FHPLD LQ ,QSDWLHQWV (QVXULQJ 6XFFHVV€¦ · mg/dL and is associated with a lower risk for hypoglycemia Current studies do not provide enough information to determine ... Striking

Current Guidelines and Evidence for Inpatient Hyperglycemic Control

Curtis L. Triplitt, Pharm.D., CDEAssociate Director

Diabetes Research Center Texas Diabetes Institute

Associate ProfessorDepartment of Medicine, Division of Diabetes

University of Texas Health Science Center at San AntonioSan Antonio, Texas

8%9%4%5%

31%

Hospitalizations

Nursing home

Office visits

ER visits

Outpatient clinics

Outpatient meds andsupplies

Hospitalizations Account for Largest Portion of Direct Cost of Diabetes Care

American Diabetes Association. Diabetes Care. 2013; 36:1033-46.

2012 Total direct cost: $176 billion

43%

Kavanagh BP et al. N Engl J Med. 2010; 363:2540-6.Qaseem A et al. Ann Intern Med. 2011; 154:260-7.

Year OrganizationPatient

Population

BG Treatment Threshold

(mg/dL)

BG Target

(mg/dL)

BG Hypoglycemia

Definition(mg/dL)

Updated since NICE-

SUGAR, 2009

2009 AACE and ADAICU patients

180 140–180 <70 Yes

2013Surviving Sepsis Campaign

ICU patients

180 <180Not stated

Yes

2009Institute for Healthcare Improvement

ICU patients

180 <180 <40 Yes

2012American College of Critical Care Medicine (ACCM)

ICU 150

<150 (Trauma)

<180(Stroke+)

<70 Yes

2013American College of Physicians

ICU patient Not stated 140–200 Not stated Yes

2008American Heart Association

ICU patients with ACS

180 90–140Not stated

No

Guidelines from Professional Organizations on ICU Blood Glucose (BG) Goal

Jacobi J. Crit Care Med. 2012; 40:3251-76.Finfer S et al. N Engl J Med. 2009; 360:1283-97.

a. BG >200 mg/dL, target 80-110 mg/dL

b. BG >200 mg/dL, target 80-140 mg/dL

c. BG >180 mg/dL, target 140-180 mg/dL

d. BG in 200s mg/dL, target 140-180 mg/dL

e. Have protocol, but none of these fit

f. Have no ICU protocol or I don’t know

At what glucose level does your ICU implement an IV insulin protocol, and what is the glycemic target?

2009 AACE/ADA Target Inpatient Glucose Levels and Hypoglycemia DefinitionsBG Value Definition Implications

>140 mg/dL Hyperglycemia* Premeal levels persistently above this level may necessitate treatment

>180 mg/dL Hyperglycemia No random blood glucose levels should be, in general, above this goal

Hypoglycemia

<70 mg/dL Hypoglycemia Standard definition in outpatients, correlates with the initial threshold for release of counterregulatory hormones

<40 mg/dL Severe hypoglycemia

Increased mortality risk, cognitive impairment begins at 50 mg/dL in normal individuals

*Reassess insulin regimen if BG levels fall below 100 mg/dL

Occasional patients may be maintained with BG below and/or above these cut-points

Moghissi ES et al. Endocr Pract. 2009; 15:353-69.

AACE = American Association of Clinical EndocrinologistsADA = American Diabetes Association

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill

patients (ACCM) In the population of critically ill injured (trauma) ICU patients, we

suggest that BG ≥ 150 mg/dL should trigger initiation of insulin therapy, titrated to keep BG < 150 mg/dL for most adult trauma patients and to maintain BG values absolutely < 180 mg/dL, using a protocol that achieves a low rate of hypoglycemia (BG ≤ 70 mg/dL) to achieve lower rates of infection and shorter ICU stays in trauma patient

We suggest that a BG ≥ 150 mg/dL triggers initiation of insulin therapy for most patients admitted to an ICU with the diagnosesof ischemic stroke, intraparenchymal hemorrhage, aneurysmal subarachnoid hemorrhage, or traumatic brain injury, titrated to achieve BG values absolutely < 180 mg/dL with minimal BG excursions <100 mg/dL, to minimize the adverse effects of hyperglycemia

Jacobi J et al. Crit Care Med. 2012; 40:3251-76.

Enlargement on page 6

Managing Hyperglycemia in Inpatients: Ensuring Success

1

We suggest that BG ≤ 70 mg/dL are associatedwith an increase in mortality, and that even briefsevere hypoglycemia (BG ≤ 40 mg/dL) isindependently associated with a greater risk ofmortality and that the risk increases withprolonged or frequent episodes

Test and adjust BG every 1-2 hours - this hasnot been studied prospectively



patients (ACCM)

We suggest continuous insulin infusion (1 unit/mL)therapy should be initiated after priming newtubing with a 20-mL waste volume

Subcutaneous (SC) insulin may be acceptable inthe ICU if BG goals are maintained



patients (ACCM)

Surviving Sepsis Campaign

Dellinger RP et al. Crit Care Med. 2013; 41:580-637.

1. A protocolized approach to BG management in ICUpatients with severe sepsis commencing insulindosing when

2 consecutive BG levels are >180 mg/dLThis protocolized approach should target an upper BG ≤180 mg/dL rather than an upper target BG ≤110 mg/dL (grade 1A)

2. BG values should be monitored every 1–2 hr untilglucose values and insulin infusion rates are stableand then every 4 hr thereafter (grade 1C)

3. Glucose levels obtained with point-of-care testing ofcapillary blood should be interpreted with caution, assuch measurements may not accurately estimatearterial blood or plasma glucose values (thisstatement is ungraded)

Surviving Sepsis: Guidelines Differences

Although all evidence taken into account,NICE-SUGAR is the main trial that influences

Dellinger RP et al. Crit Care Med. 2013; 41:580-637.

