Willard P. VanderLaan Annual Diabetes Lectureship · Medical/surgical ICU Mixed, no Cardiac 29%...

Scripps Clinic/Scripps Green Hospital Grand RoundsWednesday, Nov. 18, 2009

Guillermo E. Guillermo E. UmpierrezUmpierrez, MD, FACP, FACE, MD, FACP, FACE

1

Willard P. VanderLaan2nd Annual Diabetes Lectureship

November 18th, 2009

Guest Speaker:Guillermo E. Guillermo E. UmpierrezUmpierrez, MD, FACP, FACE, MD, FACP, FACE

November-Diabetes Awareness Month

• The CDC estimates that nearly 24 million Americans have diabetes, yet 25% of these cases are undiagnosed.

• Almost 25% of the population aged 60 and older have diabetes.

• Around 3.2 million deaths every year are attributable to complications of diabetes; six deaths every minute.

• Diabetes is the most frequently reported cause of kidney failure in the United States

• The total annual economic cost of diabetes in 2007 was estimated to be $174 billion.

• At least 171 million people worldwide have diabetes; this figure is likely to be more than double by 2030.

• Sources:• American Diabetes Association – http://www.diabetes.org/• Agency for Healthcare and Research Quality – http://www.ahrq.gov/• Center for Disease Control and Prevention – http://www.cdc.gov• Robert Wood Johnson Foundation – http://www.rwjf.org/• United States National Center for Health Statistics – http://www.cdc.gov/nchs/• World Health Organization – http://www.who.int/en/

Scripps Diabetes Inpatient Stats-2004-2007

PERCENT OF DIABETIC INPATIENTSFISCAL YEAR TOTALS

0%

5%

10%

15%

20%

25%

30%

CVENGRLJME

RA

TE

FY04 FY05 FY06 FY07

2009 Major Accomplishments

• Systemwide glucose reports

• Systemwide sub-Q insulin protocols

• Systemwide insulin pharmacy reports

Sample Glucose Reports – Scripps Enterprise Data Warehouse

StandardizedSubcutaneous Insulin Orders

Scripps Conference Services & CME www.scripps.org/conferenceservices



2

Insulin Orders - Green

Protocol = Subcut insulin order set for eating and

NPO patient; patient must be receiving basal insulin

plus nutritional or correctional; or nutritional

plus correctional insulin

RED-Sliding scale insulinYELLOW-Basal/BolusGREEN-Protocol




Guillermo E. Guillermo E. UmpierrezUmpierrez, MD, FACP, FACE, MD, FACP, FACEProfessor of MedicineProfessor of Medicine

Director, Grady Hospital Clinical Research UnitDirector, Grady Hospital Clinical Research UnitDirector, Diabetes and Endocrinology SectionDirector, Diabetes and Endocrinology Section

Emory University School of MedicineEmory University School of Medicine

InhospitalInhospital GlycemicGlycemic Management Management of Diabetes: ADA/AACE Position of Diabetes: ADA/AACE Position

StatementStatement

Case Presentation:

48 y/o male with an 8 yr history of DM admitted 3 day history of fever, cough, and RLL pneumonia on chest x-ray. Previously treated with metformin and sulfonylurea.

Lab: BG 264 mg/dL, creatinine 1.8 mg/dL, A1C: 8.4%.

Given this patientGiven this patient’’s history and laboratory values, what is the s history and laboratory values, what is the best treatment option for best treatment option for glycemicglycemic management?management?

1. Continuous IV insulin drip?

2. Sliding-scale regular insulin?

3. Split-mixed regimen – NPH + Regular insulin?

4. Basal bolus regimen – long + rapid acting analogs?

1. Umpierrez G et al. J Clin Endocrinol Metabol. 2002, 87:978-982.2. Levetan CS et al. Diabetes Care. 1998;21:246-249.3. Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.4. Falciglia M et al. 66th ADA Scientific Meeting, 2006.

