Does insulin treatment during and after acute stress have

advantage beyond the lowering effect of blood glucose ?

Krzysztof Krzysztof StrojekStrojek

Department of Internal Diseases Diabetology and NephrologyDepartment of Internal Diseases Diabetology and Nephrology

Zabrze, Zabrze, PolandPoland

Roper, N. A et al. BMJ 2001;322:1389-1393

Decreased survival in diabetic patientsDecreased survival in diabetic patients

Consequences of diabetesConsequences of diabetesConsequences of diabetes

Risk of perioperative complications in diabetic patientsRisk of perioperative complications in diabetic patients

�� HyperglycemiaHyperglycemia, , ketoacidosisketoacidosis

�� NeuroglycopoeniaNeuroglycopoenia ((drugsdrugs, , unadequateunadequate supervisionsupervision))

�� Perioperative complicationsPerioperative complications ((wounds’ infectionwounds’ infection, MI, , MI, healinghealing) )

Metabolic deterioration at acute stress

� Hormonal disorders:

�↑ cortisol

�↑ somatotropin

�↑ catecholamines;

�↑ sympathetic overactivity;

�↓ endogenous insulin secretion;

�↓ peripheral insulin sensitivity;

� Metabolic disorders:

�↑ glicogenolisis

�↑ glukoneogenesis

�↑ proteolisis

�↑ lipolisis

�↑ ketogenesis

Metabolic deterioration at acute stress

� Hormonal disorders:

�↑ cortisol

�↑ somatotropin

�↑ catecholamines;

�↑ sympathetic overactivity;

�↓ endogenous insulin secretion;

�↓ peripheral insulin sensitivity;

� Metabolic disorders:

�↑ glicogenolisis

�↑ glukoneogenesis

�↑ proteolisis

�↑ lipolisis

�↑ ketogenesis

Elliott M Clin Anaesthesiol 1983;1: 527Elliott M Clin Anaesthesiol 1983;1: 527

Van den Berghe, G. J. Clin. Invest. 2004;114:1187

Interaction between glucose toxicity and insulin deficiency in critical illness

Van den Berghe J. Clin. Invest. 2004;114:1187Van den Berghe J. Clin. Invest. 2004;114:1187

Intensive insulin infusion at ICU (surgical)(goal 110 mg/dl)

Insulin in critically ill (glycemia < 110 mg/dl)

Insulin in critically ill (glycemia < 110 mg/dl)

↓ 42% mortality

↓ 20% duration of intensive care

↓ 34% in-hospital mortality

↓ 46% septicemia

↓ 41% dialysis

↓ 50% red cell transfusion

↓ 44% critical illnes polyneuropathy

↓ 42% mortality

↓ 20% duration of intensive care

↓ 34% in-hospital mortality

↓ 46% septicemia

↓ 41% dialysis

↓ 50% red cell transfusion

↓ 44% critical illnes polyneuropathy

Van den Berghe N Eng J Med. 2001; 345: 1359Van den Berghe N Eng J Med. 2001; 345: 1359

Intensive insulin infusion at ICU (medical)(goal 110 mg/dl)

Van den Berghe N Engl J Med 2006;354:449-461

Additional metabolic effects of Additional metabolic effects of insulininsulin

� Anti-inflamatory effect

� preventing endothelial dysfunction

� preventing hypercoagulation

� anabolic effect

� improvement of dyslipidemia

� anti apoptotic effect

Van den Berghe J Clin Invest 2004;114:1187Van den Berghe J Clin Invest 2004;114:1187

Ellger B Diabetes 2006; 55:1096

Subjects

Normal insulin / normoglycemia

High insulin / normoglycemia

Normal insulin / hyperglycemia

High insulin / hyperglycemia

Survival

Other parameters

?

INSULIN OR HYPERGLYCEMIAINSULIN OR HYPERGLYCEMIA

Ellger B Diabetes 2006;55:1096

NI/NG

HI/NG

NI/HG

HI/HG

INSULIN OR HYPERGLYCEMIAINSULIN OR HYPERGLYCEMIA

� Maintaining normoglycemia, independent of insulin levels, prevented

endothelial dysfunction, liver and kidney injury.

� Benefits of intensive insulin therapy required mainly maintenance of

normoglycemia

� Glycemia-independent actions of insulin exerted only minor, organ-

specific impact.

Ellger B Diabetes 2006;55:1096

INSULIN TREATMENT IN ACUTE MIINSULIN TREATMENT IN ACUTE MI((aimaim: insulin : insulin infusioninfusion))

� ECLA- Cirulation 1998; 98:2227

� CREATE-ECLA JAMA; 2005:293:435

� Pol-GIK Caremużyński Cardiosurg Drugs Ther 1999;13:191

� Dutch GIK J Am Cardiol 2003:42: 784

Glucose/Insulin constant proportion irrespective of glycemia

No terapeutic effect

INSULIN TREATMENT IN ACUTE MIINSULIN TREATMENT IN ACUTE MI((aimaim: : glucoseglucose controlcontrol))

� DIGAMI- Am J Cardiol 1995; 26:57-65- 29% reduction of mortality

� DIGAMI-2 Eur Heart J 2005; 26:650- no effect

Diabetes Care 2006; 29: 765-770

Malmberg K et al. BMJ 1997;314:1512-1515.Malmberg K et al. BMJ 1997;314:1512-1515.