Initiate at 180 mg/dL, but no lowerthreshold for glycemic control excepthypoglycemia

No evidence for 140-180 mg/dL rangeversus 110-140 mg/dL range except forhypoglycemia

American College of Physicians

Qaseem A et al. Ann Intern Med. 2011; 154:260-7.

Recommendation 1: ACP recommends not usingintensive insulin therapy to strictly control bloodglucose in non-surgical intensive care unit(SICU)/medical intensive care unit (MICU) patientswith or without diabetes mellitus (Grade: strongrecommendation, moderate-quality evidence)

Current evidence does not support 80 to 180 mg/dL compared with higher or unspecified targets using a variety of intensive insulin therapy regimens for patients with myocardial infarction, stroke, or acute brain injury or those under perioperative care

A nonsignificant reduction in the incidence of infection has been observed

Although the target blood glucose levels in the current trials ranged widely, avoiding targets less than 7.8 mmol/L (<140 mg/dL) should be a priority because harms are likely to increase at lower blood glucose targets

American College of Physicians Recommendation 2: ACP recommends not using

intensive insulin therapy to normalize blood glucosein SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence)

Current evidence does not show a mortality benefitassociated with use of IIT to achieve a target ofnormoglycemia (blood glucose levels of 4.4 to 6.1mmol/L [80 to 110 mg/dL])

Evidence from some studies showed an increase inmortality associated with IIT and hypoglycemia. Data onthe effects of IIT targeted to normoglycemia on reductionin length of ICU stay are mixed

Qaseem A et al. Ann Intern Med. 2011; 154:260-7.IIT = intensive insulin therapy


2

American College of Physicians Recommendation 3: ACP recommends a target blood

glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL)if insulin therapy is used in SICU/MICU patients(Grade: weak recommendation, moderate-qualityevidence)

Summary - poorly controlled glucose worsens outcomes

Evidence is not sufficient to give a precise range for blood glucose levels

140 to 200 mg/dL is associated with similar mortality outcomes asintensive insulin therapy targeted at blood glucose levels of 80 to 110 mg/dL and is associated with a lower risk for hypoglycemia

Current studies do not provide enough information to determine whether allowing blood glucose levels to increase above 10.0 to 11.1 mmol/L (180 to 200 mg/dL) is associated with similar outcomes to those seen at lower target levels

Qaseem A et al. Ann Intern Med. 2011; 154:260-7.

Striking the Right Balance

Hyperglycemia Hypoglycemia

Finfer S et al. N Engl J Med. 2009; 360:1283-97.

NICE-SUGAR Study Multicenter-multinational randomized, controlled trial

(Australia, New Zealand, and Canada; N=6104 ICUpatients)− Intensive BG target: 4.5-6.0 mmol/L (81-108 mg/dL)

− Conventional BG target: <10.0 mmol/L (180 mg/dL)

Primary outcome: Death from any cause within 90days after randomization

Patient population− Mean APACHE II score: ~21; APACHE >25: 31%

− Reason for ICU admission: surgery: ~37%, medical: 63%

− History of DM: 20% (T1DM: 8%, T2DM: 92%)

− At randomization: sepsis: 22%, trauma: 15%

NICE-SUGAR: Baseline Characteristics

Age: ~60 years

Gender: ~36% female

Diabetes: ~20% (BMI ~28 kg/m2)

Interval, ICU admission to randomization: 13.4 hr

Reason for ICU admission− Operative* ~37%

− Non-operative† ~63%

Sepsis: ~22%

Trauma: ~15%

*No significant number of cardiothoracic surgery patients†No significant number of CCU patients


Outcome Measure Intensive

GroupConventional

Group

Morning BG (mg/dL) 118 ± 25 145 ± 26

Hypoglycemia(BG ≤ 40 mg/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%

NICE-SUGAR Study Outcomes


Intensive Glycemic Control in Critically Ill Adults: Severe Hypoglycemia Risk

Meta-analysis of 26 Randomized Controlled Trials (13,567 patients)


Severe Hypoglycemia(≤ 40 mg/dL)

Study

Van den Berghe et al.8

Henderson et al.31

Bland et al.25


Mitchell et al.35

Azevedo et al.22

De La Rosa Gdel et al.12

Devos et al.13

Oksanen et al.36

Brunkhorst et al.11

Iapichino et al.32

Arabi et al.10

Mackenzie et al.33

NICE‐SUGAR18

Overall

Risk Ratio (95% CI)

Favors IIT Favors conventional control

0.1 1 10

Griesdale DE et al. CMAJ. 2009; 180:821-7.


3

Pharmacists Need to Clearly Understand

Treatment goals

Treatment options

Treatment protocols

Potential medication errors and methods toreduce errors

Their important role on multidisciplinary team inensuring safe and effective management ofhyperglycemia in the hospital setting

Adapted from Kelly JL. Am J Health-Syst Pharm. 2010; 67(Suppl 8):S9-16.

Guidelines from Professional Organizations: Non-ICU Goals


Population


BG Target

BG Definition of

Hypoglycemia

Updated since NICE-

SUGAR

2009

AACE and ADA Consensus Statement

Non-critically ill patients

180 mg/dLPremeal <140 mg/dL

<70 mg/dL(Reassess treatment if <100 mg/dL)

Yes

2012

Endocrine Society Clinical Practice Guideline

Non-critically ill patients

180 mg/dLPremeal <140 mg/dL

(Reassess treatment if <100 mg/dL)

Yes

Moghissi ES et al. Endocr Pract. 2009; 15:353-69.Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.

Transition to Outpatient Status

Begin discharge planning early

Obtain A1C for discharge planning if resultnot available from previous 2 to 3 months− A1C can now also be used as a means

to make the diagnosis of diabetes

− This is often missed by inpatient team

Stabilize blood glucose before discharge

Discharge Planning: New Hyperglycemia

A1C General Guidelines

<5.7% Patient does not have diabetes nor pre-diabetes

5.7% to 6.4%Patient has pre-diabetes (at risk); follow up advisable; consider diabetes prevention strategies

6.5% to 7%Patient has diabetes; can be treated with lifestyle and consider metformin

7% to 9%Patient has diabetes and pharmacotherapy is indicated

>9%Most patients would likely benefit from basal-bolus insulin regimen at discharge

Society of Hospital Medicine Glycemic Control Task Force. Workbook for Improvement. URL in ref list.

