Able to seek BG range via
• - Hourly BG monitoring
• - Adjusts to the insulin sensitivity
• of the patient

25
IV Insulin Based Studies DIGAMI, Portland, Leuven

• All three have IV insulin protocols
• Complex
• Require ICU housing (exception Furnary)
• Specially trained nurses
• Dedicated supervision
• Consequently not widely accepted

26
Protocol of Van den Berghe and colleagues
Van den Berghe et al, NEJM 2001345(19)1359
27
ICU Survival

• Blood glucose control in Intensive Group
• Mean AM 103 mg/dl
• BG lt 40 mg/dl 5.2 (39)

In no instance was hypoglycemia considered to be
a serious event
Van den Berghe et al, NEJM 2001345(19)1359
28
Portland Protocol Furnary et al J Thorac
Cardiovasc Surg 20031231007-21
1. Start Portland protocol during surgery and
continue through 7 AM of the third POD. Patients
who are not receiving enteral nutrition on the
third POD should remain on this protocol until
receiving at least 50 of a full liquid or soft
American Diabetes Association diet. 2. For
patients with previously undiagnosed DM who have
hyperglycemia, start Portland protocol if blood
glucose is greater than 200 mg/dL. Consult
endocrinologist on POD 2 for DM workup and
follow-up orders. 3. Start infusion by pump
piggyback to maintenance intravenous line as
shown in Appendix Table 1. 4. Test blood glucose
level by finger stick method or arterial line
drop sample. Frequency of blood glucose testing
is as follows a. When blood glucose level
greater than 200 mg/dL, check every 30 minutes.
b. When blood glucose level is less than 200
mg/dL, check every hour. c. When titrating
vasopressors, (eg, epinephrine) check every 30
minutes. d. When blood glucose level is 100 to
150 mg/dL with less than 15 mg/dL change and
insulin rate remains unchanged for 4 hours
(stable infusion rate), then you may test
every 2 hours. e. You may stop testing every 2
hours on POD 3 (see items 1 and 8). f. At
night on telemetry unit, test every 2 hours if
blood glucose level is 150 to 200 mg/dL test
every 4 hours if blood glucose level is less than
150 mg/dL and stable infusion rate
exists. 5. Insulin titration according to blood
glucose level is performed as follows a. When
blood glucose level is less than 50 mg/dL, stop
insulin and give 25 mL 50 dextrose in water.
Recheck blood glucose level in 30 minutes.
When blood glucose level is greater than 75
mg/dL, restart with rate 50 of previous rate.
b. When blood glucose level is 50 to 75 mg/dL,
stop insulin. Recheck blood glucose level in 30
minutes if previous blood glucose level was
greater than 100 then give 25 mL 50 dextrose in
water. When blood glucose level is greater than
75 mg/dL, restart with rate 50 of previous
rate. c. When blood glucose level is 75 to 100
mg/dL and less than 10 mg/dL lower than last
test, decrease rate by 0.5 U/h. If blood glucose
level is more than 10 mg/Dl
lower than last test, decrease rate by 50. If
blood glucose level is the same or greater than
last test, maintain same rate. d. When blood
glucose level is 101 to 150 mg/dL, maintain rate.
e. When blood glucose level is 151 to 200 mg/dL
and 20 mg/dL lower than last test, maintain rate.
Otherwise increase rate by 0.5 U/h. f. When
blood glucose level is greater than 200 mg/dL and
at least 30 mg/dL lower than last test, maintain
rate. If blood glucose level is less than 30
mg/dL lower than last test (or is higher than
last test), increase rate by 1 U/h and, if
greater than 240 mg/dL, administer intravenous
bolus of regular insulin per initial
intravenous insulin bolus dosage scale (see item
3). Recheck blood glucose level in 30 minutes.
g. If blood glucose level is greater than 200
mg/dL and has not decreased after three
consecutive increases in insulin, then double
insulin rate. h. If blood glucose level is
greater than 300 mg/dL for four consecutive
readings, call physician for additional
intravenous bolus orders. 6. American Diabetes
Association 1800-kcal diabetic diet starts with
any intake by mouth. 7. Postmeal subcutaneous
Humalog insulin supplement is given in addition
to insulin infusion when oral intake has advanced
beyond clear liquids. a. If patient eats 50 or
less of servings on breakfast, lunch, or dinner
tray, then give 3 units of Humalog insulin
subcutaneously immediately after that meal.
b. If patient eats more than 50 of servings on
breakfast, lunch, or supper tray, then give 6
units of Humalog insulin subcutaneously
immediately after that meal. 8. On third
POD, restart preadmission glycemic control
medication unless patient is not tolerating
enteral nutrition and is still receiving an
insulin drip.
29
Two Specific IV Insulin Infusion Algorithms

