c
Distribution of patient-day-weighted mean
POC-BG values for ICU & non-ICU settings
DATA from ~49 million POC-BG testing (12 M ICU; 37 M non-ICU) from 3.5 million
patients (653,359 ICU; 2,831,436 non-ICU). The mean POC-BG was 167 mg/dL for ICU
patients and 166 mg/dL for non-ICU patients.
Swanson et al. Endocrine Practice, October 2011
1
Distribution of patient-day-weighted mean
POC-BG values for ICU & non-ICU settings
DATA from ~49 million POC-BG testing (12 M ICU; 37 M non-ICU) from 3.5 million
patients (653,359 ICU; 2,831,436 non-ICU). The mean POC-BG was 167 mg/dL for ICU
patients and 166 mg/dL for non-ICU patients.
Swanson et al. Endocrine Practice, Pub Ahead of Print, October 2011
50
Patients, %
40
Diabetes
No Diabetes
50
26%
40
78%
30
30
20
20
10
10
0
0
<110 110-140140-170170-200 >200
<110 110-140140-170170-200 >200
Mean BG, mg/dL
Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A.
2
Comparison of sensi-vity and specificity achieved for the diagnosis of diabetes based on FPG, at various levels of HbA1c, from NHANES III and 1999–2004 NHANES J Clin Endocrinol Metab, July 2008, 93(7):2447–2453 3
2-hour OGTT
IGT
Undiagnosed T2DM
Myocardial infarction
70
66
Stroke
60
Patients (%)
50
40
31
39
30
20
16
10
0
35
23
Norhammar
(n=181)
Matz
(n=238)
Norhammar A, et al. Lancet 2002;359:2140−4.
Matz K, et al. Diabetes Care 2006;792−7.
4
Mortality Rate (%)
~4x
~3x
45
40
~2x
35
30
25
20
15
10
5
0
80-99
100-119 120-139 140-159 160-179 180-199 200-249 250-299
>300
Mean Glucose Value (mg/dL)
N=1826 ICU patients.
Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.
Day of surgery: 199 mg/dL
POD #1: 176 mg/dL
POD #3: 185 mg/dL
POD#3: 181 mg/dl
(N=3554)
4.0
Day of surgery: 241 mg/dL
POD #1: 206 mg/dL
POD #2: 195 mg/dL
POD#3: 188 mg/dl
SCI
CII
Patients with diabetes
3.0
Patients without diabetes
DSWI
(%)
2.0
1.0
0.0
87
88
89
90
91
92
93
94
95
96
97
Year
DSWI, deep sternal wound infection; SCI, subcutaneous insulin; CII, continuous insulin infusion.
Furnary AP, et al. Ann Thorac Surg. 1999;67:352–362.
5
10
Postop
Mortality
P<0.0001
BG >200
n=662
5.0% *
1.8%
8.6
8
Postop Mortality (%)
BG <200
n=1369
*P<0.001
Adjusted for 19 clinical and operation variables
First Postop Glucose >200
•  2x LOS
•  3x Vent duration
•  7x mortality !!!
5.8
6
3.8
4
2
1.7
1.4
2.1
0
175200225150200
225
250
175
Blood Glucose (mg/dL)
<150
CABG, coronary artery bypass graft.
Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591.
*P<0.01
Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.
>250
Relative Risk Reduction (%)
Intensive Glucose Management in RCT
Trial
N
Setting
Van den Berghe
2006
1200
MICU
Glucontrol
2007
1101
Ghandi
2007
399
VISEP
2008
Primary
Outcome
Odds Ratio
(95% CI)
P-value
ARR
RRR
Hospital
mortality
2.7%
7.0%
0.94*
(0.84-1.06)
N.S.
ICU
ICU
mortality
-1.5%
-10%
1.10*
(0.84-1.44)
N.S.
OR
Composite
2%
4.3%
1.0*
(0.8-1.2)
N.S.
537
ICU
28-d
mortality
1.3%
5.0%
N.S.