Discharge Planning: Diagnosed Diabetes

A1C General Guidelines

<7%Continue pre-admission diabetes management therapy plan

7% to 8%Increase dose of preadmission diabetes medications and/or add a second or third oral agent or basal insulin at bedtime

>8%If on 2 diabetes medications, add basal insulin at bedtime

>9% to 10%Most patients should be on basal-bolus insulin at discharge

Society of Hospital Medicine Glycemic Control Task Force. Workbook for Improvement. URL in ref list.

Transition from Hospital to Home Reinstitute preadmission insulin regimen or oral

and non-insulin injectable antidiabetic drugs atdischarge for patients with acceptablepreadmission glucose control

Initiate insulin administration in those for whom itis indicated at least one day before discharge toallow assessment of efficacy and safety of thistransition

Provide patients and their families or caregiverswith both oral and written instructions regardingglycemic regimen


4

“Survival Skills”to Teach Before Discharge

How and when to takemedication or insulin− What to expect from the

medication− Confirm insurance

reimbursement

How and when to test BG− What are target glucose

levels

Basics on meal planning How to treat and prevent

hypoglycemia

Sick-day management plan

Date and time offollow-up visits− Including diabetes

education

When and who to call onthe health care team− Schedule follow up with

clinician (timely manner)

− Emergency numbers

− Available community resources

Moghissi E et al. Endocr Pract. 2009; 15:353-69.Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.

Conclusion Hyperglycemia

− Common in critically ill patients, both with and withoutdiabetes

− Predictor of adverse outcomes, including mortality

Good, but not stringent, glucose control is mostcommon strategy among different guidelines

Hypoglycemia should be avoided, as adversemortality consequences may result

Pharmacists can and should be part ofmultidisciplinary glycemic control team anddischarge planning in their institution


5

Kavanagh BP et al. N Engl J Med. 2010; 363:2540-6.Qaseem A et al. Ann Intern Med. 2011; 154:260-7.


Population


(mg/dL)

BG Target

(mg/dL)

BG Hypoglycemia

Definition(mg/dL)

Updated since NICE-

SUGAR, 2009

2009 AACE and ADA ICU patients 180 140–180 <70 Yes

2013 Surviving Sepsis Campaign

ICU patients 180 <180 Not stated Yes

2009 Institute for Healthcare Improvement

ICU patients 180 <180 <40 Yes

2012American College of Critical Care Medicine (ACCM)

ICU 150

<150 (Trauma)

<180(Stroke+)

<70 Yes

2013 American College of Physicians ICU patient Not stated 140–200 Not stated Yes

2008 American Heart Association

ICU patients with ACS

180 90–140 Not stated No

Guidelines from Professional Organizations on ICU Blood Glucose (BG) Goal

Jacobi J. Crit Care Med. 2012; 40:3251-76.Finfer S et al. N Engl J Med. 2009; 360:1283-97.

Intensive Glycemic Control in Critically Ill Adults: Severe Hypoglycemia Risk

Severe Hypoglycemia(≤ 40 mg/dL)

Study


Henderson et al.31

Bland et al.25


Mitchell et al.35

Azevedo et al.22

De La Rosa Gdel et al.12

Devos et al.13

Oksanen et al.36

Brunkhorst et al.11

Iapichino et al.32

Arabi et al.10

Mackenzie et al.33

NICE‐SUGAR18

Overall

Risk Ratio (95% CI)

Favors IIT Favors conventional control

0.1 1 10

Meta-analysis of 26 Randomized Controlled Trials (13,567 patients)

Griesdale DE et al. CMAJ. 2009; 180:821-7.


6

Practical Approach to Inpatient Glycemic Control

Kevin W. Box, Pharm.D.

Senior Clinical Pharmacist

UC San Diego Health System

San Diego, California

Types of Insulin

Diabetes Education Online: Diabetes Teaching Center at the University of California, San Francisco. Table of insulin action. URL in ref list. Used with permission.

HPI: 54 y/o, 100-kg man with T2DM x 8 yr admitted with diabetes-related foot

infection, eating regular meals

Outpatient Meds− Glipizide 10 mg po daily

− Metformin 1000 mg potwice daily

− NPH insulin 20 unitssubcutaneously at bedtime

Pertinent Labs− A1C 10%

− BG in ED 240 mg/dL

On admission what would you do?

a. Continue home regimen of metformin,glipizide, and NPH

b. Continue metformin and glipizide at half ofoutpatient dose

c. Withhold oral meds; start glargine 30 unitsdaily, lispro 10 units qac, and moderatecorrectional scale

d. Withhold oral meds; start high correctionalscale only

Withhold All Oral Agents

Non-insulin agents are inappropriate inmost hospitalized patients

Moghissi ES et al. Diabetes Care. 2009; 32:1119-31.