Hyperglycemia Is Common in Hospitalized Patients

Non-critically ill medical/surgical: 38%

Intensive care units (ICU): 29% – 100% Episodes of glucose >110 mg/dL: 100% Episodes of glucose >200 mg/dL: 31% Mean glucose >145 mg/dL: 39%

Hyperglycemia*: A Common Comorbidityin Medical-Surgical Patients in a Community Hospital

62%62%

12%12%

26%26%

NormoglycemiaNormoglycemia

Known DiabetesKnown Diabetes

New HyperglycemiaNew Hyperglycemia

UmpierrezUmpierrez G et al, J G et al, J ClinClin EndocrinolEndocrinol MetabolMetabol 87:978, 200287:978, 2002

n = 2,020n = 2,020

* Hyperglycemia: Fasting BG * Hyperglycemia: Fasting BG 126 mg/dl126 mg/dlor Random BG or Random BG 200 mg/dl X 2200 mg/dl X 2

Hyperglycemia: Scope of the Problem

Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A.

No Diabetes

26%

Diabetes 50

40

30

20

10

0<110 110-140

50

40

30

20

10

0<110 110-140 140-170 170-200 >200

78%

140-170 170-200 >200

Mean BG, mg/dL

Pat

ien

ts,

%

Hyperglycemia and Pneumonia OutcomesHyperglycemia and Pneumonia Outcomes

0

5

10

15

20

25

30

Mortality

HospitalComplications

BG (mg/dl) < 110 110 - <198 198 - <250 ≥250

* *

* *

* p: < 0.05 vs BG < 198 mg/dl (11 mmol/L)

Admission glucose (mg/dl)

%

McAllisterMcAllister et al, et al, DiabetesDiabetes CraeCrae 28:81028:810--815, 2005815, 2005

N= 2,471 patients with CAP




~2x

Mor

talit

y R

ate

(%)

Mean Glucose Value (mg/dL)

Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.

N=1826 ICU 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 >3000

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

Hyperglycemia and Mortalityin the MICU

~4x~3x

Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes

Total InTotal In--patient Mortalitypatient Mortality

NormoglycemiaNormoglycemia Known Known NewNewDiabetesDiabetes HyperglycemiaHyperglycemia

1.7%1.7% 3.0%3.0%

16.0% 16.0% **

Mor

talit

y (%

)M

orta

lity

(%)

* P < 0.01* P < 0.01

UmpierrezUmpierrez GE et al, J GE et al, J ClinClin EndocrinolEndocrinol MetabolMetabol 87:978, 200287:978, 2002

Study Setting Population Clinical Outcome

Furnary, 1999 ICU DM undergoing open heart surgery 65% infection

Furnary, 2003 ICU DM undergoing CABG 57% mortality

Krinsley, 2004 Medical/surgical ICU Mixed, no Cardiac 29% mortality

Malmberg, 1995 CCU Mixed 28% mortalityAfter 1 year

Van den Berghe, 2001* Surgical ICU Mixed, with CABG 42% mortality

Lazar, 2004 OR and ICU CABG and DM 60% A Fib post op survival 2 yr

*RCT, randomized clinical trial.

Kitabchi & Umpierrez. Metabolism. 2008;57:116-120.

Early Observation & Intervention Trials

Insulin Infusion Reduces Wound Infections In Diabetic Patients After Cardiac Surgery:

The Portland Protocol

Prospective study of 2,467 consecutive diabetics who Prospective study of 2,467 consecutive diabetics who underwent open heart surgery between 1/87underwent open heart surgery between 1/87--11/97.11/97.

1, 499 1, 499 968968Continuous IV insulinContinuous IV insulin Sliding scale insulin Sliding scale insulin

(CII)(CII) (SSI Q 4(SSI Q 4--hr)hr)

BG goal: 150BG goal: 150--200 mg/dl200 mg/dl BG goal: ~ 200 mg/dl BG goal: ~ 200 mg/dl

FurnaryFurnary AP et al, Ann AP et al, Ann ThoracThorac SurgSurg 67:35267:352--62, 199962, 1999

Day of surgery: 241 mg/dLPOD #1: 206 mg/dLPOD #2: 195 mg/dLPOD#3: 188 mg/dl

Day of surgery: 199 mg/dLPOD #1: 176 mg/dLPOD #3: 185 mg/dLPOD#3: 181 mg/dl

2, 467 patients2, 467 patients

DSWI, deep sternal wound infection; SCI, subcutaneous insulin; CII, continuous insulin infusion.

4.0

3.0

2.0

1.0

0.0

DSWI(%)

87 88 89 90 91 92 93 94 95 96 97

Year

Patients with diabetes

Patients without diabetes

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

CII(N=3554) SCI

Portland Diabetes Project: Insulin Infusion Reduces DSWI

Blood Glucose (mg/dL)

<150 150-175

200-225

175-200

>250225-250

P<0.0001

*P<0.001

PostopMortality

BG <200n=662

1.8%

BG >200

n=1369

5.0% *

Pos

top

Mor

talit

y (%

)

Adjusted for 19 clinical and operation variables

Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591.

