Hyperglycemia: Is
This Still a Concern?
Lauren E. Healy BA, PharmD, BCPS
NYSCHP Downstate Critical Care
Program
October 2, 2015
Conflicts of Interest
 None to disclose
2
Learning Objectives
 Explain the pathophysiology of hyperglycemia in
critically ill patients
 Define the association between hyperglycemia
and clinical outcomes
 Evaluate the recent literature on glycemic
control in critically ill patients
 Specify glycemic targets for individual patient
populations
 Compare the options for glycemic control
3
Stress Hyperglycemia
 Blood glucose (BG) > 200 - 220 mg/dL in the
presence of an acute illness
 Usually resolves with treatment of underlying
illness but can have lasting sequela
Donahey. Pharm Pract News. November 2013.
4
A Little History
 1997
 Malmberg and Colleagues of the Diabetes Mellitus
Insulin Glucose Infusion in Acute Myocardial Infarction
(DIGAMI) study group
 Considered long-term, all cause mortality in patients with
Diabetes who were post-MI
 Compared intensive insulin treatment (IIT) (126 – 180
mg/dL) vs. control
 Mean (range) follow-up was 3.4 (1.6 – 5.6) years
 102 (33%) deaths in the treatment arm and 138 (44%) in
the control arm (p = 0.011)
Malmberg. BMJ. 1997;314:1512.
5
Causes of Hyperglycemia in
Critically Ill Patients
External
Internal
 Metabolic stress
 Hormones
 Cortisol,
catecholamines,
glucagon, growth
hormone
 Insulin Resistance
 Demonstrated in > 80%
of critically ill patients
 Poor glucose control
 Lack of pharmacologic
management
 Medications
 Glucocorticoids
 Nutrition
 TPN
 Fluids
Donahey. Pharm Pract News. November 2013.
6
Effects of Hyperglycemia
 Has been associated with poor clinical outcomes
 Acute kidney injury (AKI)
 Sepsis
 Critical illness polyneuropathy (CIP)
 Respiratory failure
 Decreased wound healing
 Increased mortality rates
 Increased length of stay
 Hospital and ICU
Donahey. Pharm Pract News. November 2013.
7
Van Den Berghe et al.
 2001
 Prospective, randomized, controlled study
 IIT (80 – 110 mg/dL) versus conventional
treatment (180 – 200 mg/dL)
 1548 Surgical patients enrolled
 12 months
Van Den Berghe. N Engl J Med. 2001;345:1359 – 67.
8
Van Den Berghe et al.
Conventional
(180 – 200 mg/dL)
IIT
(80 – 110 mg/dL)
P-value
8.0 %
4.6 %
<0.04
Treatment with
antibiotics for >10d (%)
17.1 %
11.2 %
<0.001
Need for RRT (%)
8.2 %
4.8 %
0.007
EMG evidence of CIP
(on more than 2
occasions) (%)
18.9 %
7.0 %
0.001
Mortality during ICU
stay (%)
Van Den Berghe. N Engl J Med. 2001;345:1359 – 67.
9
Effects of Moderate Intensity Glycemic
Control After Cardiac Surgery
 Patients with Diabetes Mellitus or Random BG
>150 mg/dL post cardiac surgery
Targets
(mg/dL)
Glucose levels
(mg/dL)
Infection
rate (%)
Hypoglycemia
rate (%)
Control
(n = 207)
-
166 + 27
11
2.5
Intervention
(n = 410)
110 - 150
151 + 19
5
3.0
P - value
-
0.0001
0.018
1.0
Leibowitz. Ann Thorac Surg. 2010;90:1825-32.
10
Association Between Hyperglycemia
and Increased Hospital Mortality
Hospital Mortality (%)
Hospital Mortality vs. Mean BG
45
40
35
30
25
20
15
10
5
0
42.5
37.5
28.4
9.6
80 - 99
12.2
100 119
15.1
32.9
29.4
18.8
120 140 160 180 139
159
179
199
Mean BG (mg/dL)
200 249
250 299
>300
 Heterogeneous ICU patient population
Krinsley. Mayo Clin Proc. 2003;78(12):1471-8.
11
Hyperglycemia and
Mortality Risk
 Retrospective cohort
 173 United States Veteran’s Health Administration
ICU’s
 N = 259,040 admissions from 10/2002 – 9/2005
 Hyperglycemia was associated with increased
hospital mortality independent of ICU type,
length of stay and diabetes
 Mortality from hyperglycemia varied based on
admission diagnosis
Falciglia. Crit Care Med. 2009;37(12)3001-09.