Stepwise Approach to Physiologic Insulin Dosing

Estimate amount of insulin patient would need over one day, if getting adequate nutrition = total daily dose (TDD)Step 1

Assess patient’s nutritional situationStep 2Decide which components of insulin the patient will require and percentage of TDD each should representStep 3Assess blood glucose at least daily, adjusting insulin doses as appropriateStep 4



7

STEP 1: Estimate the amount of insulin the patient would need over one day, if getting

adequate nutrition = TDD Insulin drip-based estimate (for patients treated with an insulin

infusion)

For patients already treated with insulin, consider the patient’spreadmission subcutaneous regimen and glycemic control on that regimen

Weight-based estimate− TDD = 0.4 units/kg x Wt in kg− Adjust down to 0.3 units/kg x Wt in kg for those with hypoglycemia

risk factors, including kidney failure, type 1 diabetes (especially if lean), frail/low body weight/ malnourished elderly, or insulin naïve patients

− Adjust up to 0.5-0.6 units/kg (or more) x Wt in kg for those with hyperglycemia risk factors, including obesity and high-dose glucocorticoid treatment

Our Patient

Calculate TDD− No drip

− On orals and NPH as outpatient

− Weight

100 kg (0.6 units/kg) = 60 units

100 kg (0.5 units/kg) = 50 units

STEP 2: Assess the patient’s nutritional situation

Eating meals or receiving bolus tube feedings

Eating meals but with unpredictable intake

Getting continuous tube feedings

Getting tube feedings for only part of the day

Getting parenteral nutrition

NPO

Which pattern of nutrition does your patient fit into?

Eating

NPOTube feedings

Our Patient Eating regular meals

STEP 3: Decide which components of insulin the patient will require and percentage

of TDD each should represent

Basal insulin can generally be estimated to behalf of the TDD

Nutritional insulin makes up remaining half ofthe TDD

50:50



8

STEP 3: Decide which components of insulin the patient will require and percentage

of TDD each should represent

In most cases, basal insulin should be provided

When a patient is not receiving nutrition, nutritionalinsulin should not be given

Nutritional insulin needs must be matched to theactual nutritional intake

In most cases, well-designed corrective insulinregimens should be provided

Our Patient

qac = before every mealqhs = at bedtime

Step 1: TDD

− Weight 100 kg (0.6 units/kg) = 60 units

Step 2: Nutrition pattern

− Eating regular meals

Step 3: Insulin components and ratio

− 50:50

− Basal – glargine 30 units

− Bolus – lispro 10 units qac

− Correction scale - lispro qac and qhs (moderate-high)

Correction InsulinLow Dose Correction Moderate Dose Correction

High Dose Correction1:50 >150 mg/dL qacand >200 mg/dL qhs

1:25 >150 mg/dL, starting at 3 units qac and >200mg/dL, starting at 4 units qhs

1:25 >150 mg/dL qacand >200 mg/dL qhs

STEP 4: Assess blood glucose at least daily, adjusting insulin doses as appropriate

Blood glucose targets can only be achieved viacontinuous management of the insulin program

There is no “autopilot” insulin regimen for a hospitalized patient!

Our Patient Overnight the patient decompensated on

the floor (blood pressure 98/55 mm Hg),and a rapid response was called− Transferred to ICU, started on norepinephrine

drip at 10 mcg/min, and intubated

Blood glucose levels during the night− 201 mg/dL (2400)

− 248 mg/dL (0600)

What insulin regimen would you use now?

a. Continue current glycemic regimen

b. Withhold all subcutaneous insulin andstart IV insulin infusion

c. Restart home NPH of 20 unitssubcutaneous at bedtime

d. 2 units regular insulin every 1 hoursubcutaneous until BG <150 mg/dL



9

Our Patient

Patient extubated, off pressors

Team would like recommendations totransfer off insulin drip so he can go tofloor

Our Patient:Glucose Management Report

Our Patient: IV Insulin Administration

BG(mg/dL)

Insulin infusion rate(units/hr)

Transition Step 1

Is the patient ready for transition?Patient is not critically ill or requiring pressors

Blood glucose in target range all of last 6 hours

NoContinue Insulin

Drip

YesContinue to step

2

Transition Step 2Does patient need scheduled subcutaneous insulin?

NoPatients with no history of diabetes and A1c <6%

YesAll patients with T1DM

Patients with T2DM and insulin rate >1 unit/hourPatients with A1c >6%

NoTransition to correction

scale only

YesContinue to Step 3

Transition Step 3

Calculate total daily dose insulin requirement (TDD)

TDD = (average drip rate)_____ units/hr x 20 hr

Note: approximately 80% of 24 hr = 20 hr



10

Approximate 6-hour total = 14.7 units

BG(mg/dL)

Insulin infusion rate

(units/hr)

Transition Step 3

Calculate total daily dose insulin requirement (TDD)

14.7 units / 6 hours = 2.5 units/hour

TDD = (average drip rate) 2.5 units/hr x 20 hr

TDD = 50 units

Transition Step 4

Full nutrition: Patient is currently eating>50% of his/her meals, on goal parenteralnutrition or tube feedings, dextrose IV fluid>50 mL/hr

Minimal nutrition: Patient is currently NPO,eating <50% of his/her meals, is on a zerocarbohydrate clear liquid diet, or 6 hoursused in step 3 calculation is a period offasting (overnight)

Full Nutrition

• Patient currently eating >50% of his/her meals

• On goal TPN or tube feeds

• Dextrose IV fluid >50 mL/hr

• Give 50% of TDD asbasal insulin 2 hr before stopping infusion

• Give 50% of TDD asnutritional insulin divided TID if toleratingmeals (lispro) or every 6 hr if on continuoustube feeds (regular)

• Correction scale

Minimal Nutrition: Calculated insulin = basal insulin

• Patient currently NPOor eating<50% of his/her meals

• Zero carbohydrate clear liquid diet

• 6 hours used in step 3 calculation is period offasting (overnight)

• Give 100% TDD asbasal insulin 2 hr before stopping infusion

• Add nutritional insulin when clinically indicated

• Correction scale

Our Patient: Designing Transition Regimen

Transition step 1: Patient is ready to transition Transition step 2: A1C 10%, patient needs scheduled

insulin Transition step 3: TDD = 50 units (weight based 50-60

units)

Transition step 4: Eating regular mealsInsulin components and ratio50:50

− Basal – glargine 25 units− Bolus – lispro 8 units qac− Correction scale – lispro qac and qhs (moderate)


11

Transition Step 5

Assess blood glucose values at least daily,adjusting insulin doses as appropriate

Conclusion

Protocols every institution should have−How to initiate a basal-bolus insulin regimen−Continuous IV insulin infusion− Transition from IV insulin infusion to a basal

bolus regimen−Hypoglycemia−Nutrition on hold unexpectedly−Diabetic ketoacidosis−Continuous quality improvement monitoring


12

Types of Insulin

Diabetes Education Online: Diabetes Teaching Center at the University of California, San Francisco. Table of insulin action. URL in ref list. Used with permission.

