Hyperglycemia:

Is This Still a

Concern?Lauren E. Healy BA, PharmD, BCPSNYSCHP Downstate Critical Care ProgramOctober 2, 2015

2

Conflicts of Interest

None to disclose

3

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

4

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.

5

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.

6

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.

7

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.

8

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.

10

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.

31

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

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

Jacobi. Crit Care Med. 2012;40(12):3251-76.

43

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

Jacobi. Crit Care Med. 2012;40(12):3251-76.

45

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

Jacobi. Crit Care Med. 2012;40(12):3251-76.

47

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.

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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

50

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.

51

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

Hyperglycemia:

Is This Still a

Concern?Lauren E. Healy BA, PharmD, BCPSNYSCHP Downstate: Critical Care ProgramOctober 2, 2015