1.4 1.72.1

3.8

5.8

8.6

0

2

4

6

8

10

Hyperglycemia: A Predictor of Mortality Following CABG in Diabetics

CABG, coronary artery bypass graft.

First Postop Glucose >200

• 2x LOS• 3x Vent duration• 7x mortality !!!




Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study

Randomized controlled trial: 1548 patients admitted to a surgical ICU, receiving mechanical ventilation.

Conventional therapyConventional therapy: : IV insulin only if BG >215 mg/dL Target BG levels: 180-200 mg/dL Mean daily BG: 153 mg/dL

Intensive therapyIntensive therapy: : IV insulin if BG >110 mg/dL Target BG levels : 80-110 mg/dL Mean daily BG: 103 mg/dL

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

Intensive Insulin Therapy in Critically Ill Patients: SICU

**

**

**

**

**

**

*P<0.01

Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. Relative Risk Reduction (%)

AACE AACE -- Consensus Conference Consensus Conference Suggested Blood Glucose TargetsSuggested Blood Glucose Targets

Upper Limit Inpatient Upper Limit Inpatient GlycemicGlycemic Targets:Targets:

ICU: 110 mg/dl (6.1 ICU: 110 mg/dl (6.1 mmolmmol/L)/L)

NonNon--critical care (limited data)critical care (limited data)•• PrePre--prandial: 110 mg/dl (6.1 prandial: 110 mg/dl (6.1 mMmM))•• Maximum: 180 mg/Maximum: 180 mg/dLdL (10 (10 mMmM))

AACE- Endocrine Practice 10 (1): 77-82, 2004AAE – Endocrine Practice February 2006ADA- Diabetes Care 27: 553-591, 2004

The current ADA guideline for pre-prandial plasma glucose levels is 90–130 mg/dl

Intensive Glucose Management in RCT

Trial N Setting Primary

Outcome ARR RRROdds Ratio

(95% CI) P-value

Van den Berghe2006

1200 MICU Hospitalmortality

2.7% 7.0% 0.94*(0.84-1.06)

N.S.

HI-52006

240 CCU AMI 6-mo mortality

-1.8%* -30%* NR N.S.

Glucontrol2007

1101 ICU ICU mortality

-1.5% -10% 1.10*(0.84-1.44)

N.S.

Ghandi2007

399 OR Composite 2% 4.3% 1.0*(0.8-1.2)

N.S.

VISEP2008

537 ICU 28-dmortality

1.3% 5.0% 0.89*(0.58-1.38)

N.S.

De La Rosa 2008

504 SICUMICU

28-d mortality

-4.2% * -13%* NR N.S.

NICE-SUGAR2009

6104 ICU 3-mo mortality

-2.6% -10.6 1.14(1.02-1.28)

< 0.05

*not significant

Study Aim: To compare the effects of 2 insulin regimens on clinical outcome: Intensive Therapy groupIntensive Therapy group: :

•• Target BG: Target BG: 80 - 110 mg/dLAchieved mean BG: 118 mg/dl (109-131 mg/dl)

Conventional Therapy groupConventional Therapy group: : • Target BG: 140 - 180 mg/dL

Achieved mean BG: 147 mg/dl (127-163 mg/dl)

Nondiabetic patients: 872 Diabetic patients: 210

Glucose Control in the ICU: How Low Should We Go?

Glucontrol

Preiser JC et al, J Crit Care 2009

IIT(n=536)

CIT(n=546) P

Nondiabetic patients 872 patientsDeaths

Diabetic patients210 patients Deaths

44617.0%

9016.7%

42616.2%

12011.7%

0.738

0.298

Glucontrol





0.162153.8%32.6%Death among patients with hypoglycemia <40, %

0.426515.2016.97Mortality rate, %

PCIT

(n=546)IIT

(n=536)

Median (IQR)

<0.00012.4%8.6%Patients with hypoglycemia <40, %

PCIT

(n=546)IIT

(n=536)

Glucontrol


VISEP TrialVISEP Trial

Study Aim: Study Aim: to evaluate clinical outcome in 600 subjects with to evaluate clinical outcome in 600 subjects with sepsis randomized to conventional or intensive insulin therapy isepsis randomized to conventional or intensive insulin therapy in n 18 academic hospitals in Germany. 18 academic hospitals in Germany.