12
Adjusted Odds of Hospital
Mortality Based on Hyperglycemia
Odds ratio w/ 95% CI
3.5
3
2.5
2
1.5
1
0.5
0
111-145
146-199
200-300
>300
Mean Glucose (mg/dL)
Falciglia. Crit Care Med. 2009;37(12)3001-09.
13
Admission Diagnosis Associated with
Hyperglycemia and Hospital Mortality
 Acute Myocardial
Infarction
 Stroke
 Ischemic and Hemorrhagic
 Arrhythmia
 GI bleed
 Unstable Angina
 Acute Renal Failure
 Pulmonary Embolism
 Pneumonia
 Congestive Heart Failure
 Sepsis
Falciglia. Crit Care Med. 2009;37(12)3001-09.
14
Admission Diagnosis NOT Associated
with Hyperglycemia and Hospital
Mortality
 Chronic Obstructive
Pulmonary Disease
 Hepatic Failure
 Gastrointestinal
 Post Surgical
 Coronary Artery Bypass
Graft
 Peripheral Vascular Disease
 Hip Fracture
Neoplasm
Falciglia. Crit Care Med. 2009;37(12)3001-09.
15
Audience Participation
Hyperglycemia has been shown to
increase the rates of:
A. Acute Kidney Injury
B. Infection
C. Critical Illness Polyneuropathy
D. Hospital Mortality
E. All of the above
16
We can’t ignore
hyperglycemia, so what do
we do about it?
17
Audience Participation
What BG goal is generally targeted in
the ICU’s at your institution?
A. 80 - 120 mg/dL
B. 120 - 140 mg/dL
C. 140 – 180 mg/dL
D. < 200 mg/dL
18
What do the Guidelines Say?
Organization
Target
(mg/dL)
Notes
Strength of
Recommendation
AACE/ADA
2009
140 – 180
> 110 mg/dL
*110 – 140 mg/dL
A
ACP
2011
140 - 200
SCCM
2012
100 – 150
Not 80 – 110 mg/dL •Weak
• Moderate quality
evidence
< 180 mg/dL
‘Very low quality of
evidence’
*In some Critically Ill patients – level of evidence C
1.
2.
3.
4.
Moghissi. Diab Care. 2009;32(6):1119–31.
Diab Care. 2012;35(1):S11-63.
Qaseem. Ann Intern Med. 2011;154:260-67.
Jacobi. Crit Care Med. 2012;40(12):3251-76.
19
Cardiology
 Van Den Berghe et al – 2001
 63% post cardiac surgery
 Decreased mortality with BG 80 – 110 mg/dL compared
to 180 – 200 mg/dL (RRR 42%)
 High risk for hypoglycemia
 5.1 % vs. 0.8 % had BG < 40 mg/dL
 Leibowitz et al - 2010
 Post Cardiac Surgery
 Intervention group targeted 110 – 150 mg/dL
 Decreased infection rates from 11 % to 5 % (p = 0.018)
 2.5% to 3% hypoglycemia (p = 1.0)
1.
2.
Van Den Berghe. N Engl J Med. 2001;345:1359 –
67.
Leibowitz. Ann Thorac Surg. 2010;90:1825-32.
20
Neurology
Treatment Hypoglycemia episodes ICU LOS
arms
(BG <80 mg/dL)
(days)
Bilotta
2008
N = 97
Post
severe
TBI
Bilotta N = 493
2009
Brain
surgery
6 month
survival (%)
80 – 120
mg/dL
15
10
10.4
< 220
mg/dL
7
7.3
12.2
P <0 .0001
P < 0.05
NS
80 – 110
mg/dL*
8
6
74
< 215
mg/dL*
3
8
72
P < 0.0001
P= .0001
NS
*Converted from mmol.
1. Bilotta. Neurocrit care. 2008;9(2):159-66.
2. Bilotta. Anesthesiology. 2009;110:611-9.
21
Medical patients
 Surviving Sepsis guidelines - 2012
 Target BG <180 mg/dL
 Van Den Berghe - 2006
 Prospective, randomized, controlled study in a
medical ICU
 N = 1200, intention to treat
Overall hospital
mortality (%)
Hypoglycemia (%)
Conventional*
40
3.7
IIT (80 – 110 mg/dL)
37.3
18.7
*Started insulin infusion when BG > 215 mg/dL and titrated down when BG < 180 mg/dL
1. Crit Care Med. 2013;41(2):580-637.
2. Van Den Berghe. N Engl J Med. 2006;354:449-61.
22
Van Den Berghe – 2006
 IIT
 Reduced ICU length of stay
 Hazard ratio (HR) 1.15 [1.01, 1.32], p = 0.04
 Reduced hospital length of stay
 HR 1.16 [1.00 1.35] p = 0.05
 Reduced duration of mechanical ventilation
 HR 1.21 [1.02, 1.44] p = 0.03
 Less acute kidney failure
 8.9 % to 5.9 %, p = 0.04
 Decreased hospital mortality when treated > 3 days
 52.5 % to 43.0 %, p = 0.009
 But…
 Increased rates of hypoglycemia
 No mortality benefit
 Different nutritional approach
 Hard to identify patients > 3 days
Van Den Berghe. N Engl J Med. 2006;354:449-61.
