inpatient glucose control: how low should we go? glucose control: how low should we go? a. keith...

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Inpatient Glucose Control:How Low Should We Go?

A. Keith CryarDivision of Endocrinology

Scott and White Clinic

2

Diabetes in Hospitalized Patients

• Fourth most common co-morbid condition among hospitalized patients

• 10–12% of all hospital discharges

• 29% of all cardiac surgery patients

• 1–3 days longer hospital stay

Hogan P, et al. Diabetes Care. 2003;26:917–932.

3

The Increasing Rate of Diabetes Among Hospitalized Patients

Hospitalizations for Diabetes as a Listed Diagnosis

0

1

2

3

4

5

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Hospital Discharges (millions)

48%↑

Available at: http://www.cdc.gov/diabetes/statistics/dmany/fig1.htm, June 15, 2004.

4

Hospital Costs Account for Majority of Total Costs of Diabetes

Per Capita Healthcare Expenditures (2002)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

Inpatient Nursing Home Physician'sOffice

OutpatientPrescription

Insulin andSupplies

Dollars

Diabetes Without diabetes

Hogan P, et al. Diabetes Care. 2003;26:917–932.

5

Higher Costs:Diabetes in Hospitalized Patients

• Higher rate of hospitalization

• Longer stays

• More procedures, medications

• Chronic complications

• More arteriosclerotic disease

• More infections

6

Hyperglycemia in Patients With Undiagnosed Diabetes

• Hyperglycemia occurred in 38% of patients admitted to the hospital

• 26% had known history of diabetes• 12% had no history of diabetes

• Newly discovered hyperglycemia was associated with:• Higher in-hospital mortality rate (16%) compared with patients

with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P < 0.01)

• Longer hospital stays; higher admission rates to intensive care units

• Less chance to be discharged to home (required more transitional or nursing home care)

Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–982.

7

Hyperglycemia Is an Independent Marker of Inpatient Mortality in Patients With Undiagnosed Diabetes

P < 0.01

1.73

16

02468

1012141618

In-hospital Mortality Rate

(%)

Newly Discovered

Hyperglycemia

Patients With History of Diabetes

Patients With

Normoglycemia

P < 0.01

Adapted from Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–982.

8

Associations Between Glucose Levels and Inpatient Outcomes

• Hyperglycemia is a risk factor for• Mortality in critically ill patients • Complications of myocardial infarction• Complications of strokes • Complications of vascular and cardiac surgery

9

Intensive Glucose Management in Critically Ill Patients

• Hyperglycemia in the ICU is a common problem, caused by insulin resistance, and is considered an adaptive mechanism

• Historically, hyperglycemia has been treated only at very high levels

• Evidence suggests a close correlation between hyperglycemia and clinical outcome

10

Hospital Mortality Rate and Mean Glucose Levels in Critically Ill Patients

0

5

10

15

20

25

30

35

40

45

80–99 100–119 120–139 140–159 160–179 180–199 200–249 250–299 > 300

Mortality Rate (%)

Mean Glucose Value (mg/dL)

Retrospective review of 1,826 consecutive intensive care unit patients at The Stamford Hospital in Stamford, Connecticut. Krinsley JS. Mayo Clin Proc. 2003;78:1471–1478.

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Mean Glucose Values (mg/dL)

• Survivors: 137.9

• Nonsurvivors: 172.0

p < 0.0001

Retrospective review of 1,826 consecutive intensive care unit patients at The Stamford Hospital in Stamford, Connecticut. Krinsley JS. Mayo Clin Proc. 2003;78:1471–1478.

12

Intensive Insulin Therapy in Critically Ill Surgical Patients

• Setting: surgical intensive care unit in University Hospital, Leuven, Belgium

• Hypothesis: normalization of blood glucose levels with insulin therapy can improve prognosis of patients with hyperglycemia or insulin resistance

• Design: prospective, randomized, controlled study

• Conventional: insulin when blood glucose > 215 mg/dL

• Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

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Intensive Insulin Therapy in Critically Ill Surgical Patients

No serious hypoglycemic events.5.2%0.8%% BG < 40 mg/dL

100%39%% receiving insulin

103153Mean AM blood glucose achieved (mg/dL)

IntensiveConventional


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Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival

100

Intensive treatment96

92Survival in ICU (%) Conventional treatment

88

84

80

00

20 40 60 80 100 120 140 160Days After Admission

Conventional: insulin when blood glucose > 215 mg/dL.Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL.

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.Copyright ©2001 Massachusetts Medical Society. All rights reserved.