Primary Outcomes:Primary Outcomes:

Mortality (28 days) and morbidity (sequential organ failure Mortality (28 days) and morbidity (sequential organ failure dysfunction, SOFA dysfunction, SOFA Safety endSafety end--point: hypoglycemia (BG<40 mg/dl) point: hypoglycemia (BG<40 mg/dl)

Conventional TherapyConventional Therapy: : CII started at BG > 200 mg/dl and CII started at BG > 200 mg/dl and adjusted to maintain a BG 180 adjusted to maintain a BG 180 -- 200 mg/dl 200 mg/dl ((mean BG 151 mg/dL)mean BG 151 mg/dL). . Intensive Therapy groupIntensive Therapy group: : CII started at BG > 110 mg/dl and CII started at BG > 110 mg/dl and adjusted to maintain BG 80 adjusted to maintain BG 80 --110 mg/dl110 mg/dl((mean BG 112 mg/dL)mean BG 112 mg/dL). .

Brunkhorst et al, N Engl J Med 358:125Brunkhorst et al, N Engl J Med 358:125--39, 200839, 2008

Blood Glucose Overall Survival

VISEP Trial

Days

Conventional therapy

Intensive therapy

0 1 2 3 4 5 6 7 8 9

Mea

n Bl

ood

Glu

cose

(m

g/dL

)

10 11 12 13 140

50

100

150

200

0 10 20 30 40 50 60 70 80 90 100

Days

Prob

abili

ty o

f Sur

viva

l (%

)

Conventional therapy (n=290)

Intensive therapy (n=247)

0

10203040

5060

7080

90

100

Brunkhorst FM et al. N Engl J Med. 2008;358:125-139.

Data from 537 patients:247 received IIT goal: 80 – 110 mg/dL: mean BG 112 mg/dL290 received CIT goal: 180 – 200 mg/dL: mean BG 151 mg/dL

IIT, intensive insulin therapy; CIT, conventional insulin therapy.

VISEP Trial

Brunkhorst FM et al. N Engl J Med. 2008;358:125-139.

IIT(n=247)

CIT(n=290) P

Mortality rate, %28 days90 days

24.739.7

26.035.4

0.740.31

Patients with ≤40 mg/dL), hypoglycemia, % 17.0% 4.1% <0.001

SOFA score (mean)95% CI

7.87.3-8.3

7.77.3-8.2

0.16

The NICE-SUGAR Study

Multicenter-multinational RCT (Australia, New Zealand, and Canada) in 6104 ICU patients, randomized to:

• Intensive, BG target: 4.5 and 6.0 mmol/L (81 - 108 mg/dL) • Conventional, BG target: < 10.0 mmol/L (180 mg/dL)

Primary Outcome:

• Death from any cause within 90 days after randomization

Mean APACHE II score: ~ 21, Reason for ICU admission: surgery: ~37%, medical: 63%, History of DM: 20% (T1DM: 8%, T2DM: 92%)At randomization: Sepsis: 22%, trauma: 15%, APACHE > 25: 31%

NICE-SUGAR Study. N Engl J Med. 360:1283-1297, 2009.

The NICE-SUGAR Study

Blood Glucose Level, According to Treatment Group

IIT goal: 81 – 108 mg/dL(mean BG 118 mg/dL)

CIT goal: <180 mg/dL(mean BG 145 mg/dL)

Probability of Survival

90 day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%) Absolute mortality difference: 2.6% (95% CI, 0.4 to 4.8); Odds ratio for death with IIT was 1.14 (95% CI, 1.02 to 1.28; P = 0.02).

829

751

RR= 1.14





NICE-SUGAR Study Outcomes

Outcome Measure Intensive Group

Conventional Group

Morning BG (mg/dL) 118 + 25 145 + 26

Hypoglycemia

(≤ 40mg/dL)

206/3016

(6.8%)

15/3014

(0.5%)28 Day Mortality

(p=0.17) 22.3% 20.8%

90 Day Mortality (p=0.02) 27.5% 24.9%


Favors IIT Favors ControlMixed ICU

Medical ICU

Surgical ICU

ALL ICU

Intensive Insulin Therapy and Mortality Among Critically Ill Patients

Griesdale DE, et al. CMAJ. 2009;180(8):821-827.

