Bin Du - Glycemic Control in Critically Ill Patients - Magic or Myth

Glycemic Control in the Critically Ill
Magic or Myth?
Bin Du, MD
Medical Intensive Care Unit
Peking Union Medical College Hospital
Hyperglycemia in Critically Ill Patients
More than 80 to 90% ICU patients

with BS > 126 mg/dl
No DM history in about 60%
In 1548 patients in SICU, 98.7%

had a BS level > 110 mg/dl
Non ICU Mortality
20%
10.0%
10%
0.8%
1.7%
Normoglycemia
Known diabetes
ICU Mortality
40%
20%
31.0%
10.0%
11.0%
Normoglycemia
Known diabetes
0%
20%
New hyperglycemia
Total In-patient Mortality

16.0%
10%
1.7%
3.0%
0%
0%
New hyperglycemia
Normoglycemia
Known diabetes
New hyperglycemia
Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients
with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87(3): 978-82
Factors Related to Hospital Death

Predictive Factor
OR (95%CI)
Age, per decade
2.2 (1.2 4.2)
Maximal daily SOFA score > 8
9.6 (7.8 11.9)
Poor glycemic control
1.5 (1.1 2.0)
Average cumulative insulin 100 U/d
3.8 (1.8 7.7)
Defined as glucose values of 144 mg/dL or less for less than 5% of total hospital stay time
Rady MY, Johnson DJ, Patel BM, Larson JS, Helmers RA. Influence of individual characteristics on outcome of glycemic control in intensive care unit
patients with or without diabetes mellitus. Mayo Clin Proc. 2005;80:1558-1567.
Hyperglycemia and Prognosis

1826 consecutive ICU patients 10/99 thru 4/02, Stamford CT
50
Mortality (%)
40
30
20
10
0
80-99
100-119 120-139 140-159 160-179 180-199 200-249 250-299

Mean Blood Glucose in ICU (mg/dl)
Krinsley JS: Mayo Clin Proc 2003; 78: 1471-1478
>300
Hyperglycemia: Potential Risks

Impairment
of immune function
Reduction of neutrophil function

Attenuation of complement binding
Disruption of monocyte phagocytic function
Defect of PMN
Proinflammatory
& prothrombotic effects

Altered cell membrane
Insulin: Potential Benefits

Regulates
vasomotor function and contractility of

the myocardium
Stimulates nitric oxide production
Improves endothelial function
Lowers cytokines
Improves protein balance and fat metabolism
Intensive Insulin Therapy in Surgical ICU

Randomization
Blood glucose at initiation

of insulin therapy
Blood glucose during
insulin therapy
Control Group
IIT Group
> 215 mg/dL
> 110 mg/dL
180 200 mg/dL

(10.0 11.1 mmol/L)
80 110 mg/dL
(4.4 6.1 mmol/L)
Use of insulin in 39%
Use of insulin in 99%
Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367
Intensive Insulin Therapy in Surgical ICU

Mortality
Sepsis
Dialysis
Transfusion
Polyneuropathy
Percent Reduction
0%
-20%
-40%
-34%
-41%
-44%
-46%
-50%
-60%
Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367
Intensive Insulin Therapy in Medical ICU
van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin
Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-61
ICU LOS > 3 days
Intention-To-Treat
IIT: Meta-analysis (n = 35)
35 trials included in the meta-analysis

Reduction in death 15%
(RR 0.85; 95% CI 0.75-0.97)
Subgroup analysis
Surgical ICU
(RR 0.58; 95% CI 0.22-0.62)
Glucose goal
(RR 0.71; 95% CI 0.54-0.93)

All patients with diabetes mellitus
(RR 0.73; 95% CI 0.58-0.90)
Pittas AG, Siegel RD, Lau J. Insulin Therapy for Critically Ill Hospitalized Patients: A Metaanalysis of Randomized Controlled Trials. Arch Intern Med. 2004;164: 2005-2011
SSC Guideline: Glycemic Control