15

Intensive Insulin Therapy in Critically Ill Surgical Patients: Morbidity and Mortality Benefits

• Intensive therapy to achieve blood glucose levels of 80–110 mg/dL reduced mortality (-34%), sepsis (-46%), dialysis (-41%), blood transfusion (-50%), and polyneuropathy (-44%)


-60

-50

-40

-30

-20

-10

0

Reduction(%)

Mortality Sepsis Dialysis PolyneuropathyBlood

Transfusion

34%

46%41%

44%50%

N = 1,548

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Safety of Insulin Infusion

• A titration algorithm achieved and maintained blood glucose levels at < 110 mg/dL

• Insulin requirements were highest and most variable during first 6 hours of intensive care

• Normoglycemia was reached within 24 hours with a mean daily insulin dose of 77 IU; maintained with 94 IU on day 7

• Blood glucose was monitored every 4 hours by ABG • Statistically significant, but clinically harmless,

hypoglycemia was observed briefly • 5.2% of intensive insulin-treated patients• 0.8% of conventionally treated patients


17

“Effect of an intensive glucose management protocol on the mortality

of critically ill adult patients”

Krinsley JS. Mayo Clin Proc. 2004;79:992–1000.

18

Study Design

• “Before-and-after” design

• University-affiliated community hospital

• Mixed medical/surgical/cardiac ICU

• Medical and surgical house staff, but no fellows or research nurses

Krinsley JS. Mayo Clin Proc. 2004;79:992–1000

19

Treatment Goals

• Blood glucose < 140 mg/dL

• Overview• Frequent FSG checks• Insulin IV infusion if > 200 twice in a row• Intensive regular insulin coverage otherwise


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Mortality

• Baseline hospital mortality rate = 20.9%

• Treatment hospital mortality rate = 14.8%• 6.1% absolute reduction• 29.3% relative reduction

• p = 0.002


21

New Renal Insufficiency

• Defined as • baseline SCr < 1.5 with maximum > 2.5 • baseline > 1.5 with maximum 2X baseline

• Baseline group—12 patients

• Treatment group—3 patients• p = 0.034


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Transfusion Requirements

• Patients requiring PRBC transfusion• Baseline 25.2%• Treatment 20.5%

• 18.7% relative reduction; p = 0.035

• Units per patient: 3.8 vs. 3.3; p = 0.169• Excludes patients admitted with acute GI bleed (50,

44)


23

ICU Length of Stay

p = 0.011

No difference in post-ICU LOS

3.23.6Mean LOS (days)

1.61.9Median LOS (days)

TreatmentBaseline


24

Incidence of Hypoglycemia

• Percentage of glucose values < 40 mg/dL• Baseline—0.35% • Treatment—0.34%

• No Adverse Clinical Consequences


25

Summary: Glycemic Control in Critically Ill Patients

• Prospective, randomized data show a strong correlation between intensive insulin therapy (goal < 110 mg/dL) and improved outcomes in critically ill patients with hyperglycemia

• Data reproducible in medical/surgical units(goal < 140 mg/dL)

• Intervention is simple, safe, and inexpensive

26

Cardiac Surgery and Diabetes

• Patients with diabetes comprise 29% of surgical population

• Associated with:• Longer stay• Greater infection rate• Higher operative mortality• Worse long-term prognosis

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Diabetes in Open Heart Surgery Portland St. Vincent Medical Center

2467 diabetic patients

• Control Group

• N = 968

• 1987–1991

• SubQ Insulin q 4 h

• Goal 200 mg/dL

• All Mean BG’s < 200 47%

• Study Group

• N = 1499

• 1991–1997

• IV Insulin

• Goal 150–200 mg/dL

• All Mean BG’s < 200 84%

Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

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Portland Diabetic Project: Incidence of DSWI and Impact of Implementation

of Insulin Infusion Protocols

4.0

CII3.0

Patients withoutdiabetes

Patients with diabetes DSWI(%) 2.0

1.0

0.087 88 89 90 91 92 93 94 95 96 97

YearDSWI = deep sternal wound infection; CII = continuous insulin infusion.

Furnary AP, et al. Ann Thorac Surg. 1999;67:352–362

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Portland Diabetic Project:Rate of Deep Sternal Wound Infection Rates With

Different Insulin Protocols

0.0

0.5

1.0

1.5

2.0

SQI CII

Deep Wound Infection Rate (%)

2.0%

0.8%

P = 0.01

Furnary AP, et al. Ann Thorac Surg. 1999;67:352–362.

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Glucose Control Lowers Risk of Wound Infection in Patients With Diabetes After Cardiac Surgery

0

10

20

30

40

50

60

70

100–150 150–200 200–250 250–300

Deep Wound Infection Rate (%)

13% 16%25%

67%

Day 1 Blood Glucose (mg/dL)

P = 0.002

Zerr KJ, et al. Ann Thorac Surg. 1997;63:356–361

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Impact of Deep Sternal Wound Infection

• Additional cost per patient was $26,400

• Additional length of stay was 16 days

• Mortality increase 5 times

Furnary AP, et al. Ann Thorac Surg. 1999;67:352–360.

