hyperglycemia: is this still a concern? lauren e. healy ba, pharmd, bcps nyschp downstate critical...
TRANSCRIPT
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Hyperglycemia:
Is This Still a
Concern?Lauren E. Healy BA, PharmD, BCPSNYSCHP Downstate Critical Care ProgramOctober 2, 2015
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Conflicts of Interest
None to disclose
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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
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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.
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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.
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Causes of Hyperglycemia in Critically Ill Patients
Internal
Metabolic stress Hormones
Cortisol, catecholamines, glucagon, growth hormone
Insulin Resistance Demonstrated in >
80% of critically ill patients
External
Poor glucose control Lack of pharmacologic
management
Medications Glucocorticoids
Nutrition TPN Fluids
Donahey. Pharm Pract News. November 2013.
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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.
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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.
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Van Den Berghe et al.
Conventional (180 – 200
mg/dL)
IIT(80 – 110 mg/dL)
P-value
Mortality during ICU stay (%)
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
Van Den Berghe. N Engl J Med. 2001;345:1359 – 67.
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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.
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Association Between Hyperglycemia and Increased
Hospital Mortality
Heterogeneous ICU patient population
Krinsley. Mayo Clin Proc. 2003;78(12):1471-8.
80 - 99 100 - 119
120 - 139
140 - 159
160 - 179
180 - 199
200 - 249
250 - 299
>30005
1015202530354045
9.612.2
15.118.8
28.4 29.4
37.532.9
42.5
Hospital Mortality vs. Mean BG
Mean BG (mg/dL)
Hosp
ital M
ort
alit
y (
%)
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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.
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Adjusted Odds of Hospital Mortality Based on
Hyperglycemia
111-145 146-199 200-300 >3000
0.5
1
1.5
2
2.5
3
3.5
Mean Glucose (mg/dL)
Odds
rati
o w
/ 95
% C
I
Falciglia. Crit Care Med. 2009;37(12)3001-09.
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Acute Myocardial Infarction
Arrhythmia
Unstable Angina
Pulmonary Embolism
Congestive Heart Failure
Stroke Ischemic and Hemorrhagic
GI bleed
Acute Renal Failure
Pneumonia
Sepsis
Falciglia. Crit Care Med. 2009;37(12)3001-09.
Admission Diagnosis Associated with Hyperglycemia and Hospital
Mortality
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Admission Diagnosis NOT Associated with Hyperglycemia and Hospital
Mortality
Chronic Obstructive Pulmonary Disease
Hepatic Failure
Gastrointestinal Neoplasm
Post Surgical Coronary Artery Bypass
Graft Peripheral Vascular
Disease Hip Fracture
Falciglia. Crit Care Med. 2009;37(12)3001-09.
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Audience Participation
Hyperglycemia has been shown to increase the rates of:
A. Acute Kidney InjuryB. InfectionC. Critical Illness PolyneuropathyD. Hospital MortalityE. All of the above
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We can’t ignore hyperglycemia, so what do we do about it?
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Audience Participation
What BG goal is generally targeted in the ICU’s at your institution?
A. 80 - 120 mg/dLB. 120 - 140 mg/dLC. 140 – 180 mg/dLD. < 200 mg/dL
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What do the Guidelines Say?
Organization
Target (mg/dL)
Notes Strength of Recommendatio
n
AACE/ADA2009
140 – 180
> 110 mg/dL*110 – 140 mg/dL
A
ACP2011
140 - 200 Not 80 – 110 mg/dL
•Weak• Moderate quality evidence
SCCM2012
100 – 150
< 180 mg/dL ‘Very low quality of evidence’
*In some Critically Ill patients – level of evidence C
1. Moghissi. Diab Care. 2009;32(6):1119–31.2. Diab Care. 2012;35(1):S11-63.3. Qaseem. Ann Intern Med. 2011;154:260-67.
4. Jacobi. Crit Care Med. 2012;40(12):3251-76.
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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. Van Den Berghe. N Engl J Med. 2001;345:1359 – 67.
2. Leibowitz. Ann Thorac Surg. 2010;90:1825-32.
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Neurology
Treatment arms
Hypoglycemia episodes
(BG <80 mg/dL)
ICU LOS
(days)
6 month survival
(%)
Bilotta
2008
N = 97Post
severe TBI
80 – 120 mg/dL
15 10 10.4
< 220 mg/dL
7 7.3 12.2
P <0 .0001 P < 0.05
NS
Bilotta
2009
N = 493
Brain surger
y
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.
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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
1. Crit Care Med. 2013;41(2):580-637.
2. Van Den Berghe. N Engl J Med. 2006;354:449-61.
*Started insulin infusion when BG > 215 mg/dL and titrated down when BG < 180 mg/dL
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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.
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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 <0.001The COIITSS Study Investigators. JAMA. 2010;303(4):341 – 348.
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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
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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.
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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.
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Blood Glucose Targets
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
Organization
Target (mg/dL)
Notes Strength of Recommendatio
n
AACE/ADA2009
140 – 180
> 110 mg/dL*110 – 140 mg/dL
A
ACP2011
140 - 200 Not 80 – 110 mg/dL
•Weak• Moderate quality evidence
SCCM2012
100 – 150
< 180 mg/dL ‘Very low quality of evidence’
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Recurring Safety Concern is Hypoglycemia…
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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.
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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.
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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.
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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.
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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
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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
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Treatment
Avoid hyperglycemia…
Avoid hypoglycemia…
How??
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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
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38Date of download: 9/16/2015 Copyright © 2015 American Society of Anesthesiologists. All rights reserved.
From: Variability of BG Concentration and Short-term Mortality in Critically Ill PatientsAnesthesiology. 2006;105(2):244-252.
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Glycemic Variability 2008 – Retrospective review of 3,252
medical/surgical patients
Krinsley JS. Crit Care Med. 2008 Nov;36(11):3008-13
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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 15 - 25
26 - 35
36 - 45
46 - 60
60 - 70
Grams of D50W 25 20 17.5 12.5 10 7.5
Arnold. J Intensive Care Med. 2015;30(3):156-60.
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Arnold et al. continuedPre-
ProtocolPost-
ProtocolP-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.
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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
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InsulinSubcutaneous
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
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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
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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
Braithwaite. Diab Technol Ther. 2006;8(4):476-88.
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Transition to Subcutaneous Insulin
When? Consistent nutrition Hemodynamically stable Stable dose or no corticosteroids Minimal peripheral edema
How? Basal – bolus schedule With corrective scale
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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
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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.
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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-mealB. 12 basal and 12 bolus TID pre-mealC. 12 basal and 5 bolus TID pre-mealD. 12 basal and 4 bolus TID pre-meal
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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
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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?
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Continuous Glucose Monitoring
Can we decrease this workload?
Boom et al – 2014 in the Netherlands N = 78 per group were analyzed
*BG levels expressed in mmol in study and converted for purpose of presentation
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
Boom. Crit Care. 2014;18(4):453.
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Audience Participation
Which of the following are used in the ICU(s) at your hospital(s) to control patients’ BG?
A. Continuous Glucose MonitoringB. Insulin Infusion ProtocolC. Hypoglycemia ProtocolD. B and CE. All of the above
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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
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Hyperglycemia:
Is This Still a
Concern?Lauren E. Healy BA, PharmD, BCPSNYSCHP Downstate: Critical Care ProgramOctober 2, 2015