Use
IV insulin to control hyperglycemia in

patients with severe sepsis following stablization
in the ICU
(1B)
Aim to keep blood glucose < 150 mg/dl (8.3
mmol/L) using a validated protocol for insulin
dose adjustment
(2C)
Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.
Crit Care Med 2008; 36(1): 296-327. Erratum in: Crit Care Med 2008; 36(4): 1394-1396.
Intensive vs. Conventional : VISEP
Conventional
Intensive
290
247
HES
Ringers Lactate
Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125-139.
Intensive vs. Conventional : VISEP

Conventional
(n = 290)
Intensive
(n = 247)
28-day mortality
26.0%
24.7%
90-day mortality
35.4%
39.7%
12 (4.1%)
42 (17.0%)
Severe hypoglycemia (%)

p < 0.001
Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Ragaller M, Quintel M, Weiler N, Grundling M, Oppert M, Deufel T, et al. Intensive insulin
therapy in patient with severe sepsis and septic shock is associated with an increased rate of hypoglycemia - results from a randomized
multicenter study (VISEP) [abstract]. Infection 2005;33: 19-20.
Glycemic Control in ICU: More RCTs

Glucontrol Trial
Prospective, randomized, single-blinded clinical trial
BG 80 110 mg/dL vs. 140 180 mg/dL
Primary outcome: mortality
Secondary outcome: LOS, incidence of hypoglycemia
Sample size: 3500 patients
Prematurely terminated in March, 2006 after enrolment
of 1101 patients
Significantly higher incidence of adverse events in intensive

insulin therapy group
Shorr AF. Building the Evidence Base for Clinical Decision Making in the ICU. http://www.medscape.com/viewarticle/555169. accessed on July
30, 2007
Incidence of severe hypoglycemia (%)
Glycemic Control in ICU: Glucontrol

10
8.6
8
6
4
2.4
2
0
Intensive insulin
Control
Shorr AF. Building the Evidence Base for Clinical Decision Making in the ICU. http://www.medscape.com/viewarticle/555169. accessed on July
30, 2007
IIT in ICU: Data From Columbia
Prospective, randomized, non-blinded, single-center clinical trial

A medical/surgical ICU in a university hospital
Randomization
Intensive insulin therapy: 80 110 mg/dl
Standard insulin therapy: 180 200 mg/dl
Primary outcome
28-day mortality: 36.6% vs. 32.4% (p > .05)
Secondary outcome
Prevalence of severe hypoglycemia: 8.3% vs. 0.8% (p < .001)
De La Rosa GD, Donado JH, Restrepo AH, et al. Strict glycemic control in patients hospitalized in a mixed medical and surgical intensive care
unit: a randomized clinical trial. Crit Care 2008; 12: R120.
Intensive Insulin Therapy in DM

ACCORD
ADVANCE
The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559.
The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572.
Real Life Might Be Quite Different
Why Glycemic Control Ineffective

Comparison
of different protocols
Blood glucose measurement

Titration of insulin
Efficacy of
protocol in glycemic control

Blood glucose target
Patient population that may benefit
Glycemic Control in ICU (n = 7)

Author
Study Design
Setting
Case No.
End-point
van den Berghe
Prospective randomized
SICU
1548
Mortality
Krinsley
Before-and-after
M/SICU
1600
Mortality
Kanji
Before-and-after
M/SICU
50
Protocol evaluation
Laver
Prospective cohort
M/SICU
27
Protocol evaluation
Goldberg
Prospective cohort
MICU
52
Protocol evaluation
van den Berghe
MICU
1200
Mortality
Brunkhorst
M/SICU
537
Mortality
Glycemic Control in ICU (n = 7)

Author
Sample
Device
Protocol
Target
Leuven
4.4 6.1
van den Berghe
Arterial
ABL 700
Krinsley
Plasma
Vitros 950/250
Stamford
< 7.7
Kanji
Capillary
AccuCheck
Ottawa
4.5 6.1
Laver
Arterial (most)
AccuCheck
Bath IIP
4.0 7.0
Goldberg
Fingertip
One Touch
Yale IIP
5.5 7.7
van den Berghe
Arterial/Capillary
ABL 700/HemoCue
Leuven
4.4 6.1
Brunkhorst
Arterial/capillary
HemoCue
Leuven
4.4 6.1
Glucose Measurements: Various Techniques
Setting: Medical ICU in university teaching hospital