Which pattern of nutrition does your patient fit into?

Eating

NPOTube feedings


13

Correction InsulinLow Dose Correction Moderate Dose Correction

High Dose Correction1:50 >150 mg/dL qacand >200 mg/dL qhs

1:25 >150 mg/dL, starting at 3 units qac and >200mg/dL, starting at 4 units qhs

1:25 >150 mg/dL qacand >200 mg/dL qhs

Our Patient:Glucose Management Report


14

Issues and Special Populations for Inpatient Glycemic Management

Paul M. Szumita, Pharm.D., BCPS

Clinical Pharmacy Practice Manager

Director, Critical Care Pharmacy Residency

Brigham and Women’s Hospital

Boston, Massachusetts

Overview

Identify controversies in goal glucosevalues in patient specific populations

Determine whether patients in specificsituations are at greater or lesser risk ofhyperglycemia or hypoglycemia

Examine approaches for managinghyperglycemia in special populations ofhospitalized patients

What is your opinion on the goal glucose in critical care setting?

a. Guidelines have it right on the money

b. Would like goal glucose higher thancurrent guideline

c. Would like goal glucose lower thancurrent guideline

d. Would like another large RCT to putcontroversy to bed

ICU Goal Glucose Controversy

Hyperglycemia and Mortality: Stamford Hospital Analysis

Krinsley JS. Mayo Clin Proc. 2003; 78:1471-8.

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

Mor

talit

y R

ate

(%)

Mean Glucose Value (mg/dL)

Single center retrospective analysis of 1,826 consecutive MICU/SICU patients, whole blood glucose values during ICU stay, October 1, 1999 - April 4, 2002

Hypoglycemia and Mortality: Australian Database Analysis

Bagshaw SM et al. Crit Care Med. 2009; 37:463-70.

HypoglycemiaIncidence

(%)Hospital

Mortality (%)Adjusted OR

(95% CI)*

None 92.9 15.7% 1.0

< 73 mg/dL 6.2 29.5% 1.5 (1.3-1.6)

< 40 mg/dL 0.9 57.4% 2.6 (2.1-3.2)*Covariate adjustment for age, sex, surgical status, primary diagnosis, comorbid illness, APACHE II, mechanical ventilation, acute kidney injury, and hospital site

Database analysis of 24 Australian ICUs and 66,184 adult ICU admissions for >24 hours from January 1, 2000, to December 31, 2005

Similar trends were seen when patients were stratified by MICU, SICU, cardiothoracic ICU, and sepsis


15

Protocol HeterogeneityLeuven I Leuven II VISEP Glucontrol NICE SUGAR

ICU SICU MICUSepsis Mixed

ICUMixed Mixed

Centers 1 1 18 19 42

Sample size 1548 1200 488/537 1011 ~6030

Diabetic ~13% ~17 ~30% ~19% ~20%

Excluded 14 863 1,612 ? 34,067

Stopped early No No Yes Yes No

Primary diet TPN 85% TPN 85% 60% TPN 27% TPN 25% TPN

APACHE II ~9 ~23 ~20 ~15 ~21

MortalityICU: ~ 7%

Hos: ~10%

ICU: ~25%

Hos: ~40%28 Day: ~27%

ICU: ~16%

Hos: ~22%28 Day: ~21%

HypoglycemiaIIT: 5%

Control: 2%

IIT: 18.7 %

Control: 3.1%

IIT: 17%

Control: 4.1 %

IIT: 9.8

Control: 2.7%

IIT: 6.8 %

Control: 0.5%

Protocol Leuven Leuven Leuven Variable ? NICE

Target (mg/dL) 80-110 80-110 80-110 80-110 81-108

Control (mg/dL) < 180 < 180 < 180 140-180 144-180

Timing ICU admit ICU admit < 12 hrs ? < 24 hrs

Duration ICU stay ICU stay ICU/ 21 days ICU or 56 daysEating or 90

days

van den Berghe G et al. N Engl J Med. 2001; 345:1359-67;

van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97.

IIT = intensive insulin therapy

Mortality in RCTs Targeting 80-110 mg/dL

van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al.

Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97.

4.8

24.2 24.7

16.7

27.5

8

26.8 25.6

15.2

24.9

0

5

10

15

20

25

30

LeuvenSICU*

LeuvenMICU*

VISEP** Glucontrol* NICE-SUGAR***

Mo

rtal

ity

Rat

e (%

)

Intensive Control

P = 0.5

P < 0.04

P = 0.31 P = 0.74

*ICU**28 day***90 day

P = 0.02

Mortality in Patients with Extended ICU Stay



10.6

31.3

22.120.2

38.1

22.3

05

1015202530354045

Leuven SICU> 5days*

Leuven MICU> 3 days*

VISEP > 5days**

Glucontrol* NICE-SUGAR***

Mo

rtal

ity

Rat

e (%

)

Intensive Control

P = 0.005 P = 0.05 P = 0.95

*ICU**28 day***90 day

Not available

Not available

63% of cohort31% of cohort 92% of cohort

Intensive Insulin Therapy in Critically Ill Surgical Patients

van den Berghe G et al. N Engl J Med. 2001; 345:1359-67.

Reduction(%)

Mortality Sepsis Dialysis PolyneuropathyBlood

Transfusion

34%

46%41%

44%50%

Intensive Insulin Therapy in Medical ICU Patients

Mortality- Significantly reduced in patients in ICU ≥ 3 days

Morbidity significantly reduced in all patients- Decreased weaning time from mechanical ventilation

- Decreased time to discharge from ICU

- Decreased time to discharge from the hospital

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

NICE SUGAR: More Morbidity = More Mortality?