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Portland Diabetes Project: Mortality

10

CII

Patients withoutdiabetes

8

Patients with diabetes 6Mortality

(%)4

2

087 88 89 90 91 92 93 94 95 96 97 98 99 00 01

Year

Furnary AP, et al. J Thorac Cardiovasc Surg. 2003;125:1007–1021

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Portland Diabetes Project:Mortality Versus Hyperglycemia

1.8%

5.0%

Blood Glucose < 200 Blood Glucose > 200

(N = 2,110) Glucose goal < 200 mg/dL

P = 0.001

6.1

4.9

3.7

2.4

1.2

0.0

Mortality(%)

Furnary AP, et al. Circulation. 1999;18:3113 (abstract).

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CII Reduces Mortality in Patients With Diabetes Undergoing Cardiovascular Surgery

0

2

4

6

8

10

12

14

16

< 150 150–175 175–200 200–225 225–250 > 250

Mortality(%)

Average Postoperative Glucose (mg/dL)

Cardiac-related mortality

Noncardiac-related mortality

0.9% 1.3%2.3%

4.1%

6.0%

14.5%

Furnary AP, et al. J Thorac Cardiovasc Surg. 2003;125:1007–1021

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Summary • Diabetes mellitus is a risk factor for mortality after

cardiac surgery • Preoperative hyperglycemia is an independent predictor

of deep sternal wound infection and total length of hospital stay after open heart surgery

• Incidence of deep wound infection is reduced after insulin protocol implementation to maintain mean blood glucose levels < 200 mg/dL in postoperative period

• Continuous insulin infusion should be standard of care for glycometabolic control in patients with diabetes undergoing cardiac surgery

36

Hyperglycemia and Risk of Infection in General Surgery Patients

• One hundred initially uninfected patients with diabetes undergoing elective surgery

• Stratified into 2 groups• All glucose values < 220 mg/dL• At least one glucose values > 220 mg/dL

• Glucose > 220 mg/dL on postoperative day 1 is • A sensitive predictor of nosocomial infection• Associated with

• 2.7 times higher rate of infection• Excluding minor UTI, 5.9 times higher rate of severe infection

Pomposelli JJ, et al. J Parenter Enteral Nutr. 1998;22:77–81.

37

Hyperglycemia and Acute MI

• Diabetes is an independent risk factor for mortality in acute MI

• The higher the serum glucose, the greater the risk for mortality

Braunwald E. N Engl J Med. 1997;337:1360–1369. 2. Malmberg K. Eur Heart J. 1988;9:259–264. Norhammar A, et al. Eur Heart J. 2003;24:838–844 4. Mukamal KJ, et al. Diabetes Care. 2001;24:1422–1427.Malmberg K, et al. Circulation. 1999;99:2626–2632. 6. Lewis EF, et al. J Am Coll Cardiol. 2003;42:1446–1453.Wahab NN, et al. J Am Coll Cardiol. 2002;40:1748–1754. 8. Bolk J, et al. Int J Cardiol. 2001;79:207–214.Norhammar A, et al. J Am Coll Cardiol. 2004;43:585–591.

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Hyperglycemia and Mortality in Post-MI Patients

• Diabetes confers a doubling of risk for early mortality in MI • This increased risk occurs despite advances in cardiac care1

• 1-year mortality in patients with diabetes is higher (especially in younger patients)2,3

• Long-term mortality and hyperglycemia• Diabetes and long-term survival following acute MI:

comparable to risk of having had prior MI but no diabetes4

• Total long-term mortality correlates with glucose5

• Cholesterol and Recurrent Events trial (CARE): diabetes is a major predictor of late CHF and death in survivors of MI6

1. Braunwald E. N Engl J Med. 1997;337:1360–1369. 2. Malmberg K. Eur Heart J. 1988;9:259–264. 3. Norhammar A, et al. Eur Heart J. 2003;24:838–844 4. Mukamal KJ, et al. Diabetes Care. 2001;24:1422–1427. 5. Malmberg K, et al. Circulation. 1999;99:2626–2632. 6. Lewis EF, et al. J Am Coll Cardiol. 2003;42:1446–1453.

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Hyperglycemia and Mortality in Post-MI Patients

• Admission glucose level is predictive of outcome• Admission blood glucose relates to hospital

mortality and risk for CHF in MI1

• Admission plasma glucose level predicts 1-year mortality following acute MI2

• Meta-analyses: hyperglycemia (> 110 mg/dL) with or without a prior diagnosis of diabetes increases in-hospital mortality and CHF in MI patients3

1. Wahab NN, et al. J Am Coll Cardiol. 2002;40:1748–1754, 2. Bolk J, et al. Int J Cardiol. 2001;79:207–214. 3. Capes SE, et al. Lancet. 2000;355:773–778.

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Diabetes and Long-term Survival Following Acute MI: Comparability of Risk With Prior MI

PatientsAlive

FollowingAcute MI

(%)Patients without diabetes = 1,525Patients with diabetes = 396

No diabetes No diabetes No diabetes with prior MINo diabetes with prior MIDiabetesDiabetesDiabetes with prior MIDiabetes with prior MI

65432100.0

0.2

0.4

0.6

0.8

1.0 NIH ONSET STUDY

YearsMI = myocardial infarction; NIH = National Institutes of Health.

