Inpatient Management of Hyperglycemia

1
Inpatient Management of Hyperglycemia

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

2
Overview

• Observations related to hyperglycemia and
  outcomes in hospitalized patients
• Potential mechanisms for poor outcomes in
  hyperglycemic patients
• Review interventional studies related to glucose
  management
• Strategies for improving inpatient control

3
Hyperglycemia Is an Independent Marker of
Inpatient Mortality in Patients With Undiagnosed
Diabetes
P lt 0.01
P lt 0.01
In-hospital Mortality Rate ()
Newly Discovered Hyperglycemia
Patients With History of Diabetes
Patients With Normoglycemia
Umpierrez GE et al. J Clin Endocrinol Metab.
200287978-982.
4
Postoperative Glycemic Control Correlates With
Cardiac-Related Mortality

14.5

Mortality ()
6.0


4.1
2.3
1.3
0.9
Average Postoperative Glucose (mg/dL)
(Plt.001). Furnary AP et al. J Thorac
Cardiovasc Surg. 20031251007-1021.
5
Poor Outcomes Correlate With Hyperglycemia After
Acute Ischemic Stroke
Williams LS et al. Neurology. 20025967-71.
6
Rates of Nosocomial Infection in 100 Uninfected
Diabetics Undergoing Elective Surgery

• Glucose on Post-Op Day 1

Pomposelli et al. JPEN 1998 222, 77-81
7
Hyperglycemia and Poor Outcomes Following
Myocardial Infarction
In Hospital Mortality ()
Average Post-admission Glucose
Arch Intern Med. 2009169(5)438-446
8
Basic Science

• Hyperglycemia is associated with increased neuron
  damage following brain ischemia
• Hyperglycemia leads to increased platelet
  aggregation and thrombosis
• Insulin decreases arterial levels of free fatty
  acids
• Hyperglycemia leads to increased cytokine levels
  and inflammation
• Neutrophil
• Adherence, chemotaxis, phagocytosis and
  extravasation are all inhibited by increased
  glucose concentrations

Diabetes Care. 200427553-591, Diabetes
1989381031-5, Diabetes Care 2001241634-9
9
Intervention Studies
10
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 199967352-62
11
Insulin and Sternal Wound Infections
Patients with diabetes Nondiabetic patients
4 3 2 1 0
CII
DSWI ()
87 88 89 90 91 92 93 94 95 96 97 Year
Furnary AP et al. Ann Thorac Surg.
199967352-362.
12
Insulin and Mortality in CABG patients
CII
Mortality
Year
Furnary AP Endocr Pract. 200410(suppl 2)21-33.
13
Intensive Insulin in the Critically Ill- (Leuven
I)

• Van Den Berghe et al enrolled 1548 ventilated
  patients mostly post cardiac surgery
• 13 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 153
• Hypoglycemic events (glucoselt40) 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 2001345 1359-67
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Intensive Insulin in the Critically Ill
100 96 92 88 84 80 0
100 96 92 88 84 80 0
Intensive treatment
Intensive treatment
Conventional treatment
In-Hospital Survival ()
Survival in ICU ()
Conventional treatment
42.5 reduction in mortality with intensive
treatment Plt.04
34 reduction in mortality with intensive
treatment Plt.01
0 20 40 60 80 100 120 140 160
0 50 100 150 200 250
Days After Admission
Days After Admission
Van den Berghe G et al. N Engl J Med.
20013451359-1367.
15
Benefits of IV Insulin Treatment in Critically
Ill Hospitalized Patients
Reduction ()
34
41
44
46
50
Van den Berghe G et al. N Engl J Med.
20013451359-1367.
16
The Stamford Project

• Mixed medical/surgical/cardiac ICU
• Before-and-after design
• Developed an insulin protocol and followed 800
  consecutive patients
• Compared 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

Krinsley JS. Mayo Clin Proc. 2004799921000.
17
Stamford Project Improvement in Mortality



Decrease in Mortality With Treatment ()

