43rd EASD Annual MeetingAmsterdam

17-21 September 2007

PS 54 Insulin action in the critically ill

Constancy of relative insulin sensitivity and importance of absolute insulin sensitivity shift to develop insulin infusion pr

otocol in critically ill patients

M. Matsuda, M. Shigeto, Y. Akiyama, M. Masuzawa, T. Okabe

Diabetes and Endocrine Department, Kameda Medical Center, Kamogawa, Japan.

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Abstract

Diabetologia 　 Supplement, 2007

Background and Aims: To keep blood glucose conc. (BG) lower than 140 mg/dl (~8 mM) in critically ill patients, it is necessary to use an insulin infusion protocol like the Yale Protocol (Diabetes Care 27:461, 2004). However its application is difficult as demonstrated in randomized controlled trials. To reduce hypoglycemic risks, we have developed a unique algorithm.Materials and Methods: The input (X) and the output (Y) of this system to adjust the insulin infusion rate to keep BG are the insulin infusion rate (U/hr), and the difference of BG in a fixed amount of time (mg/dl per hr), respectively. These two values were plotted on a graph using X and Y axes. Glucose infusion rate (g/hr) is converted to the theoretical increase of BG (mg/dl per hr) assuming simple distribution in glucose space (20% and 25% of body weight in obese and lean subjects), and is added on the graph. BG was measured from 1 to 6 hrs intervals according to the expected Y value to have optimal BG by reading the graph. To determine the next X value to achieve optimal expected Y value, we have observed 50 diabetic cases (M/F = 36/14, age = 64 ± 12 y.o., BMI = 24 ± 4 kg/m²) before and/or after operation to keep BG from 90 to 140 mg/dl, by using the graph, resulting in no hypoglycemia (BG<60mg/dl). Operations included those in coronary artery bypass graft, orthopedics, abdominal, gynecological, and obstetric surgery. BG was measured by PCx (Abbott, USA), and human regular insulin (1 U/ml saline) and glucose were infused by infusion pumps for clinical use calibrated routinely. In vivo, it is possible that the whole body insulin resistance (IR) is defined as absolute amount of insulin to keep fixed glucose turnover and keep BG constant (IRI-abs: absolute Insulin Resistance Index). On the other hand, insulin sensitivity is defined as a decremental conc. of BG by a fixed increment of insulin (or delta insulin) (ISI-delta: relative Insulin Sensitivity Index). Glucose infusion and change of BG were approximated to calculate insulin resistance by extrapolating the line of the graph, reading X (U/hr) on X-axis (Y=0) to calculate IRI-abs. ISI-delta (mg/dl per U) was the slope of the line on the graph, when IRI-abs became fixed.Results: Total number of sampling of BG was 1626. BG before insulin infusion was 163 ± 58 mg/dl, and the average BG after insulin infusion was 126 ± 18 mg/dl. IRI-abs shifted from 0.4 ± 1.8 to 3.4 ± 10.2 U/hr. When insulin sensitivity is defined as relative amount of insulin to suppress a fixed level of BG, this ISI-delta was fairly constant during whole observation before and/or after operations. ISI-delta was roughly equal to the incremental BG (mg/dl) by basal endogenous glucose production (2.2 mg/kg lean body weight per min) divided by 1 unit/hr of incremental insulin infusion rate in almost all subjects with glucose infusion less than 5 g/hr, and the average was 57 ± 5 mg/dl per U.Conclusion: We concluded that rapidity of shifts of IRI-abs (instability) is necessary to be added to the previous protocols like the Yale Protocol that used only absolute BG, change of BG, and absolute insulin infusion rate to reduce hypoglycemic risks in critically ill patients. In addition, a decremental conc. of BG by a fixed increment of insulin (ISI-delta) was relatively constant despite the stress of operations. This phenomenon may be often masked by the shift of the IRI-abs, and neglect of emergence of ISI-delta resulting in an unexpected change of insulin sensitivity may cause sudden hypoglycemic accidents.

AIM

To keep blood glucose conc. (BG) lower than 140 mg/dl (~8 mM) in critically ill patients, it is necessary to use an insulin infusion protocol like the Yale Protocol (Diabetes Care 27:461, 2004). However its application is difficult as demonstrated in randomized controlled trials. To reduce hypoglycemic risks, we have developed a unique algorithm.