Mukamal KJ, et al. Diabetes Care 2001;24:1422–1427

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Admission Blood Glucose Relates to Hospital Mortality and Risk for CHF in MI

CHF = congestive heart failure; MI = myocardial infarction; DM = diabetes mellitus.

(n = 1,078) (n = 135) (n = 167) (n = 282)(n = 282)

0

10

20

30

40

8.1%

23.7%

18.3% 18.8%

0

10

20

30

40

13.3%

32.6%

18.9%

35.5%

- DM≤ 198 mg/dL

- DM> 198 mg/dL

+ DM≤ 198 mg/dL

+ DM> 198 mg/dL

- DM≤ 198 mg/dL

- DM> 198 mg/dL

+ DM≤ 198 mg/dL

+ DM> 198 mg/dL

In-hospital Mortality CHF

P < 0.0001

PercentagePercentage

Wahab NN, et al for the CONS Investigators. J Am Coll Cardiol. 2002;40:1748–1754

42

Admission Plasma Glucose Level Following Acute MI Independently Predicts 1-year Mortality

Even in Absence of Diabetes

0

10

20

30

40

50

< 100 mg/dL 101–150 mg/dL 151–198 mg/dL > 198 mg/dL

Glucose Levels

Mortality (%)

Bolk J, et al. Int J Cardiol. 2001;79:207–214.

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In Patients With Unstable Angina,Higher Event Rates in Patients With Diabetes

Independent predictors for composite primary endpoint (death or MI)

RR 95% CI

2.61 (1.88–3.60)

1.80 (1.35–2.40)

1.84 (1.34–2.54)

0.69 (0.53–0.90)

1.37 (1.05–1.80)

1.22 (1.02–1.48)0.5

Diabetes

Previous MI

Troponin T > 0.03 µg/L

Invasive strategy

ST-depression > 1 mm

Age years

Norhammar A, et al. J Am Coll Cardiol. 2004;43:585–591

CI = confidence interval, RR = risk ratio.

1 4

Overview of GIK Therapy for Acute MI: A 30-year Perspective

MRCMRC 21.4 23.6 -5.1 41.519681968

PentecostPentecost 15.0 16.0 -0.5 6.519681968

HjermannHjermann 10.6 20.0 -4.8 6.8 P = 0.0719711971

RogersRogers 6.5 12.3 -1.9 2.419831983

HengHeng 8.3 0.0 0.6 0.219771977

SatlerSatler 0.0 0.0 0.0 0.019871987GIKGIK ControlControl OO--EE VarianceVarianceMortality Rate (%)Mortality Rate (%)StudyStudy

GIK BetterGIK Better Placebo BetterPlacebo BetterOdds Ratio and Odds Ratio and ClsClsYearYear

StanleyStanley 7.3 16.4 -2.5 2.819781978

All Patients 16.1 21.0 -24.0 70.4 P = 0.004MittraMittra 11.8 28.3 -7.0 6.8 P = 0.00719651965

PilcherPilcher 13.9 29.3 -2.6 3.419671967

1GIK = glucose–insulin–potassium; MI = myocardial infarction; CI = confidence interval.Fath-Ordoubadi F, Beatt KJ. Circulation. 1997;96:1152–1156

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The Effect of Pre-procedure FPG on RestenosisAfter Percutaneous Coronary Intervention

N = 162 with T2DM followed X9 months

12.7 16.0

42.1

31.3

605550454035302520151050

% TVR

p = 0.03p = 0.01

A1C < 7%Glucose < 135

A1C ≥ 7%Glucose < 135

A1C < 7%Glucose > 135

A1C ≥ 7%Glucose > 135

J Am Coll Cardiol. 2004;43(suppl A): Abstract 1062-43.

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Diabetes and Insulin–Glucose Infusion in Acute MI Study (First DIGAMI)

• Prospective, randomized trial of 620 patients with acute MI and diabetes (blood glucose > 200 mg/dL)

• Intensive insulin therapy (glucose target of 126–180 mg/dL) or conventional treatment

• Intensive insulin treatment: IV insulin for > 24 hours, multiple daily injections (4/day for > 3 months)

• Stratification into 4 groups according to risk (high/low) and previous diabetes treatment (insulin/no insulin)

High risk: age > 70, previous MI, history of CHF, current treatment with digitalis.

Malmberg K, et al. J Am Coll Cardiol. 1995;26:57–65.Malmberg Kl. BMJ. 1997;314:1512–1515.

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First DIGAMI: Insulin Therapy Improves Outcomes in Patients With MI

Standard treatment

IV insulin 48 hours, then 4 injections daily

(N = 620)Risk reduction (28%)P = 0.011

All subjects

P = 0.0004

Low-risk and not previously on insulin70 70

Malmberg K, et al. BMJ. 1997;314:1512–1515

0

3020

40

10

5060

0 1Follow-up (years)

2 3 4 5

(N = 272)60Risk reduction (51%)

5040Mortality

(%) 3020100

0 1 2 3 4 5Follow-up (years)

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.

