Inpatient Management of Hyperglycemia

Russell Vinik, M.D.Hospitalist, University of Utah

Overview

Observations related to hyperglycemia and outcomes in hospitalized patientsPotential mechanisms for poor outcomes in hyperglycemic patientsReview interventional studies related to glucose managementStrategies for improving inpatient control

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

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

1.73

16

0

2

4

6

8

10

12

14

16

18

In-hospital Mortality Rate

(%)

Newly Discovered

Hyperglycemia

Patients With History of Diabetes

Patients With

Normoglycemia

P < 0.01

P < 0.01

Postoperative Glycemic Control Correlates With Cardiac-Related Mortality

0

5

10

15

<150 150-175 175-200 200-225 225-250 >250

Noncardiac-related mortality Cardiac-related mortality

* (P<.001). Furnary AP et al. J Thorac Cardiovasc Surg. 2003;125:1007-

1021.

Mo

rta

lity

(%)

0.9 1.3

2.34.1

6.0

14.5

Average Postoperative Glucose (mg/dL)

**

*

*

Poor Outcomes Correlate With Hyperglycemia After Acute Ischemic Stroke

Blood Glucose at Admission

OutcomeBG <130 mg/dL

(n=385)BG 130 mg/dL

(n=258) P value

Length of stay

Discharged to home

In-hospital mortality

30-Day mortality

1-Year mortality

6 ± 0.3

79%

5%

5%

11%

7.2 ± 0.4

73%

7%

10%

18%

.015

.07

.15

.018

.009

Williams LS et al. Neurology. 2002;59:67-71.

0%

5%

10%

15%

20%

25%

30%

35%

Infections Infections excluding

UTI's

<220 >220

Rates of Nosocomial Infection in 100 Uninfected Diabetics Undergoing

Elective Surgery

Glucose on Post-Op Day #1

Pomposelli et al. JPEN 1998; 22:2, 77-81

Hyperglycemia and Poor Outcomes Following Myocardial Infarction

0

10

20

30

<110 110-139 140-169 170-199 >200

Arch Intern Med. 2009;169(5):438-446

In H

osp

ital

Mo

rtal

ity

(%)

Average Post-admission Glucose

Basic Science

Hyperglycemia is associated with increased neuron damage following brain ischemiaHyperglycemia leads to increased platelet aggregation and thrombosisInsulin decreases arterial levels of free fatty acidsHyperglycemia leads to increased cytokine levels and inflammationNeutrophil Adherence, chemotaxis, phagocytosis and extravasation are

all inhibited by increased glucose concentrations

Diabetes Care. 2004;27:553-591, Diabetes 1989;38:1031-5, Diabetes Care 2001;24:1634-9

Intervention Studies

Insulin and Sternal Wound Infections

Furnary et al studied 2467 patients undergoing open heart operations

The first 968 patients were treated with a sliding scale to keep glucose near 200

The next 1499 patients received an insulin infusion to keep glucose 150-200

Ann Thorac Surg 1999;67:352-62

Insulin and Sternal Wound Infections

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

4

3

2

1

0

DS

WI

(%)

87 88 89 90 91 92 93 94 95 96 97Year

CII

Patients with diabetes

Nondiabetic patients

Insulin and Mortality in CABG patients

0%

2%

4%

6%

8%

10% Non-Diabetics

Diabetics

CII

Year

Furnary AP Endocr Pract. 2004;10(suppl 2):21-33.

Mo

rta

lity

Intensive Insulin in the Critically Ill- (Leuven I)

Van Den Berghe et al enrolled 1548 ventilated patients mostly post cardiac surgery13% of these patients had diabetes Patients were randomized to:

intensive treatment- infusion to maintain glucose between 80-110mg/dl

conventional treatment- targeting a glucose of 180-200mg/dl

Mean glucose in the intensive treatment group was 103 and conventional group was 153Hypoglycemic events (glucose<40) occurred in 5.1% of patients in the intensive treatment group vs. 0.76% of patients in the conventional group

Van den Berghe G et al. NEJM 2001;345: 1359-67

Intensive Insulin in the Critically Ill

Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.