Plt.01 compared with control group. Plt.05
compared with control group.
Krinsley JS. Mayo Clin Proc. 200479992-1000.
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Leuven II- Intensive Insulin in MICU Patients
with expected LOS gt3 days



plt.05

Van den Berghe G et al. N Engl J Med.
20063545449-61.
19
Intensive Insulin Meta-analysis of 29 Trials
8432 Patients

JAMA 2008300(8)933-44
20
NICE-SUGAR

• Randomized 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
  lt180mg/dl
• Mean glucose in the intensive treatment group was
  115mg/dl and conventional group was 144mg/dl

NEJM 20093601283-97
21
NICE-SUGAR Results

Critical Care Med 20083612 1-8
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How do we use this data to care for our patients?
23
American Diabetes Association 2009 Standards
of Medical Care
ADA/AACE statement March 09 promised new
guidelines and recommended targets similar to the
conventional arm of NICE-SUGAR
American Heart Association Hyperglycemia and
Acute Coronary Syndrome
International Guidelines for Management of Severe
Sepsis and Septic Shock 2008
The Endocrine Society- Position Statement March
2009
Diabetes Care 2009 32Supp 1S14-61
Circulation 20081171610-19 Critical Care Med
2008 35296-327
24
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

25
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. 200427553-591.
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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

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Source of Nutrition- Effects on Insulin Secretion
Pt. Receiving Continuous Feeds
The Eating Patient
Prandial insulin
Basal insulin
Prandial insulin
Basal insulin
Basal insulin
B L D
B L D
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Estimating a Starting Dose

• Use patients 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 302181-2186, 2007
30
Kinetics of Insulins
aspart/glulisine/lispro
Regular
NPH
glargine
0
12
6
18
24
31
Mimicking Nature With Insulin Basal/Bolus Concept
Physiologic Insulin Secretion
Insulin (µU/mL)
B L D
150
100
Glucose (mg/dL)
50
Basal glucose
0
9
7
8
9
10
11
12
1
2
3
4
5
6
7
8
AM
PM
Time of Day
Adapted from Bergenstal RM et al. In DeGroot LJ,
Jameson JL, eds. Endocrinology. 4th ed.
Philadelphia, Pa WB Saunders Co. 2001821
32
Basal-Bolus Insulin Therapy Insulin Glargine at
HS and Mealtime Lispro or Aspart
Insulin Effect
B
L
D
HS
Insulin glargine
Insulin aspart/glulisine/lispro
Adapted from Leahy J. In Leahy J, Cefalu W, eds.
Insulin Therapy. New York, NY Marcel Dekker
Inc. 200287
33
Example Patients Total Daily Insulin
Estimate60 Units
Insulin Effect
10 units aspart glulisine lispro
10 units aspart glulisine lispro
10 units aspart glulisine lispro
30 units glargine
Adapted from Leahy J. In Leahy J, Cefalu W, eds.
Insulin Therapy. New York, NY Marcel Dekker
Inc. 200287
34
Twice-Daily Split-Mixed Regimens
Endogenous insulin
Regular
NPH
Hyperglycemia
Dawn phenomenon
B
D
L
HS
B
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Example Patients Total Daily Insulin
Estimate60 Units
13 units NPH
27 units NPH
13 units regular
7 units regular
40 units of insulin in the a.m.
20 units of insulin in the p.m.
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Insulin Requirement During Continuous Dextrose,
TPN or Enteral Feedings, or Negligible
Carbohydrate Exposure
38
Regimens for patient while
NPO, on IVs, or receiving
continuous enteral feedings.
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The Insulin Infusion
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Many Protocols Exist

• DIGAMI (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. 1997314(7093)15121515. van
den Berghe G, et al. N Engl J Med.
200134513591367. Markovitz LJ, et al. Endocr
Pract. 200281018. Goldberg PA, et al. Diabetes
Care. 200427461467. Krinsley JS. Mayo Clin
Proc. 200479992-1000. Lien LF., et al. Endocr
Pract. 200511 240-53.
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Peri-Procedural Management
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Thank You