De La Rosa
2008
504
SICU
MICU
28-d
mortality
-4.2%
*
-13%*
0.89*
(0.58-1.38)
NR
NICE-SUGAR
2009
6104
ICU
3-mo
mortality
-2.6%
-10.6
1.14
(1.02-1.28)
< 0.05
N.S.
*not significant
6
Intensive Insulin Therapy and Mortality Among
Critically Ill Patients
Favors IIT
Control
Mixed ICU
Favors
Medical ICU
Surgical ICU
ALL ICU
Griesdale DE, et al. CMAJ. 2009;180(8):821-827.
Intensive Insulin Therapy and Hypoglycemic
Events in Critically Ill Patients
Hypoglycemic Events
No. Events/Total No. Patients
Study
IIT
Control
Risk ratio (95% CI)
Van den Berghe et al
Henderson et al
Bland et al
Van den Berghe et al
Mitchell et al
Azevedo et al
De La Rosa et al
Devos et al
Oksanen et al
Brunkhorst et al
Iapichino et al
Arabi et al
Mackenzie et al
NICE-SUGAR
39/765
7/32
1/5
111/595
5/35
27/168
21/254
54/550
7/39
42/247
8/45
76/266
50/121
206/3016
654/6138
6/783
1/35
1/5
19/605
0/35
6/169
2/250
15/551
1/51
12/290
3/45
8/257
9/119
15/3014
98/6209
6.65 (2.83-15.62)
7.66 (1.00-58.86)
1.00 (0.08-11.93)
5.94 (3.70-9.54)
11.00 (0.63-191.69)
4.53 (1.92-10.68)
10.33 (2.45-43.61)
3.61(2.06-6.31)
9.15 (1.17-71.35)
4.11(2.2-7.63)
2.67 (0.76-9.41)
9.18 (4.52-18.63)
5.46 (2.82-10.60)
13.72 (8.15-23.12)
Overall
Acceptable
110-140
Favors Control
5.99 (4.47-8.03)
Griesdale DE, et al. CMAJ. 2009;180(8):821-827.
Not recommended
<110
Favors IIT
0.1
1
10
Risk Ratio (95% CI)
Recommended
140-180
Not recommended
>180
Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4).
http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.
7
Strategies for Achieving Glycemic Targets in the ICU
Yale Insulin Infusion Protocol2
Leuven SICU Study1
Intensive - Mean BG 103 mg/dL
12
Conventional - Mean BG 153 mg/dL
10
8
6
4
2
0
Admission
Day 1
Day 5
Day 15
450
Blood Glucose (mg/dL)
Blood Glucose (mmol/L)
14
MICU Insulin Infusion Protocol
400
350
300
250
200
150
100
50
0
Last day
0
12
24
36
48
60
72
Hours
Glucommander3
NICE-SUGAR4
Glucose (mg/dL)
450
400
350
300
250
200
150
100
50
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours
1.  Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. 2. Goldberg PA et al. Diabetes Care. 2004;27:461-467.
3. Davidson et al. Diabetes Care. 2005;28:2418-2423. 4. Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.
Glycemic Values Achieved with
IV Insulin Protocols
IIT: Intensive insulin therapy
CIT: Control, conventional insulin therapy
Results are expressed as mean BG during hospital stay, mg/dL
Van Den Berghe G, et al. N Engl J Med. 2001; Van Den Berghe G, et al. N Engl J Med. 2006;De la Rosa,et
al, Crit Care 2008; Brunkhorst et al. N Engl J Med. 2008; Preiser JC, SCCM, 2007; Nice Sugar, NEJM 2009
8
Hypoglycemia Rates in
Intensive IV Insulin Protocols
8.6%
1.  Van Den Berghe G, et al. N Engl J Med. 2001:345:1359;
2.  Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461;
3.  Brunkhorst FM et al. N Engl J Med. 2008; 358:125-139;
4.  Preiser JC, SCCM, 2007;
5.  Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.