• Markovitz, Braithwaite and colleagues
• - Tabular form
• Davidson, Steed and Bode
• - Computerized system called
• Glucommander

30
Protocol of Markovitz and colleagues, as modified
Markovitz LJ et al Endocrine Practice 2002
8(1)10-18
31
Formula for Markovitz Protocol

• Hourly insulin rate
• hourly maintenance rate ( BG 150
  ) / ISF

32
Formula for Markovitz Protocol

• Hourly insulin rate
• hourly maintenance rate ( BG 150
  ) / ISF
• To create a table, the upper target of 150
  can be
  replaced with any upper target,
  and the insulin
  sensitivity factor ( ISF )
  may be calculated by a
  rule of 1500 or 1700.
• The hourly maintenance rate for target range
  control
  for a given patient is discovered
  during treatment
  by response to column assignments .

33
The glycemic management protocol damped the
variability of glycemic control
percent of patient days
before and with protocol
any glucose lt 70
mean gt 250 mean gt 200
Markovitz. 2002
The tabular insulin drip protocol now has been
adapted to achieve glycemic targets lower than
initially published
34
The default insulin drip column

• lt 100 off
• 100-109 0.5
• 110-129 1.0
• 130-149 1.5
• 150-169 2.0
• 170-189 2.5
• 190-209 3.0
• 210-254 4.0
• 255-299 5.0 etc.

Check BG every 1 hr and adjust rate
35
The default insulin drip column

• lt 100 off
• 100-109 0.5
• 110-129 1.0
• 130-149 1.5
• 150-169 2.0
• 170-189 2.5
• 190-209 3.0
• 210-254 4.0
• 255-299 5.0 etc.

Suppose the patient starts with CBG 254
mg/dL but after 2 hours the CBG remains about
the same
36
The next column
The default column

• 80- 89 off
• lt 100 off 90- 99 0.5
• 100-109 0.5 100-109 1.0
• 110-129 1.0 110-129 1.5
• 130-149 1.5 130-149 2.0
• 150-169 2.0 150-179 3.0
• 170-189 2.5 180-209 4.0
• 190-209 3.0 210-239 5.0
• 210-254 4.0 240-269 6.0
• 255-299 5.0 270-299 7.0

Shifting between several algorithms allows the
nurse to discover the insulin requirement that
maintains normoglycemia
37
Instructions about modified Markovitz protocol

• Default start with column 2 use priming
  bolus
• Switch to next higher column if
• BG ? 200 x 1h, falling lt 30 mg/dL over the past
  1h
• BG ? 150 x 2h, falling lt 60 mg/dL over the past
  2h
• Test BG q 1h if drip turned off by protocol
• After drip interruption for low BG, resume when
  BG gt 109
• Switch to next lower column if
• interrupted for low BG, but now resuming
• on column 4, 5 or 6 for past 8 hr and within
  target

38
Practical Closed Loop Insulin Delivery
A System for the Maintenance of Overnight
Euglycemia and the Calculation of Basal Insulin
Requirements in Insulin-Dependent Diabetics
1/slope Multiplier 0.02
6
5
4
Insulin Rate (U/hr)
3
2
1
0
0
100
200
300
400
Glucose (mg/dl)
NEIL H. WHITE, M.D., DONALD SKOR, M.D., JULIO V.
SANTIAGO, M.D. Saint Louis, Missouri Ann Int
Med 1982 97210-214
39
Historical Perspective
Glucommander Multipliers