Morbidity OutcomeIntensive

n=3014

Conventional

n=3011P Value

Days mechanical ventilation, mean ± SD

6.6 ± 6.6 6.6 ± 6.5 0.56

(+) Blood culture 12.8% 12.4% 0.57

Renal-replacement therapy 15.4% 14.5% 0.34

Red blood cell transfusion 42.1% 41.3% 0.56

What is the mechanism behind the small, but statistically significant increase in mortality with intensive insulin therapy at 90 days in NICE SUGAR?

Polyneuropathy not reported



16

Glycemic Separation in “Good” RCTs Targeting 80-110 mg/dL



103111 112 119 118

153 153 151 147 145

0

20

40

60

80

100

120

140

160

180

LeuvenSICU*

LeuvenMICU*

VISEP* Glucontrol NICE-SUGAR*

Me

an g

luco

se (

mg

/dL

)

Intensive Control

32 vs. 5 units/day

59 vs. 10 units/day

P < 0.001 P < 0.001

71 vs. 33 units/day

43 vs. 10 units/day

P < 0.001 P < 0.001

50 vs. 17 units/day

P < 0.001

* AM glucose

Hypoglycemia in RCTs Targeting 80-110 mg/dL



5

18.717

9.8

6.8

23.1

4.12.7

0.502468

101214161820

Leuven SICU Leuven MICU VISEP Glucontrol NICE-SUGAR

% P

atie

nts

Intensive ControlHypoglycemia defined < 40 mg/dL

All variables P < 0.001

Barriers to Inpatient Glucose Management

Heath care system and workers No consensus regarding goals No published “how to” No standardized approach to testing and treatment Inadequate insulin drip protocol Lack of compliance Fear of hypoglycemia Culture Accuracy of point-of-care testing (POCT) Lack of education Poor communication Lack of health care resources

Anger KE et al. Pharmacotherapy. 2006; 26:214-28.

Many have been described

Few have been rigorously evaluated

Few published protocols were everdesigned to reach blood glucose goal of80-110 mg/dL

No Ideal Protocol in the Literature

Examples of Published IV Insulin Protocols

Yale1

Markovitz2

Leuven3

Portland4

Texas Diabetes Council5

DIGAMI6

University of Washington7

Krinsley8

Rush University Protocol9

Northwestern University10

1Goldberg PA et al. Diabetes Care. 2004; 27:461-7.2Markovitz LJ et al. Endocr Pract. 2002; 8:10-8.

3van den Berghe G et al. N Engl J Med. 2001; 345:1359-67.4Furnary AP et al. Endocr Pract. 2004; 10(Suppl 2):21-33.

5Texas Diabetes Council. October 25, 2007. URL in ref list.6Malmberg K et al. Circulation. 1999; 99:2626-32.

7Ku SY et al. Jt Comm J Qual Patient Saf. 2005; 31:141-7.8Krinsley JS. Mayo Clin Proc. 2004; 79:992-1000.

9Donaldson S et al. Diabetes Educ. 2006; 32:954-62.10DeSantis AJ et al. Endocr Pract. 2006; 12:491-505.

Blood Glucose (mg/dL)

Action

< 50• Stop insulin; give 25 mL of 50% dextrose; recheck BG in 30 minutes

• When BG >75 mg/dL, restart with rate 50% of previous rate

50 – 75• Stop insulin; if previous BG >100 mg/dL, then give 25 mL of 50%

dextrose; recheck BG in 30 minutes

• When BG >75 mg/dL, restart with rate 50% of previous rate

76 –100

• If <10 mg/dL lower than last test, decrease rate by 0.5 units/hr

• If >10 mg/dL lower than last test, decrease rate by 50%

• If ≥ last test result, maintain same rate

101 – 150 • Same rate

151 – 200• If 20 mg/dL lower than previous test, same rate

• If higher than previous test, increase by 0.5 units/hr

> 200• If ≥30 mg/dL lower than last test, use same rate

• If <30 mg/dL lower than last test (OR if higher than last test), increase rate by 1 unit/hr

Furnary AP et al. Endocr Pract. 2004; 10(Suppl 2):21-33.

The “Fixed” Protocol


17

CURRENT RATEX

ADJUSTMENT FACTOR(this factor based on rate of change in

BBG over time)=

NEW RATE

BBG = bedside blood glucose

Multiplication Factor Concept “Multiplier” Protocol Concept: A Simple Calculation

(Blood glucose – 60) X multiplication factor= new insulin infusion rate for that hour

- The multiplication factor used in the equationchanges depending on the rate of change in glucose value over time

Osburne RC et al. Diabetes Educ. 2006; 32:394-403.Davidson PC et al. Diabetes Care. 2005; 28:2418-23.

What is your opinion on the importance of the diagnosis of diabetes on goal glucose?

a. All patients should have the same goal(regardless of diagnosis of diabetes)

b. Patients with diabetes should have lowergoal

c. Patients without diabetes should havelower goal

Non-Diabetics vs. Diabetics

Adaptive mechanisms developed in the settingof chronic hyperglycemia in diabetic patientsmay decrease morbidity and mortalityassociated with stress-induced hyperglycemia

Krinsley JS et al. Curr Opin Clin Nutr Metab Care. 2012; 15:151-60.Krinsley JS et al. Crit Care. 2013; 17:R37.

Association Between Mean Blood Glucose and In-Hospital Mortality

Kosiborod M et al. Circulation. 2008; 117:1018-27 (adapted).

0.8

0.4

0.6

0.2

0

No diabetes

All patients

Diabetes

Mor

talit

y R

ate

Mean Glucose (mg/dL)

Patients With Diabetes vs. Patients Without Diabetes

Krinsley et al. Crit Care. 2013; 17:R37 (adapted).