100

96

92

88

84

80

0

0 20 40 60 80 100 120 140 160

Intensive treatment

Conventional treatment

Intensive treatment

Conventional treatment

Su

rviv

al i

n I

CU

(%

)

100

96

92

88

84

80

0

0 50 100 150 200 250

In-H

osp

ital

Su

rviv

al (

%)

Days After Admission Days After Admission

42.5% reduction in mortality with intensive treatment; P<.04

34% reduction in mortality with intensive treatment; P<.01

Benefits of IV Insulin Treatment in Critically Ill Hospitalized Patients

-60

-50

-40

-30

-20

-10

0Total Mortality Blood Infection

Acute RenalFailure Transfusions Polyneuropathy

Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.

Red

uct

ion

(%

)

34%

46%41%

50%

44%

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

The Stamford Project

Mixed medical/surgical/cardiac ICU

“Before-and-after” design Developed an insulin protocol and followed

800 consecutive patientsCompared the outcomes in these patients to

a control group of 800 consecutive patients immediately prior to protocol institution

Targeted a blood glucose of less than 140

Stamford Project: Improvement in Mortality

0

10

20

30

40

50

60

70

All Cardiac Respiratory Septic Shock Neurologic GeneralSurgical

*

*P<.01 compared with control group.†P<.05 compared with control group.

†

*

†

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

Dec

reas

e in

Mo

rtal

ity

Wit

h T

reat

men

t (%

)

Leuven II- Intensive Insulin in MICU Patients with expected LOS >3 days

Van den Berghe G et al. N Engl J Med. 2006;354;5:449-61.

* p<.05

0%

10%

20%

30%

40%

50%

60%

Conventional Intensive treatment

*

*

*

Intensive Insulin Meta-analysis of 29 Trials

8432 Patients

JAMA 2008;300(8):933-44

0%

5%

10%

15%

20%

25%

30%

Total Mortality (p=.7)

Mortality in Surgical pts

Mortality in Medical pts

Septicemia

Hypoglycemia (glucose <40)

Conventional Intensive treatment

NICE-SUGARRandomized trial of 6104 patients 42 hospitals in Australia, New Zealand, and Canada Enrolled patients with an expected LOS of 3 days and had an arterial

line Intervention discontinued when patient was eating or discharged from

ICU

Reason for ICU admission: 37% Operative 63% Non-Operative

Patients were randomized to: intensive treatment- infusion to maintain glucose between 81-108

mg/dl conventional treatment- targeting a glucose of <180mg/dl

Mean glucose in the intensive treatment group was 115mg/dl and conventional group was 144mg/dl

NEJM 2009;360:1283-97

NICE-SUGAR Results

Critical Care Med 2008;36:12 1-8

0%5%

10%15%20%25%30%35%40%45%

Conventional Intensive treatment

How do we use this data to care for our patients?

American Diabetes Association 2009* “Standards of Medical Care”

Diabetes Care 2009 32;Supp 1:S14-61 Circulation 2008;117;1610-19 Critical Care Med 2008 35:296-327

International Guidelines for Management of Severe Sepsis and Septic Shock: 2008

Critical <150 mg/dL 2C

Patients Fasting Non-Fasting Evidence levelCritical surgical 110 mg/dL 110 mg/dL ACritical non-surgical <140 <140 CNoncritical <126 mg/dL <180-200mg/dL E (Expert Consensus)

American Heart Association: Hyperglycemia and Acute Coronary Syndrome

Critical 90-140 mg/dL CNoncritical <180 mg/dL C

The Endocrine Society- Position Statement March 2009

Critical <144-180 mg/dL

* ADA/AACE statement March 09 promised new guidelines and recommended targets similar to the “conventional” arm of NICE-SUGAR

Barriers to Inpatient Glucose Control

Infection, fever, stress, glucocorticoids, surgery all exacerbate hyperglycemia

Patients may eat less or have meals held

Timing of insulin administration and meals are often disrupted

Oral medications are often held

Limitations of Oral Agents for Managing In-Hospital Hyperglycemia

Sulfonylureas No rapid dose adjustment Risk of hypoglycemia in patients not eating normally

Metformin No rapid dose adjustment Mostly contraindicated due to increased risk of lactic acidosis in

hospitalized patients (ie, intravenous contrast, renal failure, congestive heart failure)

Thiazolidinediones No rapid dose adjustment Mostly contraindicated in heart failure, hepatic dysfunction