23
COIITSS trial - 2010
 Multicenter, randomized, 2x2 factorial, open-label trial
 IIT (80 – 110 mg/dL) vs. conventional BG control (2004
surviving sepsis guidelines)
 All patients with septic shock receiving corticosteroids
 n = 509
 No significant difference in In-hospital mortality or 90-
day mortality
 Increased risk of hypoglycemia (BG <40 mg/dL)
 72 vs. 44, p <0.001
The COIITSS Study Investigators. JAMA. 2010;303(4):341 – 348.
24
Mixed Medical/Surgical Patients
 Volume Substitution and Insulin Therapy in Severe Sepsis
(VISEP) - 2008
 Multicenter, 2x2 factorial trial
 Compared IIT (80 – 110 mg/dL) to conventional (180 – 200
mg/dL)
 The IIT arm was stopped early due to increased
hypoglycemia
IIT
Conventional
P – value
28 day mortality (%)
24.7
26.0
0.74
90 day mortality (%)
39.7
35.4
0.31
Hypoglycemia (%)
17
4.1
<0.001
25
Mixed Medical/Surgical Patients
 NICE-SUGAR – 2009
 IIT (81 – 108 mg/dL) vs. conventional (< 180
mg/dL)
 N = 6104 patients in ICU
 Increased mortality and hypoglycemia
BG goal
(mg/dL)
90-day
mortality (%)
Hypoglycemia rate
BG<40 mg/dL (%)
Surgical Subgroup 90
day mortality (%)
81 – 108
27.5
6.8
24.4
< 180
24.9
0.5
19.8
P - value
P = 0.02
P < 0.001
P = 0.10
NICE-SUGAR study investigators. N Engl J Med.2009;360:1283-97.
26
Glucotrol Study
 2009, multicenter trial
 Medical and surgical patients
 IIT (80 – 110 mg/dL) vs. Conventional (140 – 180 mg/dL)
 Trial stopped early due to protocol violations
 IIT
 Increased hypoglycemia (8.7 % vs. 2.7 %, p < 0.0001)
 No difference in ICU mortality
 Non-significant trend towards increased 28 day and
hospital mortality
 18.7 % IIT vs. 15.3 % conventional
Preiser. Intensive Care Med. 2009;35:1738-48.
27
Blood Glucose Targets
Organization
Target
(mg/dL)
Notes
Strength of
Recommendation
AACE/ADA
2009
140 – 180
> 110 mg/dL
*110 – 140 mg/dL
A
ACP
2011
140 - 200
SCCM
2012
100 – 150
Not 80 – 110 mg/dL •Weak
• Moderate quality
evidence
< 180 mg/dL
‘Very low quality of
evidence’
Study
Control (mg/dL)
IIT (mg/dL)
Van Den Berghe 1, 2
180 +
80 - 110
NICE-SUGAR
< 180
80 - 110
VISEP
180 - 200
80 - 110
Glucotrol
180 - 200
80 - 110
28
Recurring Safety Concern is
Hypoglycemia…
29
Hypoglycemia
 Moderate
 BG < 70 mg/dL
 Severe
 BG < 40 mg/dL
 Associated with increased morbidity and
mortality
 Seizures
 Brain damage
 Depression
 Cardiac arrhythmias
Donahey. Pharm Pract News. November 2013.
30
NICE-SUGAR
 Post-Hoc analysis of 6026 patients
 Patients with hypoglycemia had a higher risk of
death
 Casual?
BG
Hazard Ratio
95% CI
P - value
41 – 70 mg/dL
1.41
1.21 – 1.62
< 0.001
< 40 mg/dL
2.10
1.59 – 2.77
< 0.001
The NICE-SUGAR Study Investigators. N Engl J Med. 2012;367:1108-18.