With DiabetesWithout Diabetes

80-110 110-140 140-180 >180

Pe

rce

nta

ge M

ort

alit

y

50

0

25

Mean BG (mg/dL)

80-110 110-140 140-180 >180

Pe

rce

nta

ge M

ort

alit

y

50

0

25

Mean BG (mg/dL)


18

2013 DM vs. No-DM in ICU

Trial design- Multi-center, retrospective, cohort analysis from 12

ICUs in eight different hospitals part of the Intermountain Healthcare system

- Approved by the Intermountain investigational review board

Lanspa MJ et al. Chest. 2013; 143:1226-34.

Mor

talit

y P

roba

bilit

y

0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0 2 4 6 8 10 12 242220181614 26 28 30

Diabetics

90-140 mg/dL

80-110 mg/dL

Days Post ICU Admission

Lanspa MJ et al. Chest. 2013; 143:1226-34 (adapted).

Diabetes vs. No Diabetes

Diabetes vs. No Diabetes

Lanspa MJ et al. Chest. 2013; 143:1226-34 (adapted).

0 2 4 6 8 10 12 242220181614 26 28 30

0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

Mor

talit

y P

roba

bilit

y

Days Post ICU Admission

90-140 mg/dL

80-110 mg/dL

Non‐diabetics

Insulin Needs in Special Patient Populations

Patients receiving high dose steroids

Patients receiving enteral or parenteralnutrition

Patients undergoing surgery

Inpatient situations are unstable

No single algorithm is suitable for allpatients

Many scenarios require increasedmonitoring and possible adjustments ininsulin dose

Optimizing Care of the Inpatient with Hyperglycemia Is Challenging!

Case Scenario: Steroids

78-year-old woman hospitalized forworsening dyspnea and cough

Chronic obstructive pulmonary disease(COPD) since age 55

No prior history of diabetes- A1C 6.2%

Started on methylprednisolone 40 mg IVevery 6 hr

BG on day 2 climbs to 210 mg/dL


19

Hyperglycemia and Steroids Common complication of glucocorticoid therapy

- Prevalence 20-50% among patients without prior history of diabetes

Results from- Increases in hepatic glucose production

- Impairment of glucose uptake in peripheral tissues

All of this contributes to increases in postprandialglucose

Predictors- Total glucocorticoid dose

- Duration of glucocorticoid therapy

- Increasing age

Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.Clore JN et al. Endocr Pract. 2009; 15:469-74.

Medium-dose glucocorticoids (40-60mg/day) tend to cause minimal increase inFPG and marked elevation in PPG

Clement S et al. Diabetes Care. 2004; 27:553-91.Moghissi ES et al. Endocr Pract. 2009; 15:353-69.

FPG = fasting plasma glucosePPG = postprandial plasma glucose

Basal Bolus Therapy with Emphasis on Nutritional Insulin

Institute glucose monitoring for at least 48hours in all patients- Add or adjust insulin regimen based on

monitoring results

During initiation and tapering of steroidtherapy, proactive adjustment of insulintherapy can help avoid uncontrolledhyperglycemia and hypoglycemia

Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.Moghissi ES et al. Endocr Pract. 2009; 15:353-69.

Hyperglycemia and Glucocorticoid Therapy: Summary

Case Scenario: Total Parenteral Nutrition (TPN)

55-year-old obese man admitted forhemorrhagic pancreatitis, no priorhistory of diabetes

BG 200 mg/dL on admission

A1C 7.5% (previously unrecognized DM)

Patient not eating, anticipated he will notbe able to eat for one week

Total parenteral nutrition started

Cheung NW et al. Diabetes Care. 2005; 28:2367-71.Lin LY et al. Am J Med Sci. 2007; 333:261-5.

Sarkisian S et al. Can J Gastroenterol. 2010; 24:453-7.Pasquel FJ et al. Diabetes Care. 2010; 33:739-41.

Olveira G et al. Diabetes Care. 2013; 36:1061-6.35

Study

Hyperglycemia Definition (mg/dL)

Mortality Odds Ratio

Cheung (2005) > 164 10.9

Lin (2007) > 180 5.0

Sarkisian (2010) ≥ 180 7.22

Pasquel (2010) > 180 2.80

Olveira (212) > 180 5.6

TPN, Glucose, and Patient Mortality

For patients receiving PN, regular insulinadministered as part of PN formulation can be bothsafe and effective

Subcutaneous correction-dose insulin is often usedin addition to insulin mixed with the PN

- When starting PN, the initial use of a separateinsulin infusion can help in estimating the required total daily dose of insulin

Separate IV insulin infusions may be needed to treatmarked hyperglycemia during PN

Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.Moghissi ES et al. Endocr Pract. 2009; 15:353-69.

General Recommendations: Hyperglycemia Associated with Parenteral Nutrition (PN)


20

Case Scenario: Tube Feedings

70-year-old woman admitted witha stroke

Prior history of type 2 diabetes mellitus- Controlled on oral agents

BG 150 mg/dL on admission, A1C 7%

Currently unable to swallow

Continuous enteral nutrition started onhospital day 2

Prospective and observational study in 64 patients (mean age 76.2 yr) receiving EN on internal medicine inpatient unit

Most frequent complications

Pancorbo-Hidalgo PL et al. J Clin Nurs. 2001; 10:482-90.

Should blood glucose levels be checked in patients receiving enteral nutrition?Should blood glucose levels be checked in patients receiving enteral nutrition?

49% 46%

35% 33% 30%

20%13%

3%0%

10%

20%

30%

40%

50%

60%

Percent of patients

Complications of Enteral Nutrition

Glycemic Management of the Patient Receiving Enteral Nutrition Continuous enteral nutrition (EN)

- Basal: 40-50% of TDD as long- or intermediate-acting insulin

given once or twice a day

- Short-acting insulin 50-60% of TDD given every 6 hr

Cycled enteral nutrition

- Intermediate-acting insulin given together with a rapid- or short-acting

insulin with start of tube feeding

- Rapid- or short-acting insulin administered every 4-6 hr

for duration of EN administration

- Correctional insulin given for BG above goal range

Bolus enteral nutrition

- Rapid-acting or short-acting insulin given prior to each bolus feeding

Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38.