Algorithm 1
Algorithm 2
BG (mg/dL) Units/hr
BG
(mg/dL)
Algorithm 3
Units/hr
BG
(mg/dL)
Units/hr
Algorithm 4
BG
(mg/dL)
Units/hr
<60 = Hypoglycemia (See below for treatment)
<70
Off
<70
Off
<70
Off
<70
Off
70-109
0.2
70-109
0.5
70-109
1
70-109
1.5
110-119
0.5
110-119
1
110-119
2
110-119
3
120-149
1
120-149
1.5
120-149
3
120-149
5
150-179
1.5
150-179
2
150-179
4
150-179
180-209
2
210-239
2
240-269
3
270-299
3
300-329
4
330-359
4
330-359
8
330-359
14
>360
6
>360
12
>360
16
Reduce insulin
180-209
3
180-209
5
or hold
insulin6
210-239rate 4
210-239
240-269
5
240
269
infusion at a 8
270-299
6
270-299
10
higher
BG 12
300-329
7
300-329
concentration
7
180-209
9
210-239
12
240-269
16
270-299
20
300-329
24
>330
28
Newton CA et al. ADA Scientific Meeting. June 2008; J Hospital Med, in press
Protocols
9
•  Calculate 24-h insulin requirement based on last 6 hr IV
insulin (6-h total dose x 4)
•  Initial basal dose = 80% of the 24h insulin requirement
•  Stop IV infusion of insulin 2 h after basal insulin dose
•  Monitor blood glucose AC, HS, at 3:00 AM
•  Use correction doses of rapid-acting insulin
•  Revise total 24-h dose of insulin daily
•  Basal and prandial insulin= 50% basal and 50% prandial
Furnary et al. Am J Cardiol 98:557–564, 2006; Bode et al Endocr Pract 2004;10(Suppl. 2):71–80
Mean BG after surgery
% BG 80-140 mg/dl
BG < 60 mg/dl
Yeldandi & Baldwin. DIABETES TECHNOLOGY & THERAPEUTICS 8 (6) 2006
Results:
During first day ~ half of BG
values within target range of
100–140mg/dL before meals
and 100–180 after meals
BG <70mg/dL occurred in
7.7% on the first day and in
26.8% on the first 3 days after
transition
Avanzini et al. Diabetes Care 34:1445–1450, 2011
10
Grady / Emory Protocol.
Smiley & Umpierrez, Ann. N.Y. Acad. Sci 1212:1-11, 2010
Grady / Emory Protocol.
Smiley & Umpierrez, Ann. N.Y. Acad. Sci 1212:1-11, 2010
11
Recommendations for Managing Patients
With Diabetes in Non-ICU Setting
Antihyperglycemic Therapy
SC Insulin
Recommended for
most medical-surgical
patients
OADs
Not Generally
Recommended
1. ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009
2. Diabetes Care. 2009;31(suppl 1):S1-S110..
Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009
12
Study Type:
Prospective, multicenter, randomized,
open-label trial
Patient Population:
130 subjects with DM2
Diet and/or oral hypoglycemic agents
Umpierrez et al, Diabetes Care 30:2181–2186, 2007
Umpierrez et al, Diabetes Care 30:2181–2186, 2007
Sliding Scale Insulin Regimen
•  Before meal: Supplemental Sliding Scale Insulin (number of units)
–  Add to scheduled insulin dose
•  Bedtime: Give half of Supplemental Sliding Scale Insulin
Blood Glucose
Insulin Sensitive
(mg/dL)
Usual
Insulin Resistant
>141-180
2
4
6
181-220
4
6
8
221-260
6
8
10
261-300
8
10
12
301-350
10
12
14
351-400
12
14
16
>400
14
16
18
Umpierrez GE et al. Diabetes Care. 2007;30:2181-2186.
13
240
220
a
BG, mg/dL
200
a
a
b
180
b
b
b
Sliding-scale
160
140
Basal-bolus
120
100
Admit 1
aP<.05.
2
3
4
5
6
7
8
9
10
Days of Therapy
bP<.05.
•  Sliding scale regular insulin (SSRI) was given 4 times daily
•  Basal-bolus regimen: glargine was given once daily; glulisine was given before meals.
0.4 U/kg/d x BG between 140-200 mg/dL
0.5 U/kg/d x BG between 201-400 mg/dL
Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.