Griesdale DE, et al. CMAJ. 2009;180(8):821-827.

Favors IIT Favors Control

Hypoglycemic Events

Intensive Insulin Therapy and Hypoglycemic Events in Critically Ill Patients

No. Events/Total No. Patients

Study IIT Control Risk ratio (95% CI)

Van den Berghe et al 39/765 6/783 6.65 (2.83-15.62)

Henderson et al 7/32 1/35 7.66 (1.00-58.86)Bland et al 1/5 1/5 1.00 (0.08-11.93)Van den Berghe et al 111/595 19/605 5.94 (3.70-9.54)Mitchell et al 5/35 0/35 11.00 (0.63-191.69)Azevedo et al 27/168 6/169 4.53 (1.92-10.68)De La Rosa et al 21/254 2/250 10.33 (2.45-43.61)Devos et al 54/550 15/551 3.61(2.06-6.31)Oksanen et al 7/39 1/51 9.15 (1.17-71.35)Brunkhorst et al 42/247 12/290 4.11(2.2-7.63)Iapichino et al 8/45 3/45 2.67 (0.76-9.41)Arabi et al 76/266 8/257 9.18 (4.52-18.63)Mackenzie et al 50/121 9/119 5.46 (2.82-10.60)NICE-SUGAR 206/3016 15/3014 13.72 (8.15-23.12)

Overall 654/6138 98/6209 5.99 (4.47-8.03)

0.1 1 10

Risk Ratio (95% CI)Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.

AACE/ADA Recommended Target Glucose Levels in ICU Patients

ICU setting: Starting threshold of no higher than 180 mg/dL Once IV insulin is started, the glucose level should be

maintained between 140 and 180 mg/dL Lower glucose targets (110-140 mg/dL) may be appropriate

in selected patients Targets <110 mg/dL or >180 mg/dL are not recommended

Recommended140-180

Acceptable110-140

Not recommended<110

Not recommended>180

Is Hypoglycemia Life Threatening?

Strategies for Preventing Hypoglycemia

Svensson AM et al. Eur Heart J. 2005 26:1255-1261.

Blood Glucose During Hospitalization and Incidence of Death Within 2 Years

Lowest blood glucose recorded during hospital stay

≤3.0 mmol/L or 55 mg/dLn+44; 20 deaths

3.1-6.5 mmol/L or 56-119 mg/dLn=364; 101 deaths

≥6.6 mmol/L or ≥120 mg/dLn=276; 107 deaths

1.93 (1.18-3.17)

-3.5 -2.5 -1.5 -.5 .5 1.5 2.5 3.5

Referent

1.48 (1.09-1.99)




Krinsley JS, Grover A. Crit Care Med. 2007;35(10):2262-2267.

Severe hypoglycemia (<40 mg/dL) was associated with an increased risk of mortality (OR, 2.28; 95% CI, 1.41-3.70; P=.0008)

Severe Hypoglycemia in Critically Ill Patients Associated With Increased Risk of Mortality

0

10

20

30

40

50

60

SH Controls No SH

Mo

rtal

ity

Rat

e, %

Mean Glucose & In-Hospital Mortality in 16,871 Patients with AMI

(Reference: Mean BG 100-110 mg/dl)

Kosiborod M et al. Circulation 2008:117:1018

Unadjusted Results

Hypoglycemia in ACS

Hypoglycemia No hypoglycemia p-value

All Patients n=482 n=7338

In-hospital mortality 61 (12.7%) 701 (9.6%) 0.026

No insulin treatment

n=136 n=4639


Insulin-treated patients n=346 n=2699


Kosiborod M, et al. JAMA. 2009;301(5):1556-1564.

Multivariable Analysis

Hypoglycemia in ACS

Kosiborod M, et al. JAMA. 2009;301(5):1556-1564.

Is hypoglycemia life-threatening?

• No direct evidence indicating insulin-induced hypoglycemia results in increased mortality

• Similar to hyperglycemia, severe hypoglycemia appears to be a marker of poor ICU outcome

• Hypoglycemia is a predictor of higher mortality in patients not treated with insulin, but not in insulin treated patients

Hypoglycemia and Cardiovascular Events

Tachycardia and high blood pressure Myocardial ischemia Silent ischemia, angina, infarction

Cardiac arrhythmias Transiently prolonged corrected QT interval, Increased QT dispersion

Sudden death

Wright RJ, Frier BM, Diabetes Metab Res Rev 2008; 24: 353–363.