Case Scenario: Surgery

60-year-old woman with type 2 diabetesmellitus treated with insulin is admitted forhip fracture- Admission glucose = 180 mg/dL

Umpierrez GE et al. Diabetes Care. 2007; 30:2181-6.

*P < 0.01, †P < 0.05. Error bars denote standard deviation.

Insulin glargine + glulisine: 0.4 units/kg for BG 140-200 mg/dL; 0.5 units/kgfor BG 201-400 mg/dL (1/2 daily dose given as basal insulin)

SSI = regular insulin 4 times daily for BG > 140 mg/dL

No differences in rate of hypoglycemia or hospital length of stayNo differences in rate of hypoglycemia or hospital length of stay

Days of Therapy

Mea

n B

G (

mg

/dL

)

100

120

140

160

180

200

220

240

Admit 1

SSI

Basal-bolus insulin

** *

†

2 3 4 5 6 7 8 9 10

††

†

Basal-Bolus Superior to Sliding Scale Insulin (SSI) Treatment for Inpatient Hyperglycemia

Achievement of Glucose Goals

Outcomes and Hypoglycemia

Hospital Complications*

BG <70 mg/dL

BG <40 mg/dL

Basal bolus

8.6% 23.1% 3.8%

Sliding scale

24.3% 4.7% 0%

P value 0.003 < 0.001 0.057

*Composite of postoperative complications including wound infection, pneumonia, bacteremia, respiratory, and acute renal failure

Basal-Bolus vs. Sliding Scale Insulin in RABBIT 2 Surgery Study

Umpierrez GE et al. Diabetes Care. 2011; 34:256-61.


21

Clear definition of hypoglycemia- (BG < 70 mg/dL)

Nursing order to treat without delay- Stop insulin infusion (if patient on one - unless type 1

diabetes mellitus)- Oral glucose (if patient able to take oral)- IV dextrose or glucagon (if patient unable to take oral)- Repeat BG monitoring 15 min after treatment for

hypoglycemia and repeat treatment if BG not up to target- Directions for when and how to restart insulin

Look for cause of hypoglycemia and determine if othertreatment changes are needed

Moghissi ES et al. Endocr Pract. 2009; 15:353-69.

Essential Part of Insulin Therapy:Hypoglycemia Protocol

Roe ED et al. Hosp Pract (1995). 2012; 40:116-25.

If patient CAN safely swallow without aspirating

If BG 50-69 mg/dL: Give 4 oz. juice or regular soda

If BG ≤49 mg/dL: Give 8 oz. juice or regular soda

If patient CANNOT safely swallow or patient has NPO

status

If BG 50-69 mg/dL: Give D50W 25-50 mL (12.5-25

g dextrose) IV push

If BG ≤ 49 mg/dL: Give 1 mg glucagon IM

• Recheck BG in 15-20 min. If BG <70 mg/dL, then continuously repeat until BG ≥70 mg/dL and notify provider.

• Once BG >70 mg/dL, repeat BG monitoring in 1 hour and check again in 2 hours. Notify provider of insulin adjustments and changes in BG monitoring.

• If BG level has not remained ≥70 mg/dL for both BG checks, notify provider for further insulin adjustments and changes in BG level monitoring.

Example Hypoglycemia Protocol

• Determine yesterday’s total insulin doseactually administered

• Review yesterday’s glycemic control• Calculate today’s scheduled insulin dose

– Some BG values < 90 mg/dL 80% ofyesterday’s total

– BG values 90-179 mg/dL 100% ofyesterday’s total

– Some BG values ≥ 180 mg/dL, no BG < 90mg/dL 110% of yesterday’s total

McDonnell ME et al. Supplement to ACP Hospitalist. December 15, 2009: pages 24-30. URL in ref list.

Daily Dose Adjustment Conclusion “Best” blood glucose goal for ICU patients is yet

to be established

Not All IV insulin protocols are created equal(regardless of the goal)

Non-diabetes patients MAY BE different frompatients with diabetes and may benefit from tightglycemic control

Large prospective, RCT of non-diabetic patientsfollowing tight glycemic control with multiplicationfactor protocol intervention is warranted

All efforts to reduce hypoglycemia are warranted


22

Protocol HeterogeneityLeuven I Leuven II VISEP Glucontrol NICE SUGAR

ICU SICU MICU Sepsis Mixed ICU Mixed Mixed

Centers 1 1 18 19 42

Sample size 1548 1200 488/537 1011 ~6030

Diabetic ~13% ~17 ~30% ~19% ~20%

Excluded 14 863 1,612 ? 34,067

Stopped early No No Yes Yes No

Primary diet TPN 85% TPN 85% 60% TPN 27% TPN 25% TPN

APACHE II ~9 ~23 ~20 ~15 ~21

MortalityICU: ~ 7%Hos: ~10%

ICU: ~25%Hos: ~40%

28 Day: ~27%ICU: ~16%Hos: ~22%

28 Day: ~21%

HypoglycemiaIIT: 5%

Control: 2%IIT: 18.7 %

Control: 3.1%IIT: 17%

Control: 4.1 %IIT: 9.8

Control: 2.7%IIT: 6.8 %

Control: 0.5%

Protocol Leuven Leuven Leuven Variable ? NICE

Target (mg/dL) 80-110 80-110 80-110 80-110 81-108

Control (mg/dL) < 180 < 180 < 180 140-180 144-180

Timing ICU admit ICU admit < 12 hrs ? < 24 hrs

Duration ICU stay ICU stay ICU/ 21 days ICU or 56 days Eating or 90 days

van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39;

Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97.

IIT = intensive insulin therapy


23

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