BG, mg/dL
Rabbit 2 Trial: Treatment Success With
Basal-Bolus vs. Sliding Scale Insulin
300
280
260
240
220
200
180
160
140
120
100
Slidingscale
Basal-bolus
  Basal Bolus Group:
  BG < 60 mg/dL: 3%
  BG < 40 mg/dL: none
Admit 1
2
3 4 1 2 3 4
Days of Therapy
5
6
7
  SSRI:
  BG < 60 mg/dL: 3%
  BG < 40 mg/dL: none
Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.
Umpierrez GE et al. Diabetes Care 2007;30:2181-2186.
14
Study Type:
Prospective, randomized, open-label trial
Patient Population:
130 subjects with DM2
Oral hypoglycemic agents or insulin therapy
Study Sites:
Grady Memorial Hospital, Atlanta, GA
Rush University Medical Center, Chicago, IL
Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009
240
Detemir + aspart
NPH + regular
BG, mg/dL
220
200
P=NS
180
160
140
120
100
Pre-Rx
BG
0
1
2
3
4
5
6-10
Duration of Therapy, d
Data are means ±SEM.
Basal-bolus regimen: detemir was given once daily; aspart was given before meals.
NPH/regular regimen: NPH and regular insulin were given twice daily, two thirds in AM, one third in PM.
Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569.
DEAN Trial: Hypoglycemia
 NPH/Regular
  BG < 40 mg/dl: 1.6%
  BG < 60 mg/dl: 25.4%
 Detemir/Aspart
  BG < 40 mg/dl: 4.5%
  BG < 40 mg/dl: 32.8%
To determine risk
factors for
hypoglycemic events
during SC insulin
therapy
Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009
15
Summary of Univariate Analyses
p-value*
variable
BG < 60 mg/dl
BG < 70 mg/dl
AGE
0.036
0.001
wt
0.027
0.001
A1C
0.521
0.658
Creatinine
0.011
0.002
Enrollment BG
0.166
0.319
Previous treatment
0.005
<.001
Previous insulin Rx
<0.001
<.001
Treatment group
<0.001
<.001
*p-values are from Wilcoxon Two-Sample Test
Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009
Study Type:
Prospective, multicenter, randomized,
open-label trial in general surgery (non-ICU)
Patient Population:
211 subjects with DM2
Diet and/or oral hypoglycemic agents or low
dose insulin <0.4 U/kg/day
Differences between groups in mean daily
BG concentration
Primary outcome:
•  Composite of hospital complications: wound
infection, pneumonia, respiratory failure,
acute renal failure, and bacteremia.
Umpierrez et al, Diabetes Care, Diabetes Care 34 (2):1–6, 2011
Basal Bolus Insulin Regimen
  D/C oral antidiabetic drugs on admission
  Starting total daily dose (TDD): 0.5 U/kg/day
  TDD reduced to 0.3 U/kg/day in patients ≥ 70 years of
age or with a serum creatinine ≥ 2.0 mg/dL
  Half of TDD as insulin glargine and half as insulin
glulisine*
–  Glargine - once daily, at the same time of the day
–  Glulisine- three equally divided doses (AC)
The goal of insulin therapy was to maintain fasting and pre-meal glucose concentration between
100 mg/dl and 140 mg/dl.
*If a patient was not able to eat, insulin glargine was given but, insulin glulisine was held until
meals were resumed.
16
Blood glucose levels
Change in Daily
Insulin Dose*
Fasting and pre-meal BG between 100-140 mg/dl in
the absence of hypoglycemia
no change
Fasting and pre-meal BG between 141-180 mg/dl in
the absence of hypoglycemia
Increase by 10%
Fasting and pre-meal BG between >181 mg/dl in the
absence of hypoglycemia
Increase by 20%
Fasting and pre-meal BG between 70-99 mg/dl in the
absence of hypoglycemia
Decrease by 10%
Fasting and pre-meal BG between <70 mg/dl
Decrease by 20%
*Daily insulin adjustment was primarily focused on glargine dose.