0

20†

(2‡)

40†

(4‡)

60†

(6‡)

80†

(8‡)

100†

(10‡)

120†

(12‡)

0 30 60 90 120 150 180 210 240

0

5*(0.5**)

10*(1.0**)

15*(1.5**)

20*(2.0**)

25*(2.5**)

30*(3.0**)

35*(3.5**)

40*(4.0**)

45*(4.5**)

50*(5.0**)

IL-6 (μg/ml)

Glucose (mg/dl) Cortisol (μg/dl)

140†

(14‡)

160†

(16‡)

IL-8 (μg/ml)

Epinephrine (μg/ml)

Proinflammatory cytokines in response to insulin-induced hypoglycemia

Razavi L, et al. Metabolism. 2009;58:4434481.ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 20092.Diabetes Care. 2009;31(suppl 1):S1-S110..

Antihyperglycemic Therapy

InsulinRecommended

OADsNot Generally

Recommended

IV Insulin

Critically ill patients in the ICU

SC Insulin

Non-critically ill patients

Recommendations for Managing Patients With Diabetes in the Hospital Setting

Methods for Managing Hospitalized Persons With Diabetes

ICU Continuous IV insulin Infusion

Non-ICU Basal/bolus therapy (MDI)

• NPH and Regular insulin• Long-acting and rapid-acting insulin

Premix insulin

Sliding Scale Short-Acting Insulin

Leuven SICU Study1 Yale Insulin Infusion Protocol2

MICU Insulin Infusion Protocol (N=69)

0

50

100

150

200

250

300

350

400

450

0 12 24 36 48 60 72

Hours

Blo

od G

luco

se (

mg/

dL)

Glucommander3

050

100150

200250

300350

400450

0 2 4 6 8 10 12 14 16 18 20 22 24

Hours

Glu

cose

(m

g/d

L)

1. Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. 2. Goldberg PA et al. Diabetes Care. 2004;27:461-467.3. Davidson et al. Diabetes Care. 2005;28:2418-2423. 4. Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.

Admission Day 1 Day 5 Day 15

Blo

od G

luco

se (

mm

ol/L

) Intensive - Mean BG 103 mg/dL Conventional - Mean BG 153 mg/dL

0

2

4

6

8

10

12

14

Last day

Strategies for Achieving Glycemic Targets in the ICU

NICE-SUGAR4

BG, mg/dL

1 8 0

1 6 0

1 4 0

1 2 0

1 0 0

8 00

1 2 3 4 5 86 7 9 1 0 1 1 1 2 1 3 1 4B a s e -

lin e

D a y s A f te r R a n d o m iz a t io n

C IT

I IT

1 0 8

ProtocolProtocol IITIIT CITCITLeuven SICULeuven SICU 103103 153 153

Leuven MICULeuven MICU 111111 153 153

De la RosaDe la Rosa 120120 149 149

GlucontrolGlucontrol 118118 143143

VISEPVISEP 112112 151151

NICE SUGARNICE SUGAR 118118 145145

Van Den Berghe G, et al. N Engl J Med. 2001; Van Den Berghe G, et al. N Engl J Med. 2006;De la Rosa,et al, Crit Care 2008; Brunkhorst et al. N Engl J Med. 2008; Preiser JC, SCCM, 2007; Nice Sugar, NEJM 2009

Glycemic Values Achieved with IV Insulin Protocols

IIT: Intensive insulin therapyCIT: Control, conventional insulin therapyResults are expressed as mean BG during hospital stay, mg/dL

ProtocolProtocol Hypo definitionHypo definition % patients% patients RRRR

Leuven SICULeuven SICU11 <40 mg/dL<40 mg/dL 5.1%5.1% 77

Leuven MICULeuven MICU22 <40 mg/dL<40 mg/dL 19%19% 66

GlucontrolGlucontrol33 <40 mg/dL<40 mg/dL 8.6% ----

VISEPVISEP44 <40 mg/dL<40 mg/dL 17.4%17.4% 4.114.11

NICE SUGARNICE SUGAR55 <40 mg/dL<40 mg/dL 6.5%6.5% 13.713.7

1. Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; 2. Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; 3. Brunkhorst FM et al. N Engl J Med. 2008; 358:125-139; 4. Preiser JC, SCCM, 2007; 5. Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.