Patients: 49 consecutive admissions
Age 63.9 18.8, male 29/49 (59%), DM 15/49 (31%)
APACHE II 20.3 7.2
ICU mortality 15/49 (31%)
Glucose measurement
Venous blood/Blood chemistry

Capillary blood/Surestep TM
Arterial blood/Surestep TM
Arterial blood/ABL 735
Arterial blood/Blood chemistry
Peng J, Liu Y, Meng Y, et al. Factors influencing accuracy of blood glucose measurements in critically ill patients. Crit Care 2008; 12 (Suppl 2):
P163
Liu Y, Wu D, Song X, et al. Accuracy of point-of-care blood glucose measurements in the medical ICU. Crit Care 2008; 12 (Suppl 2): P167
Discrepancy with Reference Method

10
> 20% difference for

laboratory level 4.12
mmol/L (75 mg/dl)
8
Difference (mmol/l)
6
4
2
0
-2
-4
> 0.83 mmol/L (15 mg/dl)
difference for laboratory values <
4.12 mmol/L (75 mg/dl)
-6
-8
-10
10
12
14
16
18
20
The reference glucose (mmol/l)

Point-of-care blood glucose testing in acute and chronic care facilities, approved guideline 2002, 2nd edition (document C30-A2), CLSI:
http://www.nccls.org, accessed 9 January 2007

Methods
Mean SD (mmol/l) Bias SD (mmol/l) Discrepancy (%)
Venous/Blood chemistry
7.4 2.7
NA
NA
Capillary/Surestep TM
9.1 2.7
1.7 1.4
66.2 (96/145 )
Arterial/Surestep TM
8.9 2.5
1.6 1.4
60.9 (84/138 )
Arterial/ABL-735
8.5 2.9
1.2 1.2
40.0 (58/145 )
Arerial/Blood chemistry
7.9 2.7
0.6 1.2
23.7 (33/139)
Peng J, Liu Y, Meng Y, et al. Factors influencing accuracy of blood glucose measurements in critically ill patients. Crit Care 2008; 12 (Suppl 2):
P163
Liu Y, Wu D, Song X, et al. Accuracy of point-of-care blood glucose measurements in the medical ICU. Crit Care 2008; 12 (Suppl 2): P167
% Agreement
% Agreement in
hypoglycemia
Arterial/Glucose Meter
69.9%
55.6%
Arterial/ABG or Chemistry
76.5%
64.9%
Capillary/Glucose Meter
56.8%
26.3%
Kanji S, Buffie J, Hutton B, Bunting PS, Singh A, McDonald K, Fergusson D, McIntyre LA, Hebert PC. Reliability of point-of-care testing for
glucose measurement in critically ill adults. Crit Care Med 2005; 33: 2778-2785

Conclusion
The magnitude of the differencesbydifferent
methodsled to frequent clinical disagreements
regarding insulin dose titration
Kanji S, Buffie J, Hutton B, Bunting PS, Singh A, McDonald K, Fergusson D, McIntyre LA, Hebert PC. Reliability of point-of-care testing for
glucose measurement in critically ill adults. Crit Care Med 2005; 33: 2778-2785
Glycemic Control in ICU: Protocol
Wilson M, Weinreb J, Soo Hoo GW. Intensive Insulin Therapy in Critical Care. A review of 12 protocols. Diabetes Care 2007; 30: 1005-1011
Ineffective Glycemic Control by Protocol
BG 4.4 5.6 mmol/L
BG < 11.1 mmol/L
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, OBrian PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM.
Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery. A Randomized Trial. Ann Intern Med 2007;
146: 233-243

Insulin
Control
Difference
P value
Baseline BG
6.2 1.2
6.2 1.7
0 (-0.3 to 0.3)
0.98
Post-CPB BG
6.8 1.3
8.2 1.9
-1.4 (-1.8 to -1.1)
< 0.001
Baseline BG
6.3 1.6
8.7 2.3
-2.4 (-2.8 to -1.9)
< 0.001
BG at 24 h
5.7 0.9
5.8 1.2
-0.1 (-0.3 to 0.2)
0.72
Intraoperative
ICU
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, OBrian PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM.
Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery. A Randomized Trial. Ann Intern Med 2007;
146: 233-243