48

First DIGAMI: Insulin Therapy Improves Long-term Survival in Patients With MI

All Patients

Control Patients IGI Patients MortalityIn-hospital 11% 9% ↓ 18% (p = NS)3 months 16% 12% ↓ 21% (p = NS)1 year 26% 19% ↓ 29% (p = 0.03)Total (3.4 years) 44% 33% ↓ 28% (p = 0.01)

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction; IGI = insulin–glucose infusion.

Malmberg K, et al. J Am Coll Cardiol. 1995;26:57–65; Malmberg K. BMJ. 1997;314:1512–1515.

49

First DIGAMI: Subgroup AnalysisShort- and Long-term Benefits in

Patients With Diabetes• Significant mortality benefits evident prior to hospital discharge

Control Patients IGI Patients Mortality

In-hospital 12% 5% ↓ 58% (p < 0.05)

3 months 14% 7% ↓ 52% (p < 0.05)

1 year 18% 9% ↓ 52% (p < 0.02)

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction; IGI = insulin–glucose infusion.

50

Glycemic Control in Patients With Acute MI

• First DIGAMI• Underscores the importance of early and

aggressive glucose control, regardless of prior diabetes status

Malmberg K. BMJ. 1997;314:1512–1515.

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction; MI = myocardial infarction.

51

Cost-Effectiveness in First DIGAMI

For every 9 patients treated with intensive insulin regimen, one life was saved


Almbrand B, et al. Eur Heart J. 2000;21:733–739.

52

Second DIGAMI

• Results were not confirmatory

• However:• Statistically powered for 3000, but only 1200

recruited• Did not achieve the glucose control needed• Entering diabetics were better controlled• Protocol violations with additional insulin

therapy in the control group

53

Hyperglycemia andAcute Myocardial Infarction: Summary

• Hyperglycemia increases in-hospital mortality and CHF in MI patients, regardless of previous diabetes history

• Mortality after MI is reduced by insulin therapy

• Results of DIGAMI• Underscore the importance of early and aggressive

glucose control, regardless of prior diabetes status• Insulin therapy is cost-effective

CHF = congestive heart failure; MI = myocardial infarction; DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.

54

Link Between High Blood Glucose and Poor Outcomes: Potential Mechanisms

Transcription factors

Metabolic stress response↑ Stress hormones and peptides

GlucoseInsulin

FFAKetonesLactate

Cellular injury/apoptosisInflammation

Tissue damageAltered tissue/wound repair

AcidosisInfarction/ischemia

Immune dysfunction Reactive O2 species

Infection dissemination Secondary mediators

Prolonged hospital stayDisability

Death

From Clement S, et al. Diabetes Care 2004;27:553–591

55

Candidate Mechanisms for Insulin’s Protective Effects

• Enhances synthesis of endothelial Nitric Oxide

• Suppresses FFA

• Inhibits proinflammatory cytokines

56

Nitric Oxide• Inhibits

• Vascular smooth muscle cell growth and migration

• Platelet aggregation and thrombosis• Monocyte adhesion• Inflammation• Oxidation

• Under physiologic conditions, production from vascular endothelium contributes to coronary blood flow

57

FFA Causes Endothelial Dysfunctiony = 1361.182x r = 0.497 p < 0.005-0.310600

500

400Maximum ∆% in

Leg Blood Flow

300

200

100

00 1000 2000 3000 4000 5000 6000

FFAµmol

Change in LBF in response to the vasodilator methacholine chloride. Reprinted from Steinberg HO et al. J Clin Invest. 1997;100:1230-1239 with permission from the Copyright Clearance Center.”

58

Candidate Mechanism for Poor Outcome in Critically Ill: FFA

• Increased levels result in endothelial dysfunction

• Increased FFA associated with increased oxidative stress and cardiac sympathetic over-activity

1. Manzella D, et al. Diabetologia. 2002;45:1737–1738.2. Wilsson L, et al. Arterioscler Thromb Vasc Biol. 1998;18:1679–1685.

59

Pro-inflammatory Cytokines

• TNF-α, IL-6, IL-1, IL-2

• Data strongly suggest a cause/effect relationship as opposed to just a marker of inflammation

60

Insulin and Cytokines

• Hyperinsulinemia in the hyperglycemic environment leads to an increase in inflammatory cytokines

• Insulin deficiency in the hyperglycemic environment leads to a modest increase in inflammatory cytokines

• Hyperinsulinemia in the euglycemicenvironment suppresses inflammatory cytokines

Circ Res. 2000;87:746–752.Circulation. 2002;106:2067. Circulation. 2004;109:849.