31
Risk Factors for and Outcomes of
Hypoglycemia
 Retrospective, case-control analysis (1:3)
 Define risk factors that increase the risk for severe
hypoglycemia (SH) (< 40 mg/dL)
 Assess whether a single occurrence increases risk of
death
 Results
 N = 102 patients had SH out of 5,365 medical, surgical,
and cardiac admissions
 Risk factors (next slide)
 Mortality rates for SH group were 55.9 % compared to
39.5 % in control group (p = 0.057)
Krinsley. Crit Care Med. 2007;35(10):2262-67.
32
Risk Factors for Developing
Hypoglycemia
Risk Factor
Odds Ratio (95 % CI)
P value
Diabetes
3.07 (2.03 – 4.63)
< 0.0001
Septic Shock
2.03 (1.19 – 3.48)
0.0096
Mechanical
Ventilation
2.11 (1.28 – 3.48)
0.0032
Higher APACHE II
score
1.07 (1.05 – 1.10)
< 0.0001
Krinsley. Crit Care Med. 2007;35(10):2262-67.
33
Hypoglycemia and ICU Mortality
 Hermanides et al. - 2010
 Retrospective database cohort study in a medical/surgical
ICU; N = 5961
 Increased risk for ICU death up to cutoff BG of 85 mg/dL
Hermanides. Crit Care Med. 2010;38(6):1430-34
34
Treating Hypoglycemia
 If we can’t avoid it, and it causes harm…we
need to know how to treat it
 Prevention
 Decrease un – planned nutrition interruptions
 Be careful with renal, and hepatic dysfunction
 Early treatment and recognition
35
Treatment
 Avoid hyperglycemia…
 Avoid hypoglycemia…
 How??
36
Decrease Glycemic Variability?
 Egi et al. - 2006
 Retrospective chart review of 7,049 critically ill patients
 Average of 4.2 hourly glucose measurements
 Mean + SD of BG
 30 + 22 mg/dL in survivors and 40 + 27 mg/dL in non-
survivors
 Mean and SD were significantly associated with both ICU
and hospital mortality (P < 0.001 for both)
Egi. Anesthesiology. 2006;105:244-52
37
From: Variability of BG Concentration and Short-term Mortality in Critically Ill Patients
Anesthesiology. 2006;105(2):244-252.
38
Date of download: 9/16/2015
Copyright © 2015 American Society of Anesthesiologists. All rights reserved.
Glycemic Variability
 2008 – Retrospective review of 3,252
medical/surgical patients
39
Krinsley JS. Crit Care Med. 2008 Nov;36(11):3008-13
A Hypoglycemia Protocol that
Minimizes Glycemic Variability?
 2013 – Retrospective analysis
 N = 772
 Nursing driven hypoglycemia protocol
 BG < 70 mg/dL  give varying amounts of
dextrose 50 %
 Less Glycemic variability (GV) than giving full 50
grams
 BG rechecked every 15 minutes
BG (mg/dL)
< 15
Grams of D50W
25
15 - 25 26 - 35
20
17.5
Arnold. J Intensive Care Med. 2015;30(3):156-60.
36 - 45 46 - 60 60 - 70
12.5
10
7.5
40
Arnold et al. continued
Pre-Protocol
Post-Protocol
P-value
Coefficient of GV (%)
49.3
40.9
.048
Amount of D50W
(grams)
21.2*
11.5
<.001
Degree of BG
overcorrection (%)
86.3
54.5
.009
Time to repeat BG
(minutes)
61
36
.003
ICU mortality (%)
25
22.6
NS
*Pre-protocol patients generally received 12.5 or 25 grams of D50.
Arnold. J Intensive Care Med. 2015;30(3):156-60.
41
Easier Said Than Done…
 Avoid hyperglycemia, hypoglycemia, and GV?
 How?
 Insulin
 Intermittent subcutaneous
 Intravenous continuous infusion
 When?
 Persistently elevated BG
 > 2 readings >180 mg/dL
Jacobi. Crit Care Med. 2012;40(12):3251-76.
42
Insulin
Subcutaneous
 Pros
 Less time
 “Set it and forget it”
 More types/dosing options
 Cons
 Less adjustable
 Who?
 More stable patients
 No nutrition interruptions
Continuous Infusion
 Pros
 Most Physiologic
 Short half life
 Easy titration
 Cons
 Increased workload
 Who?
 Hemodynamically
unstable
 Edematous
 Unpredictable nutrition
43
Intravenous Insulin Infusion
Protocols
 Reach and maintain target BG quickly
 Often a bolus is used
 Monitor BG hourly initially
 In range for 2 – 3 hours; monitor every 2 hours
 Adjustment based on
 Current BG
 Rate of change
 Result in minimal hypoglycemia
Jacobi. Crit Care Med. 2012;40(12):3251-76.