Medical
ICU at university teaching hospital

55 consecutive admissions
3 phases
Control: personal judgment
Intervention 1: BG 4.5 7.5 mmol/L without protocol
Intervention 2: BG 4.5 7.5 mmol/L with protocol
According
to protocol by Meynaar
Meynaar IA, Dawson L, Tangkau PL, et al. Introduction and evaluation of a computerised insulin protocol. Intensive Care Med 2007; 33:
591-596

Control
(n = 17)
Intervention 1
(n = 20)
Intervention 2
(n = 18)
11
11
10
Age
64.6 16.5
69.6 11.2
60.8 19.7
APACHE II
22.5 7.5
24.1 10.8
22.7 11.0
History of DM
Medical admission
17
19
17
Respiratory
10
Septic shock
4.4 2.2
3.8 2.0
4.4 1.9
Male sex
Major reason for ICU admission
LOS

Control
(n = 17)
Intervention 1
(n = 20)
Intervention 2
(n = 18)
9.4 4.8
10.5 6.5
9.7 3.4
8.6 [7.5, 10.0]
8.5 [7.4, 9.3]
7.1 [6.3, 8.3]
Time (h)
6.6 [2.4, 11.4]
7.2 [3.2, 10.8]
11.0 [ 6.9, 19.1]
(%)
27.4 [9.8, 47.6]
30.3 [13.3, 45.1]
46.0 [28.8, 79.4]
Time (h)
17.1 [10.9, 21.5]
15.9 [10.8, 20.6]
10.1 [2.4, 16.6]
(%)
71.1 [45.5, 89.4]
66.2 [44.9, 85.9]
42.2 [10.1, 69.1]
1.52 [0.69, 2.77]
1.30 [0.76, 2.14]
0.25 [0.03, 1.03]
BG at ICU admission
Mean BG level
Within target BG
Above target BG
HGI (mmol/L)

Control
(n = 17)
Intervention 1
(n = 20)
Intervention 2
(n = 18)
Time (h)
0.0 [0.0, 0.0]
0.0 [0.0, 1.1]
0.0 [0.0, 2.2]
(%)
0.0 [0.0, 0.0]
0.0 [0.0, 4.4]
0.0 [0.0, 9.3]
Episode (%)
1 (0.4)
2 (0.4)
3 (0.6)
Hospital-days (%)
1 (1.3)
2 (2.6)
2 (2.5)
Below BG level
Severe hypoglycemia (< 2.2 mmol/L)
IIT: Risk Factor for Hypoglycemia

van
den Berghe
Pittas
7.50 (4.50 12.50)

3.4 (1.9 6.3)
Glycemic Control in ICU: Guideline?

Is the evidence enough?
Strict glycemic
control
Grade C
Single-center clinical trial
No, not quite
Angus DC, Abraham E. Intensive insulin therapy in critical illness: when is evidence enough? Am J Respir Crit Care Med 2005; 172: 1358-1359
IIT: More Questions Than Answers

Target
BG level
Inconsistent results of RCTs
Lack of multicenter RCTs
Risk of severe hypoglycemia
Workload for euglycemia
Bellomo R, Egi W. Glycemic control in the intensive care unit: why should we wait for NICE-SUGAR. Mayo Clin Proc 2005; 80: 1546-1548
Glycemic Control in ICU: Underlying Dis.