Hypoglycemia Rates in IV Insulin Protocols




Glucommander vs StandardGlucommander vs StandardMean Glucose ValuesMean Glucose Values

Mean Glucose Maintained once Target AchievedGlucommander = 103.4 ± 9 mg/dLStandard = 120.4 ± 18 mg/dL

* p < 0.0001Newton CA et al. ADA Scientific Meeting. June 2008.

Glucommander vs. StandardGlucommander vs. Standard

% of Glucoses Maintained within Target AchievedGlucommander = 68.6%Standard = 46.4%*

* p < 0.0001Newton CA et al. Diabetes 57 (Suppl. 1) 136A, 2008.

Hypoglycemia & Hyperglycemia After Target Achieved (patients)

p = NS

p = NS

p = 0.02

Newton CA et al. Diabetes 57 (Suppl. 1) 136A, 2008.

Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 4

BG (mg/dL) Units/hr BG (mg/dL) Units/hr BG

(mg/dL) Units/hr BG (mg/dL) Units/hr

<60 = Hypoglycemia (See below for treatment)

<70 Off <70 Off <70 Off <70 Off

70-109 0.2 70-109 0.5 70-109 1 70-109 1.5

110-119 0.5 110-119 1 110-119 2 110-119 3

120-149 1 120-149 1.5 120-149 3 120-149 5

150-179 1.5 150-179 2 150-179 4 150-179 7

180-209 2 180-209 3 180-209 5 180-209 9

210-239 2 210-239 4 210-239 6 210-239 12

240-269 3 240-269 5 240-269 8 240-269 16

270-299 3 270-299 6 270-299 10 270-299 20

300-329 4 300-329 7 300-329 12

330-359 4 330-359 8 330-359 14 >330 28

>360 6 >360 12 >360 16


Newton CA et al. Diabetes 57 (Suppl. 1) 136A, 2008.

24300-329

Reduce insulin rate or hold insulin

infusion at a higher BG

concentration

140-180

NEJM 360:1346 2009

There is no clear benefit to using IV

insulin infusion protocols that

target BG range 80-110 mg/dl. This target has been shown to

increase the risk for severe

hypoglycemia.

Observational and RCT have

shown that inpatient glycemic

control reduces hospital

complications, length of

hospital stay, and mortality.

Recommended140-180

Acceptable110-140

Not recommended>180

Not recommended<110

110-140

Methods for Managing Hospitalized Methods for Managing Hospitalized NonNon--ICU Patients With DiabetesICU Patients With Diabetes

Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)••NPH and Regular insulinNPH and Regular insulin•• LongLong--acting and rapidacting and rapid--acting insulinacting insulin

Premix insulinPremix insulin

Sliding Scale ShortSliding Scale Short--Acting Insulin Acting Insulin




AACE/ADA Target Glucose Levels in Non–ICU Patients

Non–ICU setting: Premeal glucose targets <140 mg/dL Random BG <180 mg/dL To avoid hypoglycemia, reassess insulin regimen if

BG levels fall below 100 mg/dL Occasional patients may be maintained with a glucose

range below and/or above these cut-points

Hypoglycemia = BG <70 mg/dLSevere hypoglycemia = BG <40 mg/dL

Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf

Study Type: Prospective, multicenter, randomized, open-label trial

Patient Population: 130 subjects with DM2 Diet and/or oral hypoglycemic agents

Umpierrez et al, Diabetes Care 30:2181–2186, 2007

Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs. Sliding Scale Insulin

Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.

Days of Therapy

BG

, m

g/d

L

100

120

140

160

180

200

220

240

Admit 1

Sliding-scale

Basal-bolus

bP<.05.

aa a

b bb

b

2 3 4 5 6 7 8 9 10

aP<.05.

• Sliding scale regular insulin (SSRI) was given 4 times daily • Basal-bolus regimen: glargine was given once daily; glulisine was given before meals.0.4 U/kg/d x BG between 140-200 mg/dL0.5 U/kg/d x BG between 201-400 mg/dL

Persistent hyperglycemia (BG>240 mg/dl) is common (15%) during SSI therapy

Days of Therapy

BG

, mg

/dL

100120140160180200220240

Admit 1

Sliding-scale Basal-bolus

260280300

3 3 4 5 6 72 4 21

Rabbit 2 Trial: Treatment Success With Basal-Bolus vs. Sliding Scale Insulin

Hypoglycemia rate: Basal Bolus Group:

BG < 60 mg/dL: 3% BG < 40 mg/dL: none

SSRI: BG < 60 mg/dL: 3% BG < 40 mg/dL: none

Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.