* The treating physicians were allowed to adjust prandial (glulisine) insulin
dose, and to use the total supplemental dose, patient’s nutritional intake, and
results of BG testing to adjust insulin regimen.
Glargine+Glulisine
Sliding Scale Insulin
* * R R= Randomiza-on 1
2
† 3
4
‡ † 5
6
† 7
8
9
10
Duration of Treatment (days)
* p<0.001; † p=0.01 ‡p=0.02
Umpierrez et al, Diabetes Care 34 (2):1–6, 2011
17
P=0.003
Glargine+Glulisine
Sliding Scale Insulin
P=0.05
P=0.10
P=0.24
P=NS
* Composite of hospital complications: wound infection, pneumonia, respiratory
failure, acute renal failure, and bacteremia.
Umpierrez et al, Diabetes Care 34 (2):1–6, 2011
Postsurgical ICU Admission
ICU Length of Stay
P=0.003
P=0.16
SSI = sliding scale insulin
ICU=intensive care unit
BG <70 mg/dL
P <0.001
25
20
BG <60 mg/dL
25
23
15
10
10
5
0
20
20
15
5
Insulin Glargine SSI
+ Insulin
Glulisine
BG <40 mg/dL
25
P <0.001
15
10
12
5
2
0
Insulin Glargine
+ Insulin
Glulisine
SSI
5
0
P =0.057
4
0
Insulin Glargine SSI
+ Insulin
Glulisine
There were no differences in hypoglycemia between patients treated with insulin prior to
admission compared to insulin-naïve patients.
Umpierrez et al, Diabetes Care 34 (2):1–6, 2011
18
SSI: range of daily regular insulin= 9.7 to 14.4 units after 24hr treatment
88.5% of patients received <20 units and 39.4% <10 units per day.
Basal Bolus versus SSRI – non-ICU
19
Hospital Complications: Primary outcome
•  Sliding scale regular insulin (SSRI) was given 4 times daily
•  Basal-bolus regimen: glargine was given once daily; glulisine was given before meals.
TDD: 0.5 U/kg/d x BG
Elderly (>70 yrs) and with serum creatinine > 2.0 mg/dl: TDD reduced to 0.3 U/kg/d
Hypoglycemia: Univariate Analyses
p-value*
variable
BG < 60 mg/dl
BG < 70 mg/dl
AGE
0.036
0.001
wt
0.027
0.001
A1C
0.521
0.658
Creatinine
0.011
0.002
Enrollment BG
0.166
0.319
Previous treatment
0.005
<.001
Previous insulin Rx
<0.001
<.001
Treatment group
<0.001
<.001
*p-values are from Wilcoxon Two-Sample Test
Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009
Umpierrez et al, Diabetes Care 2007; JCEM 2009; Diabetes Care 2011
20
Initial Insulin Treatment in Medical and
Surgical in Non-ICU
T2DM with BG > 140 mg/dl (7.7 mmol/l)
NPO
Uncertain oral intake
Basal insulin
- Start at 0.2-0.25 U/Kg/day*
- Correction doses with rapid
acting insulin AC
- Adjust basal as needed
Adequate
Oral intake
Basal Bolus
TDD: 0.4-0.5 U/Kg/day
- ½ basal, ½ bolus
- - adjust as needed
BG Target: fasting and pre-meal glucose concentration between 100 mg/dl and 140 mg/dl.
* Reduced TDD to 0.15 U/kg/day if age ≥ 70 yr or creatinine ≥ 2.0 mg/dL
Insulin Action
Glulisine before meals per
sliding scale (correction)
Glargine once
daily
0.25 U/kg
Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy.
New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342
Basal Plus:
glargine once daily
0.25 U/kg plus
glulisine supplements
Basal Bolus:
TDD: 0.5 U/kg/d
Glargine 50%
glulisine 50%
Preliminary results: Basal bolus 51 patients, basal-plus: 49 patients
Umpierrez et al, not for reproduction
21
140-180
110-140
Not recommended
<110
Acceptable
110-140
Recommended
140-180
Not recommended
>180
22