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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