Methods 1The input (X) and the output (Y) of this system to adjust the insulin infusion rate to keep BG are the insulin infusion rate (U/hr), and the difference of BG in a fixed amount of time (mg/dl per hr), respectively. These two values were plotted on a graph using X and Y axes. Glucose infusion rate (g/hr) is converted to the theoretical increase of BG (mg/dl per hr) assuming simple distribution in glucose space (20% and 25% of body weight in obese and lean subjects), and is added on the graph.

Methods 2

BG was measured from 1 to 6 hrs intervals according to the expected Y value to have optimal BG by reading the graph. BG was measured by PCx (Abbott, USA), and human regular insulin (1 U/ml saline) and glucose were infused by infusion pumps for clinical use calibrated routinely.

Methods 3In vivo, it is possible that the whole body insulin resistance (IR) is defined as absolute amount of insulin to keep fixed glucose turnover and keep BG constant (IRI-abs: absolute Insulin Resistance Index). Insulin sensitivity is defined as a decremental conc. of BG by a fixed increment of insulin (or delta insulin) (ISI-delta: relative Insulin Sensitivity Index).

Y = ISI-delta × (X Y = ISI-delta × (X － － IRI-abs)IRI-abs)

Y: delta BG (mg/dl per hr), X: Insulin infusion rate (U/hr)ISI-delta: a slope, IRI-abs[olute]: a cross point with x-axis

Graphic ProtocolXN(Ins.Inf.)to achievedelta PG=0

X: Insulin Infusion　 (U/hr)XA

XB

XA

XB０

XN

０XN

m

XN(Ins.Inf)to obtaindeltaBG=YN

XXB０

X

YG YN

XNaXNb

IRI-abs

BG decreases with increase of insulin infusion

　 ISI-delta: slope of the curve

　 IRI-abs：cross point with X-axis and the curve

IRI-absolute may shift with change of ISI-delta.

Move Y-axis to YN when desired delta BG is not zero. Obtain XN by speculating the move of IRI-abs on the graph.

XN(Ins.Inf.) toachieve deltaPG=0, whenglucose wasinfused.

XA

XB０X

YG

YG= － G × 1000 ÷ (DV × BW)

　 G[g/hr],DV(distribution volume)[L/kg], BW[kg]

YN

ISI-delta

This complicated procedure may be deliniataed in the EXCEL form.

Move the Y-axisto YN, whendelta BG = YN-YG

Y = ISI-delta × (X 　－ IRI-abs)

Y:　delta　BG　(mg/dl　per　hr)

Y:　delta　BG　(mg/dl　per　hr)

Glucose infusion and change of BG were approximated to calculate insulin resistance by extrapolating the line of the graph, reading X (U/hr) on X-axis (Y=0) to calculate IRI-abs. ISI-delta (mg/dl per U) was the slope of the line on the graph, when IRI-abs became fixed.

n 50(M/ F=36/ 14)

Age　(y.o.) 64.0 ± 12.2

Duration　(years) 10.0 ± 8.0

Height　(cm) 160.6 ± 11.0Weight　(kg) 67.8 ± 12.0BMI　(kg/m2) 24.2 ± 4.4

SubjectsSubjects

(mean ± SD)

（ coronary artery bypass graft 15, other cardiac surgery 4, orthopedics 14, abdominal 11, gynecological and obstetric surgery 3, other 3 ）

(mean ± SD)ISI-delta and IRI-absolute was estimated by EXCEL solver function to obtain the minimum error with expected BG by the model. Shift of IRI-absolute was estimated by 5 ways (linear, holding the state, back linear, 2nd order, exponential change), and the method that yield the minimum error was adopted for this calculation.

ParametersParametersIRI-absolute　(U/hr) 64.0 ± 12.2

IRI-absolute　(lowest) 0.4 ± 1.8IRI-absolute　(highest) 3.4 ± 10.2IRI-absolute　(last) 0.8 ± 4.7

ISI-delta　(mg/dl　per　hr)ISI-delta　(low　IR) 57 ± 5ISI-delta　(high　IR) 50 ± 8

Initial　BG　(mg/dl) 163 ± 58Average　BG　(mg/dl) 126 ± 18

Average　GIR　(g/hr) 3.9 ± 3.9Average　Ins.IR　(U/hr) 1.5 ± 1.4

ResultsTotal number of sampling of BG was 1626. BG before insulin infusion was 163 ± 58 mg/dl, and the average BG after insulin infusion was 126 ± 18 mg/dl. IRI-abs shifted from 0.4 ± 1.8 to 3.4 ± 10.2 U/hr. When insulin sensitivity is defined as relative amount of insulin to suppress a fixed level of BG, this ISI-delta was fairly constant during whole observation before and/or after operations. ISI-delta was roughly equal to the incremental BG (mg/dl) by basal endogenous glucose production (2.2 mg/kg lean body weight per min) divided by 1 unit/hr of incremental insulin infusion rate in almost all subjects with glucose infusion less than 5 g/hr, and the average was 57 ± 5 mg/dl per U.

