Safe and Effective Insulin Infusion Therapy

Judith Jacobi, PharmD, FCCP,BCPSCritical Care Pharmacist

Indiana University Health Methodist Hospital

Indianapolis, INjjacobi@iuhealth.org

Disclosure

• No Disclosures

Guidelines Committee

Judith Jacobi, PharmD Nicholas Bircher, MD James Krinsley, MDMichael Agus, MDSusan S. Braithwaite, MDClifford Deutschman, MDAmado Friere, MD, MPHDouglas Geehan, MDBenjamin Kohl, MD

Stanley Nasraway, MDMark Rigby, MD, PhDKaren Sands, APRN-BC,

ANP, MSNLynn Schallom, RN, MSN,CSBeth Taylor, MS, RD, CNSDGuillermo Umpierrez, MDJohn Mazuski, MDHolger Schunemann, MD

Objectives

• Define elements needed for insulin infusion therapy

• Describe elements of a safe insulin infusion protocol

• Review literature on treatment of hypoglycemia• Describe potential metrics for insulin infusion

therapy

Questions to AddressIntravenous Insulin Therapy

• What is the impact of hyperglycemia on outcome of CC patients? – What is the glucose trigger for intensive insulin

therapy?• What is the impact of IIT on patient outcome?• What is the optimal glucose range during IIT?• What are the population-specific

considerations for glycemic control?

Questions to Address

• How should glucose be monitored in ICU patients?

• How often should glucose be monitored?• What other interventions may impact glucose

control?• What is the impact of hypoglycemia? • How should hypoglycemia be treated?

Questions to Address

• What metric should be used to assess the achievement of glycemic goals?

• What is the economic/workload impact of tight glycemic control?

• When/how should patient’s transition off an insulin infusion?

What is the impact of hyperglycemia?

• Hyperglycemia is common– Stress response– Drug therapy (corticosteroids)– Nutrition (overfeeding, IV dextrose)

• Hyperglycemia contributes to organ dysfunction– Mitochondrial injury– WBC dysfunction – Reduced respiratory chain complex activity– Oxidative injury– Elevated cytokine levels and NFκB

Glucose vs. Mortality

N= 259,040 ICU patients

Falciglia Crit Care Med 2009; 37:3001–3009

Intensive Insulin Therapy – Big Impact

• Mortality reduced from 8% to 4.6% with target mean morning glucose 180-200 (10-11.1 mmol/L) vs. 80-110 mg/dL (4.4-6.1 mmol/l)– RCT, adequate power– Mechanical ventilation

• 2/3 CV surgery- most with short LOS– Confounders present

• Single center • One glucose per day- mean morning glucose• Role of IV dextrose/TPN- clamp to high glucose levels

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

IIT in Critically Ill Patients: SICU

*

*

*

*

*

*

*P<0.01

Adapted from Van den Berghe N Engl J Med. 2001;345:1359-1367.

Relative Risk Reduction (%)

Mortality vs. Glucose

Van den Berghe Crit Care Med 2003;31:359-366

Glu <110 mg/dl(< 4.4 mmol/l)

Glu 110-150 mg/dl(6.1 – 8.3 mmol/l)

Glu > 150 mg/dl(>8.3 mmol/l)

Subset > 5 days in the ICU

The NICE-SUGAR Study

Multicenter-multinational RCT (Australia, New Zealand, and Canada)N = 6104 ICU patients• Intensive, BG target: 4.5 and 6.0 mmol/L (81 and 108 mg/dL), • Conventional, BG target: < 10.0 mmol/L (180 mg/dL)

Primary Outcomes: • Death from any cause within 90 days after randomization

Finfer N Engl J Med 360;13: 1283-1297

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%

The NICE-SUGAR StudyBlood glucose

3054 received IIT goal: 81 – 108 mg/dL(mean BG 118 mg/dL)3050 received 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).

Finfer N Engl J Med 360;13: 1283-1297

Subset Outcomes

Finfer N Engl J Med 360;13: 1283-1297

Meta-Analysis

Griesdale CMAJ 2009;180(8):821-827

Hypoglycemia Comparison

0

2

4

6

810

12

14

16

18

20

Hypoglycemia

ClarianGlucommanderNICE SugarSICUMICUVISEPGlucontrol

17%

%

Reproduced with permission from 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. PatientsStudy 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 10Risk Ratio (95% CI)18

Hypoglycemia Impact

• Increased mortality risk reported with glucose < 40 mg/dL (< 2.2 mmol/l) (odds ratio 2-3)– Values < 80 mg/dL may be significant– Duration vs. absolute occurrence

• Prevention is important– System level

• Avoid intermittent glucose administration• Safe protocol• Accurate monitor

– Patient level• Adequate frequency of monitoring• Recognition and response to change in feeds, meds, status

Severe Hypoglycemia

Blood Glucose Frequency During Insulin Infusion• Every 30 minutes – 2 hours

– ADA Standards of Medical Care 2010• Protocols glucose every 4 hours when stable-

demonstrate > 10% severe hypoglycemia rate– Risk of failure to detect a change

• Continuous monitors future solutionDiab Care 2010: 33, Suppl 1, s11-s61Quinn Pharmacotherapy 2006; 1410-1420