• IV Insulin Algorithm
• Insulin (u/h) (BG-60) x Multiplier
• Whites Multiplier Not Applicable
• for Majority
• Based on Type 1 Pediatric Pump Patients
• IV Insulin Used Frequently in Stressed Type 2
• Only 14 Stabilized at 0.02

N2364 Runs
White 0.02
40
Continuous Variable Rate IV Insulin Drip
(Davidson 1982)

• Mix Drip with 125 units Regular Insulin into
• 250 cc NS
• Starting Rate Units / hour (BG 60) x 0.02
• where BG is current Blood Glucose
• and 0.02 is the multiplier
• Check glucose every hour and adjust drip
• Adjust Multiplier to keep in desired glucose
• target range (100 to 140 mg/dl)

41
Continuous Variable Rate IV Insulin Drip
(Davidson 1982)

• Adjust Multiplier (initially 0.02) to obtain
  glucose in target range
• If BG gt 140 mg/dL and not falling by 50mg/dl,
  
• increase by 0.01
• If BG lt 100 mg/dL, decrease by 0.01
• If BG 100 to 140 mg/dL, no change in current
  multiplier
• If BG is lt 80 mg/dL, Give IV D50 cc (100 BG)
  x 0.3
• Give continuous rate of Glucose in IVFs
• Once eating, continue drip till 2 hour post SQ
  insulin

42
Glucommander AN ADAPTIVE, COMPUTER-DIRECTED
SYSTEM FOR IV INSULIN, SHOWN TO BE SAFE, SIMPLE,
AND EFFECTIVE IN 120,618 HOURS OF OPERATION

• Invented in 1984 Davidson and Steed
• 19 Years Experience with this Computer Based
  Algorithm for the Administration of IV Insulin
• Currently used as a software program housed in
  lap top computer in over 60 U.S. hospitals

43
Glucommander

44
Glucommander Orders
45
GlucommanderPrinciples
Insulin Units / Hour
Glucose mgm / dl
46
Glucommander 5802 Runs and 120,618 BGs 1985-1998
47
Glucose Management System (GMS)

• In 1997, MiniMed and Roche purchased the
  marketing rights to the Glucommander
• Changed the name to GMS
• Multicenter U.S. trials done for FDA approval
• Useful and Safe for Any Application of IV Insulin
• Shelved Pending FDA Approval of IV Use of Insulin

48
Glucose Management System
49
Glucommander

.Complete Data Set 1985 to 1998 Beyond
Data Analyzed by Boehringer Manheim/MiniMed in
1995

• 13 years of data from Glucommander.
• 5802 Runs over 120,618 hours.
• Correction of hyperglycemia
• Mean starting BG259 mg/dL (SD 127).
• Mean stable lt150 after three hours.
• Subsequent stability in target range for 60 hrs.
• Hypoglycemia
• BGs lt50 were 0.6 of total BGs.
• 2.6 all runs had one BG lt40. All were
  immediately corrected to 100 with IV glucose
• No severe hypoglycemia.

50
Glucommander Average and Standard Deviation of of
All Runs 1985 to 1998 5808 runs, 120,618 BGs
51
Glucommander

. Summary of Performance Glucose Averages for
3404 Patients
Glucose mg/dl
Percentiles
Percentiles
90
50
10
Hours
52
Conformity of Blood Glucose to Glucommander Target
53
Typical Glucommander Run
Glucose
Glucose
Hi
Low
Multiplier
Multiplier
Insulin
Insulin
Hours
54
Hypoglycemia on Glucommander 5772 Runs
Leuven lt40 mg/dl 5.2
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Protocol for Insulin in Hospitalized Patient

• Treatment of Hypoglycemia
• Any BG lt80 mg/dl D50 (100-BG) x 0.4 ml IV
• Do not treat with oral CHO
• Do Not Hold Insulin When BG Normal

