Tight Glycemic Control in Critically Ill Patients – A Critical Assessment of Current Status

Lingtak-Neander Chan, PharmD, BCNSP Associate Professor University of Washington School of & Graduate Program in Nutritional Sciences [email protected] OBJECTIVES

• Re-examine the rationale and the most important clinical trials

• Discuss the science behind critical illness, , and the benefits of insulin

• Critically assess inter-trial variances and their clinical implications towards patients

• Future directions The Mother of All Trials….Leuven I Impact of Intensive Insulin Therapy on ICU Survival

Van den Berghe G. et al. New Engl J Med 2001;345:1359-67. Relationship between APACHE II Score and Survival

Van den Berghe G. et al. New Engl J Med 2001;345:1359-67. Kaplan-Meier cumulative risk of in-hospital death among long-stay (5 days in the intensive care unit) patients

mean blood glucose level of 150 mg/dL (8.25 mmol/L)

mean blood glucose level between 110 and 150 mg/dL (6.05 mmol/L to 8.25 mmol/L

mean blood glucose level of 110 mg/dL (6.05 mmol/L)

80 mg/dL = 4.4 mmol/L

Van den Berghe G. et al. Crit Care Med 2003;31(2):359-66. Critical Illness-Induced Hyperglycemia

• Stress response (e.g., HPA axis) • Shock-mediated • Altered cellular signaling • Treatment-mediated • End organ failure • Insulin resistance

Predisposing Factors for Stress- induced Hyperglycemia Insulin as a Therapeutic Agent

• Euglycemic effect

• Anti-inflammatory effect

• Immunomodulating effect Physiological Effect of Insulin Binding to its Receptor

Impact of Intensive Insulin Therapy (Leuven I Data) on Systemic Inflammatory Responses in ICU Patients

Intensive insulin therapy Conventional treatment

Hansen et al. J Clin Endocrinol Metab 2003;88:1082-8. Relationship between Blood Glucose Concentration and Risk of ICU Morbidity and Mortality

Van den Berghe G. et al. Crit Care Med 2003;31(2):359-66. Cardiac 63%

APACHE II Score Median = 9 Interquartile Range = 7-13 Important Trials on Glycemic Control in the ICU

• Leuven I • Leuven II • Stamford Trial (by Krinsley et al) • Glucontrol • VISEP • NICE- SUGAR Survival Comparison Between Leuven I and Leuven II Stamford Trial

METHODS: Implementation of an insulin infusion protocol in a combined Medical-Surgical ICU

RESULTS: • Reduction of mean blood glucose from 152.3 to 130.7 mg/dL (p < 0.001) • Reduction of glucose > 200 mg/dL by 56.3%, without a significant change in . • New renal insufficiency decreased 75% (p = 0.03) • Decreased PRBC transfusion by 18.7% (p = 0.04) • Hospital mortality decreased 29.3% (p =.0002) • Length of stay in the ICU decreased 10.8% (p = 0.01).

Krinsley et al. Mayo Clin Proc. 2004 Aug;79(8):992-1000 . Glucontrol Trial Update

• University Hospital of Liege & Belgian Government (NCT00107601)

• Prospective, randomized, controlled, multi-centric study

• Compare the effects of two regimens of insulin therapy titrated to achieve a blood sugar level between 80 and 110 mg/dL vs 140 and 180 mg/dL

• After the first interim analysis, the steering committee and the data safety monitoring board decided to stop the enrollment of patients

http://www.glucontrol.org http://clinicaltrials.gov/ct/gui/show/NCT00107601 Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP)

• Glycemic targets: – Conventional arm: 180 – 200 mg/dL – Intensive-therapy arm: 80 – 110 mg/dL

• Fluid and resuscitation trial: – Ringer’s Lactate (each liter contains Na 140 mEq, K 4.0 mEq, Ca 2.5 mmol, Mg 1.0 mmol, Cl 106 mEq and lactate 45 mEq) – 10% hydroxyethyl starch (HES) (molecular weight of 200,000 Dalton; each 1L contains Na154 mEq and Cl 154 mEq) – Achieve a central venous pressure (CVP) of 8 mmHg, mean arterial blood pressure (MAP) 70 mmHg or central venous oxygen saturation (ScvO2) was less than 70% – HES not to be used as a maintenance fluid; daily limit of 20 mL/kg/day, then preferentially Ringer’s or other non-colloid fluids.

Brunkhorst et al. New Engl J Med 2008;358(2):125-39; plus online supplement. Baseline Characteristics

Adapted from: Brunkhorst et al. New Engl J Med 2008;358(2):125-39 Comparison of Glycemic Response Between Conventional and Intensive Therapy

Adapted from: Brunkhorst et al. New Engl J Med 2008;358(2):125-39 Morbidity and Safety Endpoint Comparison

Adapted from: Brunkhorst et al. New Engl J Med 2008;358(2):125-39 Kaplan–Meier Curves for Overall Survival Between Treatment Arms

Insulin Therapy

Adapted from: Brunkhorst et al. New Engl J Med 2008;358(2):125-39 Hypoglycemic Events

Serious adverse event

Adapted from: Brunkhorst et al. New Engl J Med 2008;358(2):125-39 NICE-SUGAR Update: Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation

• Sponsors: – Australian and New Zealand Intensive Care Society Clinical Trials Group – Canadian Critical Care Trials Group – National Health and Medical Research Council – Australia New Zealand Health Research Council

• Multi-centre, open label, randomized controlled trial with blood glucose targeted to 81-108mg/dL vs 140-180 mg/dL

• 6100 patients will be recruited in over 35 Intensive Care Units in Australia, New Zealand, Canada and the USA

• As of August 2008, over 6,000 have been recruited

http:/ /www.thegeorgeinstitute.org Am J Respir Crit Care Med 2005 (online supplement) Clinical Outcome Comparison Between Tight Glycemic Control and Usual Care in ICU Patients Favors Tight Control Conventional Care

Adapted from: Wiener et al. JAMA 2008;300(8):933-44. Should we jump off the tight glycemic control bandwagon ?