61

Potential Benefits of Improving Glucose Control in the Hospital

• Reduce mortality• Reduce morbidity• Reduce costs of care

• Length of stay (LOS)• Cost of inpatient complications• Fewer rehospitalizations• Reduced extended care

• There is no evidence that the benefits observed in ICU settings disappear when patients are on regular floors

62

Insulin Therapy

• JCAHO considers insulin to be one of the 5 highest-risk medicines in the inpatient setting

• Primarily because the consequences of errors with insulin therapy can be catastrophic

JCAHO = Joint Commission on Accreditation of Hospitals Organization.

63

Glycemic Targets in Hospitalized Patients

• Intensive care unit• 110 mg/dL

• Medical/surgical floors• 110 mg/dL preprandial• 180 mg/dL maximal glucose• Values above 180 mg/dL are an indication to

monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more intensive intervention

American Association of Clinical Endocrinologists Consensus

64

Indications for Intravenous Insulin Therapy: Summary

• Diabetic ketoacidosis• Nonketotic hyperosmolar

state• Critical care illness

(surgical, medical)• Postcardiac surgery• Myocardial infarction or

cardiogenic shock• NPO status in Type 1

diabetes

• Labor and delivery

• Glucose exacerbated by high-dose glucocorticoidtherapy

• Perioperative period

• After organ transplant

• Total parenteral nutrition therapy

American Association of Clinical Endocrinologists Consensus Conference

65

The Ideal IV Insulin Protocol

• Easily ordered (signature only or a minimal number of checks/circles)

• Effective (gets to goal quickly)

• Safe (minimal risk of hypoglycemia)

• Easily implemented

66

Various Protocols Exist• There are several protocols already proven to

be safe and effective • There is little justification in the efforts required to

develop an new institutional protocol

• DIGAMI (studied in acute MI setting)• van den Berghe (studied in critical care setting)• Portland protocol (used in surgical setting)• Markovitz (studied in postoperative heart

surgery patients)• Yale protocol (studied in medical intensive care

setting)

67

DIGAMI: Insulin RegimenInsulin drip: 80 U in 500 mL 5% dextrose (1 U/6 mL)

– Starting dose = 30 mL/h = 5 U/h – Subsequent rate adjustments:

Blood Glucose (mg/dL) Instructions≥ 270 8 U IV bolus, then ↑ drip by 1 U/h198–269 ↑ drip by 0.5 U/h126–197 Leave drip unchanged72–125 ↓ drip by 1 U/h≤ 71 Stop drip x 15 min.

When blood glucose > 156 mg/dL, restart drip ↓’d by 1 U/h


68

DIGAMI: Insulin Regimen• Has the advantage of simplicity

• No provisions for individualized starting rates

• May be slow to get to target since initial rates and increases in the rates are small

• Rate adjustments fail to take into account the rate of change from previous

• Dilute insulin concentration requires higher volume infusions

69

Protocol of van den Berghe and Colleagues

Adjust insulin dose by 0.1–0.5 IU/hBG approaching normal range

Increase insulin dose by 0.5–1 IU/h110–140

Increase insulin dose by 1 IU/h> 140Measure glucoseevery 1–2 h until within normal range

Do not start insulin but continue BG monitoring every 4 h

< 110

Start insulin 1–2 IU/h220–110

Start insulin 2–4 IU/h> 220Measure glucoseon entry to ICU

ActionBlood Glucose Result (mg/dL)Test


70

Protocol of van den Berghe and Colleagues, continued

Stop insulin infusion, assure adequate baseline glucose intake, administer glucose per 10-g IV boluses and check BG within 1 h

< 40

Stop insulin infusion, assure adequate baseline glucose intake and check BG within 1 h

40–60

Reduce insulin dose and check BG within 1 h60–80

Reduce insulin dose by half and check more frequently

BG falling steeply

Insulin dose unchangedBG normal

Adjust insulin dose by 0.1–0.5 IU/hBG approaching normal range

Measure glucoseevery 4 h

ActionBlood Glucose Result (mg/dL)Test


71

Protocol of van den Berghe and Colleagues

• Has the advantage of simplicity

• Relies significantly on nursing experience• For example, there is no parameter to define if the

glucose is falling “steeply” and the rate needs to be halved

• May be slow to get to target for patients with high insulin requirements because the initial rates and increases in the rates are small (if the protocol is followed)

72

Portland Protocol for Continuous IV Insulin Infusion – Start up

86.516≥ 360

6.5512300–359

53.58240–299

3.524180–239

210120–179

10.5080–119

Type 1 DMPreoperatively

Type 2 DMPreoperatively

Initial Insulin Rate (Units/hour) (circle one)

Intravenous Insulin Bolus (U)

Blood Glucose (mg/dL)

Furnary AP, et al. Endocr Pract. 2004;10:21–33.

73

Portland Protocol for Continuous IV Insulin Infusion – Rate adjustments

If ≥ 30 mg/dL lower than last BG, keep same rate.If < 30 mg/dL lower than last test (OR if higher than last test), increase rate by 1 Unit/h Recheck BG in 30 minutes

151 - 180

If < 20 mg/dL lower than last test– increase rate by 0.5 units/h. If 20 - 80 mg/dL lower than last test – keep same rateIf more than 80 mg/dl lower – decrease rate by 25%.