Study Type: Prospective, randomized, open-label trial

Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy

Study Sites: Grady Memorial Hospital, Atlanta, GARush University Medical Center, Chicago, IL

Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

DEAN Trial: Changes in Mean Daily Blood Glucose Concentration

BG

, m

g/d

L

Duration of Therapy, d

Data are means SEM.

Detemir + aspartNPH + regular

Basal-bolus regimen: detemir was given once daily; aspart was given before meals.NPH/regular regimen: NPH and regular insulin were given twice daily, two thirds in AM, one third in PM.

Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569.

P=NS

100

120

140

160

180

200

220

240

Pre-RxBG

0 1 2 3 4 5 6-10




NPH/Regular BG < 40 mg/dl: 1.6% BG < 60 mg/dl: 25.4%

Detemir/Aspart BG < 40 mg/dl: 4.5% BG < 40 mg/dl: 32.8%

Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

Half of patients were receiving insulin prior to admission and received similar outpatient insulin dose in the hospital

DEAN Trial: Hypoglycemia

To determine risk factors for

hypoglycemic events during SC insulin

therapy

p-value*

variable BG < 60 mg/dl BG < 70 mg/dl

AGE 0.036 0.001

wt 0.027 0.001

A1C 0.521 0.658

Creatinine 0.011 0.002

Enrollment BG 0.166 0.319

Previous treatment 0.005 <.001Previous insulin Rx <0.001 <.001

Treatment group <0.001 <.001*p-values are from Wilcoxon Two-Sample Test

Summary of Univariate Analyses

Umpierrez et al. Diabetes (Suppl 1) A516, 2009

Does 1 Size Fit All For Glycemic Targets For All Patients?

0 1 2 3 4 5

111111--145145

146146--199199

200200--300300

> 300> 300

Me

an

BG

(m

g/d

L)

Me

an

BG

(m

g/d

L)

NonNon--diabeticsdiabetics153,910153,910

Odd RatioOdd Ratio

0 1 2 3 4 5

DiabeticsDiabetics62,86862,868

Odd RatioOdd Ratio

ICU Mortality Risk Greater in Hyperglycemic Patients Without History of Diabetes

No History Diabetes History Diabetes

Falciglia et al, J Crit Care Med Dec 2009

216,775 consecutive first admission

177 surgical, medical, cardiac ICUs

73 geographically diverse VAMC

0 1 2 3 4 5

111111--145145

146146--199199

200200--300300

> 300> 300

Me

an

BG

(m

g/d

L)

Me

an

BG

(m

g/d

L)

N= 13,051N= 13,051

Odd RatioOdd Ratio

0 1 2 3 4 5

N= 4,782N= 4,782

Odd RatioOdd Ratio

Mortality Risk in AMI and COPD

AMI COPD

P: NSP: NSP: < 0.01P: < 0.01


Hyperglycemia and Mortality

Positive Association

Unstable anginaArrhythmiaStrokePneumoniaGI bleedRespiratory failureSepsisAcute renal failureCHF

No Association

COPDHepatic failureDKAGI neoplasmMusculoskeletalPVD with bypassHip fracturePVD- amputationProstate surgery





Inpatients Diabetes ManagementSummary:

Hyperglycemia is frequent in hospitalized patients with and without history of diabetes

Hyperglycemia (hypoglycemia?) is a marker of poor outcome in critically and non-critically ill patients

Improvement in clinical outcome has been shown by improved glycemic control in a variety of inpatient settings

Intensive Glycemic Control in Acutely Ill Patients

80-110

80-130

100-140

140-180

<200

IV Insulin Infusion Protocol

Basal Bolus Insulin

Glycemic Management Teams


In-service training on new treatment modalities and the actions of new antihyperglycemic agents

Avoidance of sliding-scale insulin alone

Reducing outpatient insulin dose in patients treated with insulin prior to admission

Basal Bolus is preferred over SSRI and NPH/regular combination


Willard P. VanderLaan Annual Diabetes Lectureship · Medical/surgical ICU Mixed, no Cardiac 29%...

Documents

Transcript of Willard P. VanderLaan Annual Diabetes Lectureship · Medical/surgical ICU Mixed, no Cardiac 29%...