• Dose tight glycemic control really reduce mortality ?

• How should the patients be monitored ?

• How to minimize hypoglycemia ?

• Does a universal titration protocol exist ? Comparison of clinical characteristics between ICU survivors and non-survivors

Freire et al. Chest 2005; 128(5):3109-16 Comparison of the mean highest glucose concentration within 24 hours of ICU admission stratified by APACHE II score on hospital outcomes

Freire et al. Chest 2005; 128(5):3109-16 Does the Timing of Intervention Matter ?

* • 178 MICU patients • Early : Late = 127:51 • Age 63 ± 17 years • BMI : 26.1 kg/m2 • APACHE III 84 ± 29

• Diagnosis: –Sepsis 39 % – Acute Resp 38 % – Other 23 % * Early therapy = Within 48 hrs MICU admission Target blood glucose: < 110 mg/dL

Honiden et al. Intensive Care Med 2008;34:881-7. Paired differences between glucose meter analysis of capillary blood and reference standard

Kanji et al. Crit Care Med 2005;33:2778-85. Paired differences between glucose meter analysis of arterial blood and reference standard

Kanji et al. Crit Care Med 2005;33:2778-85. Paired differences between blood gas/chemistry analysis of arterial blood and reference standard

Kanji et al. Crit Care Med 2005;33:2778-85. Correlation between fingerstick glucose and laboratory glucose measurement

Critchell et al. Intensive Care Med 2007;33:2079-84. Deviation of capillary blood measurement compared with laboratory measurement in MICU patients

Predictors of biases

(i) Concurrent vasopressor (ii) UE edema

Critchell et al. Intensive Care Med 2007;33:2079-84. Comparison of clinical characteristics between ICU patients who developed hypoglycemia and those who did not

Vriesendorp TM. et al. Crit Care Med 2006;34:96-101. Predictors of Hypoglycemia

• Medical ICU admissions • Use of bicarbonate-based IV fluids during renal replacement therapy • Decreased nutrition intake • History of diabetes • Sepsis • Need for inotropic support

Vriesendorp TM. et al. Crit Care Med 2006;34:96-101. Insulin Requirement in Different ICU Patient Groups

Van den Berghe G. et al. Crit Care Med 2003;31(2):359-66. Predictors of Poor Glycemic Control

Characteristics OR (95% CI)

Propofol infusion 1.5 (1.3 – 1.7) Nosocomial infections 1.6 (1.4 – 1.9) Post-op complications 1.7 (1.4 – 2.0) Vasopressor use 1.8 (1.6 – 2.1) Mechanical ventilation (>96 hrs) 2.5 (1.6 – 4.1) Corticosteroid use 2.6 (2.3 – 3.0) Max daily SOFA score > 8 2.7 (2.1 – 3.5) Age (per decade) 3.2 (2.3 – 4.3) History of diabetes 5.6 (4.7 – 6.9) Are All ICU Patients Created Equal ?

Favors Tight Control Conventional Care

Adapted from: Wiener et al. JAMA 2008;300(8):933-44. Decreased fluctuation of blood glucose is more beneficial towards improved survival ?

Pre-intervention With Insulin Protocol

Krinsley et al. Crit Care Med. 2008 Nov;36(11):3008-13. Comparison of Clinical Outcomes

Study Period 123 n 2366 3322 4786 SAPS II Score 39.1 ± 18.1 39.3 ± 18.9 37.2 ± 18.4 Mean 6am glucose 144 mg/dL 139 mg/dL 129 mg/dL

ICU mortality 9.1 % 10.8 % 9.8 % Hospital mortality 14.1 % 15.7 % 14.4 %

Study period 1: 120 – 180 mg/dL Study period 2: 80 – 130 mg/dL Study period 3: 80 – 110 mg/dL Treggiari M et al. Crit Care 2008;12:R29. Relative Odds Ratio Compared to Period 1 (control period)

Study Period 23

ICU Mortality: Surg/TICU 1.27 (0.97 – 1.67) 1.40 (1.08 – 1.82) TICU 1.25 (0.85 – 1.84) 1.76 (1.23 – 2.53) MICU 1.12 (0.83 – 1.52) 1.10 (0.82 – 1.41) Hospital Mortality Surg/TICU 1.18 (0.94 – 1.48) 1.18 (0.95 – 1.47) TICU 1.12 (0.81 – 1.54) 1.16 (0.85 – 1.57) MICU 1.02 (0.87 – 1.41) 1.11 (0.87 – 1.41)

Treggiari M et al. Crit Care 2008;12:R29. Where do we go from here ?

• Preventing hyperglycemia with continuous insulin infusion is clinically beneficial • The approach of “tight glycemic control” should be re-examined • The range 80 – 110 mg/dL should not be applied to all ICU patients – 80 – 110 mg/dL for patients – 80 – approx 150 mg/dL for other patients • Patient characteristics must be taken into account when determining target glucose range Where do we go from here ?

• Intervention probably should be started early

• Blood samples from a central venous catheter or arterial catheter should be used for glucose monitoring

• Pay special attention to EN/PN regimen

• Staffing issues

• Institutional-specific and ICU-specific approach

• Await the results from NICE-SUGAR