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

Using Insulin in the Hospital

First, Determine Source/Route of Nutrition

Second, Estimate a Starting Dose of Scheduled Insulin

Third, Know the Kinetics of the insulin you are using and make a plan

Prandial insulin

Source of Nutrition- Effects on Insulin Secretion

B L D B L D

Basal insulinBasal insulin Basal insulin

Prandial insulin

The Eating Patient Pt. Receiving Continuous Feeds

Estimating a Starting Dose

Use patient’s home regimen Adjust as clinically indicated

Make a weight based estimate* Start 0.4units/kg for glucose 140-200 Start 0.5 units/kg for glucose 201-400 Consider lower starting dose with significant renal or hepatic

impairment

Estimate basal insulin and carb count Difficult to achieve in the hospital If attempting, estimate basal insulin (.2-.25 units/kg/day)

Type I: Give 1 unit per 15g carbohydrates Type II: Give 1 unit per 10g carbohydrates

Diabetes Care 30:2181-2186, 2007

Kinetics of Insulins

Regular

NPH

0 126 18 24

aspart/glulisine/lispro

glargine

Mimicking Nature With Insulin Basal/Bolus ConceptPhysiologic Insulin Secretion

Insu

lin

(µU

/mL

)

Glu

cose

(mg

/dL

)

9

B L D

150

100

50

07 8 91011121 2 3 4 5 6 7 8

AM PMTime of Day

Basal glucose

50

25

0

24-hr profile

Basal insulin

Adapted from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821

Insulin aspart/glulisine/lispro

Insulin glargine

Basal-Bolus Insulin Therapy: Insulin Glargine at HS

and Mealtime Lispro or Aspart

B DL HS

Insu

lin E

ffe

ct

Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY:

Marcel Dekker Inc.; 2002:87

Example: Patient’s Total Daily Insulin Estimate=60

Units

10 units aspart

glulisine lispro

10 unitsaspart

glulisine lispro

10 unitsaspart

glulisine lispro

30 unitsglargine

Insu

lin E

ffe

ct

Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker Inc.; 2002:87

Twice-Daily Split-Mixed Regimens

Regular

NPH

B DL HS B

Endogenous insulin

Dawn phenomenon

Hyperglycemia

13 units NPH

Example: Patient’s Total Daily Insulin Estimate=60 Units

27 units NPH

40 units of insulin in the a.m.

20 units of insulin in the p.m.

+13 units regular +7 units regular

Insulin Requirement During Continuous Dextrose, TPN or Enteral Feedings,or Negligible Carbohydrate Exposure

8 12 6 10

6 12 6 12

NPH

6 12 6 12

Regular at least 50 % - - - -

Glargine not more than 50 %

Regular ~ 33 % (hold if low) - - -

NPH ~ 67 % —

q 6 – 8 h

Regimens for patient while NPO, on IV’s,

or receiving continuous enteral

feedings.

The Insulin Infusion

Many Protocols ExistDIGAMI (IV insulin glucose infusion followed by outpatient multidose subcutaneous insulin regimen)van den Berghe (IV insulin therapy to maintain blood glucose between 80 and 110 mg/dL)Portland protocol (perioperative use of IV insulin)Markovitz (IV insulin therapy to maintain blood glucose between 120 and 199 mg/dL)Yale Protocol (IV insulin therapy to maintain blood glucose between 100 and 139 mg/dL)Stamford Protocol (IV/SQ insulin only given if glucose is greater than 140)Duke Protocol (IV insulin to maintain blood glucose 101-150)

Malmberg K. BMJ. 1997;314(7093):1512–1515.van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.Markovitz LJ, et al. Endocr Pract. 2002;8:10–18.Goldberg PA, et al. Diabetes Care. 2004;27:461–467.Krinsley JS. Mayo Clin Proc. 2004;79:992-1000.Lien LF., et al. Endocr Pract. 2005;11: 240-53.

43

8 12 6 10

aspart, glulisine, lispro

Glargine

Peri-Procedural Management

8 12 6 10RegularNPH

Hold short acting insulin and give ½ regular dose of NPH

8 12 6 10

Insulin Requirement High a.m. dose corticosteroids

Solution B.

8 am 12 6 10

R - - -

NPH —

8 12 6 10

Lispro or aspart

Glargineduringcortico-steroids( ~ 30 % )

Solution A.

Thank You