111–150

Same rate -- EXCELLENT! You are in the Target Range!TITRATE DRIP AT WILL TO MAINTAIN BG in TARGET RANGE70–110

If ≥ last test result, continue current rate. If lower than last BG by 20 mg/dl or more, decrease rate by 50%If within 20 mg/dL of last BG, decrease rate by 0.5 units/hour.

60–69

Stop insulin; if previous BG >100, give 25 mL D50. Recheck BG in 30 minutesWhen BG > 60, restart with rate 50% of previous rate.

50–59

Stop insulin; give 25 mL D50; Recheck BG in 30 minutes. When blood glucose > 60, restart with rate 50% of previous rate.< 50

ActionBlood Glucose (mg/dL)

Furnary AP, et al. Endocr Pract. 2004;10:21–33. 73

Portland Protocol for Continuous IV Insulin Infusion – Provision for meal coverage

7 units SQ14 units SQ>10

6 units SQ12 units SQ8-10




2 units SQ4 units SQ 0-2

Eats < 50% of mealEats > 50% of mealDrip Rate

75

Portland Protocol for Continuous IV Insulin Infusion

• More complex and prescriptive than the van den Bergheprotocol

• Criteria for rate adjustments based on rate of rise or fall in the glucose

• Provision for meal coverage while on infusion• Available for various target ranges

• Not every area is ready for the published targets• They have also a floor insulin infusion protocol for patients

transitioning to the wards or not quite ill enough to warrant ICU admission

76

Protocol of Markovitz and Colleagues

Column 1 Column 2 Column 3 Column 4 Column 5 Column 6 CBG units/hr CBG units/hr CBG units/hr CBG units/hr CBG units/hr CBG units/hr < 70 off < 70 off < 70 off < 70 off < 70 off < 70 off 70- 79 off 70- 79 off 70- 79 off 70- 79 off 70- 79 0.5 70- 79 1 80- 89 off 80- 89 off 80- 89 off 80- 89 0.5 80- 89 1 80- 89 1.5 90- 99 off 90- 99 off 90- 99 0.5 90- 99 1 90- 99 1.5 90- 99 2 100-109 off 100-109 0.5 100-109 1 100-109 1.5 100-109 2 100-109 3 110-129 0.5 110-129 1 110-129 1.5 110-129 2 110-129 3 110-129 4 130-149 1 130-149 1.5 130-149 2 130-149 3 130-149 4 130-149 6 150-179 1.5 150-169 2 150-179 3 150-169 4 150-179 6 150-169 8 170-189 2.5 170-189 5 170-189 10 180-209 2 190-209 3 180-209 4 190-209 6 180-209 8 190-209 12 210-269 3 210-254 4 210-239 5 210-229 7 210-239 10 210-229 14 240-269 6 230-269 8 240-269 12 230-249 16 270-329 4 255-299 5 270-299 7 270-309 10 270-299 14 250-269 18 300-345 6 300-329 8 310-349 12 300-329 16 270-309 20 330-389 5 330-359 9 330-359 18 310-349 24 346-389 7 360-389 10 350-389 14 360-389 20 350-389 28 ≥ 390 6 ≥ 390 8 ≥ 390 11 ≥ 390 16 ≥ 390 22 ≥ 390 32

Adapted from Markovitz LJ, et al. Endocr Pract. 2002;8:10–18.

77

0

5

10

15

20

25

30

35

40

45

50 79 110 140 171 201 232 263 293 324 354 385 416 444 475

Blood Glucose (mg/dL)

Insulin Infusion Rate

(Units/h)

Column 1Column 2Column 3Column 4Column 5Column 6

Insulin Infusion Protocol Targeting Blood Glucose 80–110 mg/dL

78

Protocol of Markovitz and Colleagues

• Uses multiple columns of scales for varying degrees of insulin resistance

• Physician determines initial scale with nursing rules for moving to different columns

• Very simple to determine prescribed rate for nursing

• Logistical limitations on the number of scales and goals that can be supported

• Each range and sensitivity require another column

79

Yale Insulin Infusion ProtocolInsulin infusion: Mix 1 U regular human insulin per 1 mL 0.9% NaCl

Administer via infusion pump in increments of 0.5 U/h

Bolus and initial infusion rate:Divide initial BG by 100, round to nearest 0.5 U for bolus and initial infusion rates

Example: Initial BG = 325 mg/dL: 325/100 = 3.25, round up to 3.5: IV bolus = 3.5 uU + start infusion at 3.5 U/h

Subsequent rate adjustments:Changes in infusion rate are determined by the current infusion rate and the hourly rate of change from the prior BG level

Goldberg PA, et al. Diabetes Care. 2004;27:461–467.