No Glycemic
Control
(n = 4459)
Glycemic Control
Nondiabetic
(n = 1743)
Diabetic
(n = 1083)
Maximal daily SOFA score
3 (0 8)
7 (4 11)
5 (1 10)
Mechanical ventilation
652 (15)
1179 (67)
390 (36)
BG (mg/dL)
118 (97 153)
134 (110 181)
170 (121 238)
Stay time with BG 144 mg/dL (%)
93 (32 100)
71 (18 91)
30 (0 81)
5 (4 6)
10 (9 12)
6 (4 7)
4.4 (1.2 11.3)
8.0 (4.2 22.0)
6.7 (2.3 15.6)
Hospital death (%)

LOS (day)

Conclusion
Different BG range for glycemic control in
diabetic and nondiabetic patients
Higher in diabetic patients?
One size does not fit all

Different Thresholds for Glycemic Control in Diabetic
Physiologic readjustment to higher glucose level in
diabetic patients
Greater increments necessary for hyperglycemia to exert its

adverse effects
Less intense injury sufficient to increase glucose in

diabetic patients
Hyperglycemia in diabetics not a reflection of severity-ofillness
Bellomo R, Egi W. Glycemic control in the intensive care unit: why should we wait for NICE-SUGAR. Mayo Clin Proc 2005; 80: 1546-1548
Glycemic Control in Trauma Patients

Collier
et al
Before-and-after study
> 700 trauma patients
No benefit of strict glucose control
van
den Berghe et al
Subgroup analysis (trauma)

Higher mortality in intensive insulin therapy: 12.1%
(4/33) vs. 8.6% (3/35)
Collier B, Diaz J Jr, Forbes R, et al. The impact of a normoglycemic management protocol on clincial outcomes in the trauma intensive care unit.
JPEN J Parenter Enteral Nutr. 2005;29:353-359.
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367.
Summary
Hyperglycemia
as independent prognostic factor

for critically ill patients
Significantly less hyperglycemia with protocol
Significantly more hypoglycemia with protocol
No evidence of improvement of outcome in
patients with strict glycemic control

Bin Du - Glycemic Control in Critically Ill Patients - Magic or Myth

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Glycemic Control in the Critically Ill

Hyperglycemia in Critically Ill Patients

More than 80 to 90% ICU patients

No DM history in about 60%

In 1548 patients in SICU, 98.7%

Total In-patient Mortality

Factors Related to Hospital Death

Age, per decade

2.2 (1.2 4.2)

Maximal daily SOFA score > 8

9.6 (7.8 11.9)

Poor glycemic control

1.5 (1.1 2.0)

Average cumulative insulin 100 U/d

3.8 (1.8 7.7)

Hyperglycemia and Prognosis

100-119 120-139 140-159 160-179 180-199 200-249 250-299

Krinsley JS: Mayo Clin Proc 2003; 78: 1471-1478

Hyperglycemia: Potential Risks

Reduction of neutrophil function

& prothrombotic effects

Insulin: Potential Benefits

vasomotor function and contractility of

Intensive Insulin Therapy in Surgical ICU

Blood glucose at initiation

> 215 mg/dL

> 110 mg/dL

180 200 mg/dL

Use of insulin in 39%

Use of insulin in 99%

Intensive Insulin Therapy in Surgical ICU

Intensive Insulin Therapy in Medical ICU

Intensive Insulin Therapy in Medical ICU

ICU LOS > 3 days

Intensive Insulin Therapy in Medical ICU

IIT: Meta-analysis (n = 35)

35 trials included in the meta-analysis

(RR 0.71; 95% CI 0.54-0.93)

SSC Guideline: Glycemic Control

IV insulin to control hyperglycemia in

Intensive vs. Conventional : VISEP

Intensive vs. Conventional : VISEP

Severe hypoglycemia (%)

Glycemic Control in ICU: More RCTs

Significantly higher incidence of adverse events in intensive

Incidence of severe hypoglycemia (%)

Glycemic Control in ICU: Glucontrol

IIT in ICU: Data From Columbia

Prospective, randomized, non-blinded, single-center clinical trial

28-day mortality: 36.6% vs. 32.4% (p > .05)

Prevalence of severe hypoglycemia: 8.3% vs. 0.8% (p < .001)

Intensive Insulin Therapy in DM

Real Life Might Be Quite Different

Real Life Might Be Quite Different

Real Life Might Be Quite Different

Why Glycemic Control Ineffective

Blood glucose measurement

protocol in glycemic control

Glycemic Control in ICU (n = 7)

van den Berghe

van den Berghe

Glycemic Control in ICU (n = 7)

van den Berghe

van den Berghe