Insulin Infusion Potential Benefit in TPN

Marik Chest 2010; 137:544-551

Glucose Meters in the ICU

• Not developed for ICU use• Significant error risk in critically ill

– Anemia (Hct < 25-30%)– Drug interactions

• Avoid fingerstick if poor perfusion, on vasopressors, significant edema– Whole blood (arterial/venous) preferable– Potential to double-correct for plasma equivalent

• Lab standards: Over 95% of discrepancy is< 15mg/dL (< 75 mg/dL = 4.2 mmol/l) or up to

20% for glucose ≥ 75 mg/dL (CLIA)Mahoney Diab Technol Ther 2007; 9:545-552

Glucose Meter – Capillary Blood

73% within goal for glucose meter analysis of capillary bloodKanji Crit Care Med 2005; 33:2778–2785

Confounders in POC Glucose Assay

Dungan Diab Care 2007; 30:403-409

GO= glucose oxidaseGD= glucose dehydrogenase

Patient variablesHypotensionHctpO2TemperatureDrugs

Glucose Meter – Arterial Blood

88% within goal for glucose meter analysis of arterial bloodKanji Crit Care Med 2005; 33:2778–2785

Insulin Titration Protocols

• Over 30 publications describing protocols• Many derivatives of a few protocols• Standard approach reduces variability• Challenge to balance prescriptive (complex)

with less defined (simpler) • Can 1 protocol work in all populations?

LeuvenProtocol

Van den BergheInt J Obesity 2002:26, Suppl 3, S3–S8

Portland Protocol

Ref: PortlandProtocol.org

Ideal Solution

• Computer-directed insulin infusion– Complexity is moved to the computer– Standardization is achieved

• Insulin = (Glucose – 60) x Multiplier– Multiplier = 0.02 baseline

• Increase 0.01 for each value above target• Decrease 0.01 for each value below target

Davidson PC, et al. Diabetes Care. 2005; 28:2418-2423.33

Protocol Compliance

Lipshutz, A et al. Strategies for Success: A PDSA Analysis of Three QI Initiatives in Critical Care, The Joint Commission Journal on Quality and Patient Safety, August 2008 ,Volume 34 Number 8.

Algebraic Protocols

Osburne Diabetes Educator 2006; 32:392-403Chart Copyright Georgia Hospital Association

Insulin Titration & Concomitant Therapies

• Critical thinking skills• System support for safe insulin therapy

– Double checks– Avoid intermittent dextrose administration

• Multidisciplinary communication of patient specific goals

• ∆ Clinical status• ∆ Nutritional support• ∆ medications

• Protocol driven assessment guidelines• If change, reassess more frequently

Treatment of Hypoglycemia During Insulin Infusion• ½ to 1 amp 50% Dextrose

– Incomplete order• Guidelines suggest 15 gm oral glucose

– Average change 38 mg/dL in 20 minutes– Retest BG in 15 minutes

• Canadian Guidelines: with IV access– 10-25 gm (20-50 ml) 50% Dextrose over 1-3 minutes

Diabetes Care Jan 2004 Supplementwww.diabetes.ca.cpg2003

IV Dextrose During Insulin Infusion• Give a metered dose of dextrose and titrate

based on BG• Dose 50% Dextrose (ml) = (100-BG) x 0.4

– Example: Glucose 50 mg/dL = 20 ml– Glucose = 65 mg/dL = 14 ml

• Repeat BG in 15 minutes– Corrects BG from ≤ 50 to 106.4 mg/dL in 20

minutes1

– Corrects BG from 49 10 to 83 10 mg/dL in 33 minutes2

1. Junega Diabetes Technol Ther 2007;9:203-2112. Davidson Diabetes Care 2005;28:2418-2423

Metrics

• Reliable documentation and data review– Transcription errors– Protocol deviaitons

• Potential measures– % time in goal range– Rate of severe hypoglycemia < 40 mg/dL (<2.2 mmol/L)

per 100 hours of infusion• % of patients with hypoglycemia

– Rate of all hypoglycemia < 70 mg/dL (<3.9 mmol/l) per 100 hours

• Real-time reporting

• Glycemic variability – assess rate of high and low values

Glycemic Variability

Egi Anesthesiology 2006; 154:244-252

Clinical Practice Guidelines for Insulin Infusion-SCCM/ASPEN

• Important aspects of safe insulin therapy– Administration– Monitoring– Metrics

• Glucose goal depends on what can be given safely– Suggest maintaining glucose < 180 mg/dL (< 10

mmol/l)– Lower trigger for intervention (approx 150 mg/dL, <

8.3 mmol/l)• Some populations may benefit from lower

glucose values

Schultz Crit Care 2010; 14:233

Influence of literature on Practice

Today- Equipoise

• Glucose control is still important– Optimal target unknown in most populations– Glucose less than 180 mg/dL (10 mmol/L)

• Greater use of computerized protocols– Many untested algorithms remain in use

• Hypoglycemia remains a risk– Frequency must be measured

• Is another study feasible?– May be a component of continuous sensor research