44
A Protocol Example
 Braithwaite et al. described a tabular, dose-defining
protocol for intravenous insulin
 Critically ill trauma service patients in surgical
intensive care unit
 N = 27 runs
 Mean pre-infusion BG was 230 + 67.9 mg/dL
 BG < 140 mg/dL: 100% of the time; median time of 5
hours
 BG < 110 mg/dL: 25/27 runs; median time of 11 hours
 Hypoglycemia
 < 70 mg/dL: 2.4 % of BG measurements
 < 50 mg/dL: none
45
Braithwaite. Diab Technol Ther. 2006;8(4):476-88.
Transition to Subcutaneous
Insulin
 When?
 Consistent nutrition
 Hemodynamically stable
 Stable dose or no corticosteroids
 Minimal peripheral edema
 How?
 Basal – bolus schedule
 With corrective scale
Jacobi. Crit Care Med. 2012;40(12):3251-76.
46
Basal - Bolus
 Based on continuous infusion requirements and
carbohydrate intake
 80 % of past 24 hour infusion requirement
 50 % Basal – long or intermediate acting insulin
 50 % Bolus – short acting divided into three doses
‘pre-meal’ insulin
 Continuous feeds
 Basal (intermediate acting q6h)
 Corrective scale
 Overlap intravenous insulin and subcutaneous insulin
for 2 hours
Jacobi. Crit Care Med. 2012;40(12):3251-76.
47
How to Convert?
 40 vs. 60 vs. 80% of 24 hour requirement?
 Schmeltz et al.; N = 75
 % of patients with capillary BG monitoring within 80 –
150 mg/dL during 24 hours after conversion
 40 % - 58.7%
 60% - 44.4%
 80% - 67.6%

Hypoglycemia
 < 50 mg/dL: 1 patient in 40 % group
 < 70 mg/dL: 8 incidences (2% of total)
Schmeltz. Endoc Pract. 2006;12(6):641-649.
48
Patient Case
In the last 24 hours MM has required 30 units
of insulin via intravenous infusion. The team
wants to convert MM to subcutaneous
insulin therapy as her clinical status is
improving. What dose of basal/bolus would
you recommend in addition to a corrective
scale?
A. 15 basal and 5 bolus TID pre-meal
B. 12 basal and 12 bolus TID pre-meal
C. 12 basal and 5 bolus TID pre-meal
D. 12 basal and 4 bolus TID pre-meal
49
BG Monitoring
 POC vs. Arterial sampling
 Variability has been shown
 Convenience
 Time
 Acceptable error varies
 FDA – 20 %
 ADA – 5 %
 Clinical and Laboratory Standards Institute and
International Organization for Standardization
 +15 mg/dL for BG < 75 mg/dL
 20 % for BG > 75 mg/dL
Jacobi. Crit Care Med. 2012;40(12):3251-76.
50
BG Monitoring
 POC meter variability
 Low hematocrit
 Glucose Oxidase based assay
 Elevated PO2
 Drugs
 Uric acid
 Billirubin
 Glucose Dehydrogenase based assay
 Maltose containing medications
 Q1 - 2 hour testing…unrecognized hypoglycemia?
51
Continuous Glucose Monitoring
 Can we decrease this workload?
 Boom et al – 2014 in the Netherlands
 N = 78 per group were analyzed
CGM
POC
P - value
Severe Hypoglycemia
detected by CGM
(<40 mg/dL*)
7(3/4)
0
-
Time BG in range
(90 – 160 mg/dL*) (%)
69
66
0.47
Nursing time (minutes)
17
36
<.001
Cost (Euros)
40.74
52.89
.02
*BG levels expressed in mmol in study and converted for purpose of presentation
Boom. Crit Care. 2014;18(4):453.
52
Audience Participation
Which of the following are used in the
ICU(s) at your hospital(s) to control
patients’ BG?
A. Continuous Glucose Monitoring
B. Insulin Infusion Protocol
C. Hypoglycemia Protocol
D. B and C
E. All of the above
53
In Summary
 Yes, hyperglycemia is still a concern
 Exact glycemic goal is still unknown
 May depend on population
 What we do know
 Minimize hyperglycemia (BG > 180 mg/dL)
 Minimize hypoglycemia (BG < 40 mg/dL)
 Minimize GV
 Monitor as closely as possible
 Future studies
 Define more specific BG goals
 Compare GV to mean BG level
54
Hyperglycemia: Is
This Still a Concern?
Lauren E. Healy BA, PharmD, BCPS
NYSCHP Downstate: Critical Care
Program
October 2, 2015