No insulin before

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Mortality

Overall

Yrs Yrs

Control

Insulin iv

0 1 2 3 4 5 0 1 2 3 4 5

Control

p = .0111 p = .004

n=133

n=139

n=314

n=306

Insulin iv

INSULIN in acute MIINSULIN in acute MI

Malmberg, K. et al. Eur Heart J 2005 26:650-661Malmberg, K. et al. Eur Heart J 2005 26:650-661

Mortality in Digami Mortality in Digami 22

Insulin use in DIGAMI 2Insulin use in DIGAMI 2

44 (14,4)44 (14,4)444 (93,9)444 (93,9)446 (94,1)446 (94,1)Insulin iv Insulin iv in acute phasein acute phase

GroupGroup 33

N=306N=306

GroupGroup 22

N=473N=473

GroupGroup 11

N=474N=474

Malmberg, K. et al. Eur Heart J 2005 26:650Malmberg, K. et al. Eur Heart J 2005 26:650

124 (40,5)124 (40,5)154 (32,6)154 (32,6)Insulin Insulin sc in hospitalsc in hospital

GroupGroup 33

N=306N=306

GroupGroup 22

N=473N=473

393945458484Insulin Insulin at discharge at discharge (%)(%)

57 57 ±± 424246 46 ±± 303036 36 ±± 2222IU (IU (meanmean ±± SD)SD)

GroupGroup 33

N=306N=306

GroupGroup 22

N=473N=473

GroupGroup 11

N=474N=474

Postprandial hyperglycemia and macroangiopathy

(CVD, CHD, stroke)

Postprandial hyperglycemia and macroangiopathy

(CVD, CHD, stroke)

DECODE Arch Int Med., 2001, 161DECODE Arch Int Med., 2001, 161

FPG 2 h

POSTPRANDIAL HYPERGLYCEMIA AND CV RISK

HEART2D Study

POSTPRANDIAL HYPERGLYCEMIA AND CV RISK

HEART2D Study

Milicevic, Raz, Strojek: J Diabtic Compl 2005; 19:80Milicevic, Raz, Strojek: J Diabtic Compl 2005; 19:80

Acute MI

Acute MI

Type 2 diabetes(n=1355)

Type 2 diabetes(n=1355)

18 days18 days

LysPro preprandiallyLysPro preprandially

18 months18 months

Long-acting1 – 2 daily

Long-acting1 – 2 daily

Mortality

CV events

other events

metabolic control

Mortality

CV events

other events

metabolic control

Ann Thorac Surg 1999; 67: 352-360Ann Thorac Surg 1999; 67: 352-360

J Thorac Cardiovasc Surg 2003;125:1007J Thorac Cardiovasc Surg 2003;125:1007

Insulin infusion vs subcutanous in cardiosurgery

Ann Thorac Surg, 1999, 67; 352-362Ann Thorac Surg, 1999, 67; 352-362

Scott J. et al. Stroke 1999; 30: 793-799

The Glucose Insulin in Stroke Trial (GIST)

Goldberg, Diabetes Care 2004; 27: 461

Goldberg , Diabetes Care 2004; 27: 461Goldberg , Diabetes Care 2004; 27: 461

Efficacy of insulin infusionEfficacy of insulin infusion

73

86

75

0

20

40

60

80

100

easy effective overall

improvement

[%]

MICU nursing reaction(anonymus survey)

MICU nursing reaction(anonymus survey)

Goldberg, Diabetes Care 2004; 27: 461Goldberg, Diabetes Care 2004; 27: 461

Cost effectiveness Cost effectiveness by insulin by insulin useuse

-30

-25

-20

-15

-10

-5

0

Laboratory Pharmacy Imaging Total

Krinsley Chest 2006;129:644Krinsley Chest 2006;129:644

% r

eductio

n

p<0.001p<0.001

p<0.003

p<0.099

Diabetes Care 2006; 29:1750–1756

Diabetes Care 2006;29:1750–1756

Continuous glucose monitoring at ICU

Summary

� Acute stress induced by criticall illnes causes complex metabolic and hormonal disorders

� Maintenance blood glucose in critically ill patients (both diabetic and non-diabetic)

improves survival and other outcomes

� Intrvenous infusion has an advantage over subcutaneous injections

� Trained staff and precise protocol for dose titration is necessary

� Insulin application is cost effective

� Novel (end expensive) continuous glucose monitoring devices are similarly effective as

standard methods

� Acute stress induced by criticall illnes causes complex metabolic and hormonal disorders

� Maintenance blood glucose in critically ill patients (both diabetic and non-diabetic)

improves survival and other outcomes

� Intrvenous infusion has an advantage over subcutaneous injections

� Trained staff and precise protocol for dose titration is necessary

� Insulin application is cost effective

� Novel (end expensive) continuous glucose monitoring devices are similarly effective as

standard methods

... an umbiased opinion

is always absolutely valueless

... an umbiased opinion

is always absolutely valueless

Oscar Wilde „ The Critic as Artist” 1890