80

Yale Insulin Infusion Protocol

• Individualized starting doses and highly responsive rate adjustments that compensate for insulin sensitivity and rate of glucose change

• Utilization requires substantial ongoing calculations to determine hourly rate of change

• May increase the likelihood of error in many clinical settings

81

Summary

• Several tested, safe protocols are available• Each has its own advantages and disadvantages

• Protocol development is time and resource intense:

• Consensus must be reached across multiple areas within the hospital, physician practice, nursing, pharmacy…

• The protocol then has to be tested for efficacy, safety, etc.

• Adoption of an established protocol is significantly more efficient

82

Use of Subcutaneous Insulin

• Effective insulin therapy must provide both basal and nutritional coverage to achieve target goals

• Hospitalized patients often require high insulin doses to achieve desired target glucose levels

• In addition to basal and nutritional insulin requirements, patients often require supplemental or correction insulin for treatment of unexpected hyperglycemia

83

Common Features Increasing Risk of Hypoglycemia in an Inpatient Setting

• Advanced age

• Decreased oral intake

• Chronic renal failure

• Liver disease

• Beta-blockers

84

Use of “Sliding Scale” Insulin Alone Is Discouraged

• Evidence does not support this technique without basal insulin because it has resulted in unacceptably high rates of

• Hyperglycemia• Hypoglycemia• Iatrogenic diabetic ketoacidosis in hospitalized

patients with Type 1 diabetes

85

Insulin Requirements in Health and Illness

Clement S, et al. Diabetes Care 2004;27:553–591

Units

CorrectionNutritionalPrandialBasal

Healthy Sick/Eating Sick/NPO

86

Constructing a profile for scheduled subcutaneous insulin

Lispro/ Aspart/ GlulysineSQ Regular

NPH Glargine

6 pm 12 am 6 am 12 pm

87

Example of Components of Standardized Subcutaneous Insulin Orders

NPH

Glargine

NPH

Glargine

NPH

Glargine

Give __ units:

NPH

Glargine

Basal insulin

Suggested lag times for prandial insulin:Lispro/aspart/glulysine —0–15 minutes before eatingRegular 30 minutes before eating.

Give __ units:

Lispro

Aspart

Regular

Give __ units:

Lispro

Aspart

Regular

Give __ units:

Lispro

Aspart

Regular

Give __ units:

Lispro

Aspart

Regular

Nutritionalinsulin

BedtimeDinnerLunchBreakfastInsulin

88

Factors Increasing Risk of Sub-optimal Glucose Control in an Inpatient Setting• Lack of coordination between dietary

and nursing leads to mistiming of insulin dosage with respect to food

• Inadequate glucose monitoring• Lack of coordination between transportation and nursing• Indecipherable orders• Separate locations for glucose results and insulin

administration records• Absent or poorly maintained glucose flow sheets

89

Core Knowledge for Physicians

• Impact of blood glucose on hospital outcomes

• Hospital targets for blood glucose

• Terminology: basal/nutritional/correction

• Insulin product knowledge

• Hypoglycemia prevention and treatment

90

Core Competencies for Nurses

• Bedside glucose monitoring technique

• Critical and target blood glucose values

• Insulin administration technique

• Optimum timing of SC insulin shots

• Hypoglycemia prevention and treatment

• Blood glucose and insulin dose documentation

91

Learning Objectives• Discuss the prevalence of hyperglycemia among

hospitalized patients • Discuss the impact of hyperglycemia on clinical outcome

and cost • Understand the background literature supporting

intensive glucose management • Understand the biochemical and physiological

mechanisms involved in intensive insulin therapy that reduce morbidity and mortality

• Compare existing protocols for achieving tight glucose control in an inpatient setting

92

The End

• Proceed to the post test

• Print the post test

• Complete the post test

• Return the post test to Dr. Sandra Oliver

407i TAMUII

93

Post test question 1

Which of the following correctly reflects the prevalence of hyperglycemia among hospitalized patients ?

1. Fourth most common co-morbid condition among hospitalized patients

2. 40-50% of all hospital discharges

3. 60% of all cardiac surgery patients

4. 7 days longer hospital stay

94

Post test question 2Which of the following is a false statement ?1. Diabetes mellitus is a risk factor for mortality after

cardiac surgery 2. Preoperative hyperglycemia is an independent

predictor of length of hospital stay after open heart surgery

3. Incidence of deep wound infection is increased after insulin protocol implementation to maintain mean blood glucose levels < 200 mg/dL in postoperative period

4. Continuous insulin infusion should be standard of care for glycometabolic control in patients with diabetes undergoing cardiac surgery

95

Post test question 3Evidence does not support use of sliding scale ALONE

because it results in unacceptably high rates of all the following except

1. Hyperglycemia

2. Hypoglycemia

3. Hypomagnesemia

4. Iatrogenic diabetic ketoacidosis in hospitalized patients with Type 1 diabetes

96

Post test question 4

Potential physiological mechanisms of hyperglycemia and poor outcomes includes all of the following except:

1. Accelerated catabolism

2. Increased transcription factors

3. Deceased FFA

4. Hypoinsulinemia.

inpatient glucose control: how low should we go? glucose control: how low should we go? a. keith...

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