56
Correction of Hypoglycemia with Glucose100-BG X
0.2 Grams
100-BG X 0.15 Grams
N 827
Richardson Diabetes 1999 50A200
Before
After
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GlucommanderSimilar Systems

• Features in Common
• Early high dose
• Decrease in parallel with BG
• End up at common dose
• Similar total dose

ADA 38 u
IV DRIP 38 u
Glucommander 33 u
Insulin Units / Hour
MARKOVITZ 33 u
Glucose mgm / dl
58
Glucommander

. Surgical Series Compared to Watts Algorithm
Watts
Glucommander
Watts et al Diab Care 1987 10722-728
59
Glucommander

. Surgical Series Compared to Watts Algorithm
Glucommander
Watts
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How has the Glucommander been used?

• Treatment of ketoacidosis
• Hyperosmolar non-ketotic state
• Perioperative glucose management
• Labor and delivery
• Myocardial infarction
• Critically ill patients in ICU
• Hyperalimentation
• Gastroparesis with intractable nausea and
  vomiting
• Estimating a patients insulin sensitivity
• A guide for dosing insulin
• Estimating total insulin dose, correction factor,
  CHO/Ins

61
Clinical Experience with Glucommander

• Simple, safe, and effective method for
  maintaining glycemic control thru out the
  hospital
• Extensively studied
• Standardized treatment method applicable in a
  wide variety of conditions
• Available for review, www.glucommander.com

62
Transitioning off IV Insulin Infusion Therapy
63
Converting to SC insulin

• If More than 0.5 u/hr IV insulin required with
  normal BG, start long-acting insulin (glargine)
• Must start SC insulin at least 2 hours before
  stopping IV insulin
• Some centers start long-acting insulin on
  initiation of IV insulin or the night before
  stopping the drip

64
Intravenous insulin infusion under basal
conditions correlates well with subsequent
subcutaneous insulin requirement.
Overwrite
Units SQ
Units IV
Hawkins et al Endocrine Practice 1995 1(6)
385-389
65
A nurse-managed overnight insulin infusion
predicts insulin dose
requirement in a wide range of otherwise well
patients having poorly controlled diabetes
predicted actual
insulin dose
Pre and post blood glucose
Mao et al. JCEM 1997822466-70
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Converting to SC insulin

• Establish 24 hr Insulin Requirement
• Extrapolate from average over last 6-8 hours if
  stable
• Give One-Half Amount As Basal
• Give p.c. Boluses Based on CHO Intake
• Start at CHO/Ins 1 CHO 1.5 units Rapid-acting
• Monitor a.c. tid, hs, and 3 am
• Supplement All BG gt140 mg/dl
• (BG-100)/(1700/Daily Insulin Requirement)

67
The Accurate Insulin Management (AIM) Formulae

• Prescription for insulin therapy includes
• Basal Insulin (BI)
• Carbohydrate-to-Insulin Ratio (CIR)
• Correction Factor (CF)
• 1801 Records from Pump Patients Studied
• Data from best-controlled of 591 pump patients
• Analyzed for optimum parameters
• Resulting formulae used as model for others
• The Accurate Insulin Management (AIM) formulae

Davidson PC et al Diabetes Tech Ther 2003 5327
68
The Accurate Insulin Management (AIM) Formulae
Davidson PC et al Diabetes Tech Ther 2003 5327
69
Questions that need further study

• What is the glucose threshold and target glucose
  for IV insulin in acute MI, pre-CABG, other
  states, etc?
• lt110 mg/dl or lt140 mg/dl ?
• What is the best IV insulin infusion protocol?
• What is the best way to transition to SC?

70
Conclusion

• All hospital patients should have normal glucose

71
The Paradigm for the MilleniumHyperglycemia A
Mortal Sin

• A blood glucose over 110 in a hospitalized
  patient causes increased morbidity and mortality.
• In the 21st Century
• Neglecting BG gt200
• Is Malpractice

72

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