ConclusionConclusionWe concluded that rapidity of shifts of IRI-abs (instability) is necessary to be added to the previous protocols like the Yale Protocol that used only absolute BG, change of BG, and absolute insulin infusion rate to reduce hypoglycemic risks in critically ill patients. In addition, a decremental conc. of BG by a fixed increment of insulin (ISI-delta) was relatively constant despite the stress of operations. This phenomenon may be often masked by the shift of the IRI-abs, and neglect of emergence of ISI-delta resulting in an unexpected change of insulin sensitivity may cause sudden hypoglycemic accidents.

Comparison with 12 protocols

Diabetes Care 30:1005, 2007 with modification

Graphic Protocol variable Y N Both Y Y NA NA NA/Y adjustable

Yale Insulin Infusion Protocol

Diabetes Care 27:461, 2004

1. Bode BW, Braithwaite SS, Steed RD, Davidson PC: Intravenous insulin infusion therapy: indications, methods, and transition to subcutaneous insulin therapy. Endocr Pract 2 (Suppl. 10):71– 80, 2004

2. Boord JB, Graber AL, Christman JW, Powers AC: Practical management of diabetes in critically ill patients. Am J Respir Crit Care Med 164:1763–1767, 2001

3. Chant C, Wilson G, Friedrich JO: Validation of an insulin infusion nomogram for intensive glucose control in critically ill patients. Pharmacotherapy 25:352–359, 2005

4. Davidson PC, Steed RD, Bode BW: Glucommander: a computer-directed intravenous insulin system shown to be safe, simple, and effective in 120,618 h of operation. Diabetes Care 28:2418–2423, 2005

5. Furnary AP, Wu Y, Bookin SO: Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract 2 (Suppl. 10):21–33, 2004

6. Goldberg PA, Siegel MD, Russell RR, Sherwin RS, Halickman JI, Cooper DA, Dziura JD, Inzucchi SE: Experience with the continuous glucose monitoring system in a medical intensive care unit. Diabetes Technol Ther 6:339 –347, 2004

7. Kanji S, Singh A, Tierney M, Meggison H, McIntyre L, Hebert PC: Standardization of intravenous insulin therapy improves the efficiency and safety of blood glucose control in critically ill adults. Intensive Care Med 30:804–810, 2004

8. Krinsley JS: Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 79:992–1000, 2004

9. Marks JB: Perioperative management of diabetes. Am Fam Physician 67:93–100, 2003

10. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 345: 1359–1367, 2001

11. Watts NB, Gebhart SS, Clark RV, Phillips LS: Postoperative management of diabetes mellitus: steady-state glucose control with bedside algorithm for insulin adjustment. Diabetes Care 10:722–728, 1987

12. Zimmerman CR, Mlynarek ME, Jordan JA, Rajda CA, Horst HM: An insulin infusion protocol in critically ill cardiothoracic surgery patients. Ann Pharmacother 38:1123–1129, 2004

References

Graphic Protocol Example 1

Insulin　IR

0.0

1.0

2.0

3.0

4.0

5.0

6.0

U/hr

PG

50100150200250300

4/2

4/3

4/4

4/5

4/6

4/7

4/8

4/9

4/10

mg/dl

Kameda Medical Center

GP

34 y.o. female, acute pancreatitis

Glucose　IR

0

1

2

3

4

5

6

g/hr

After stabilization, it was possible to measure BG every 4 hours.

Yale Insulin Infusion Protocol Example

Insulin　IR

0.0

2.0

4.0

6.0

8.0

10.0

12.0

U/hr

PG

50100150200250300350400

4/23

4/24

4/25

4/26

4/27

4/28

4/29

4/30 5/1

5/2

5/3

5/4

5/5

5/6

5/7

5/8

5/9

5/10

5/11

5/12

5/13

5/14

5/15

5/16

5/17

5/18

mg/dl

Kameda Medical Center

SS YP

67 y.o. male, injury

Sliding scale protocol was used before the start of Yale Insulin Infulsion Protocol with significant increase of BG. Yale Insulin Infusion Protocol reduced BG to optimal levels.

YaleYale 大学プロトコール／若干の修正大学プロトコール／若干の修正

Diabetes Care 27:461, 2004 　を改変