Published on February 5, 2014
Blood Sugar Control in ICU Muhammad Asim Rana MBBS, MRCP, FCCP, SF-CCM, EDIC Department of Critical Care Medicine King Saud Medical City Riyadh Saudi Arabia
Introduction • Hyperglycemia is common in critically ill patients . • Current literature shows conflicting results on the effects of more intensive glucose controls versus conventional glucose control in critically ill patients.
Case Study 1 • 32 years male without any prior medical history, admitted to surgical ICU after an assault with head & chest injuries • Second day routine labs showed random blood sugar to be more than 10mmols • Repeated labs failed to show a fall below 8.5mmols • Is he a diabetic? • What should be our plan to control the blood sugar? Why control of blood sugar is necessary?
Case Study 2 • 52 years male with prior medical history of HTN on Rx, admitted to surgical ICU post laparotomy for bowel perforation & septic shock • Labs showed random blood sugar to be more than 8.0mmols • Repeated attempts failed to control blood sugar on subcut insulin • Are we on right track? • What should be our plan to control the blood sugar? Why control of blood sugar is necessary?
Remember • Hyperglycemia commonly ensues, even in patients who do not have pre-existing diabetes mellitus. • The rationale behind the use of insulin therapy in critically ill patients is that severe injury or infection alters carbohydrate metabolism, which results in insulin resistance.
Three Types of Hyperglycemic Patient • Known history of diabetes • Existing, but unrecognized, diabetes • Stress hyperglycemia Clement et al. Diabetes Care. 2004;27:553-591.
Why blood sugar control is important ? Hyperglycemia Adversely Affects Outcomes • Hyperglycemia impacts • • • • Mortality Morbidity Rate of infections Length of stay in ICU (LOS)
Hyperglycemia and Mortality in the MICU ~3x 45 Mortality Rate (%) 40 ~4x ~2x 35 30 25 20 15 10 5 0 80-99 100-119 120-139 140-159 160-179 180-199 200-249 Mean Glucose Value (mg/dL) N=1826 ICU patients. Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478. 250-299 >300
Hyperglycemia: A Predictor of Mortality Following CABG in Diabetics 10 Postop Mortality P<0.0001 BG >200 n=662 5.0% * 1.8% *P<0.001 Adjusted for 19 clinical and operation variables First Postop Glucose >200 8.6 8 Postop Mortality (%) BG <200 n=1369 • 2x LOS • 3x Vent duration • 7x mortality !!! 5.8 6 3.8 4 2 1.4 1.7 2.1 0 CABG, coronary artery bypass graft. Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591. <150 175200150200 225 175 Blood Glucose (mg/dL) 225250 >250
Wake up… here comes… The milestone study which revolutionized … … THE HISTORY OF ICM
Intensive Insulin Management in Medical-Surgical ICU P < 0.001 P < 0.002 29.3% Reduction Mean BG Levels (mg/dL) Baseline group (n = 800) Krinsley JS. Mayo Clin Proc. 79:992-1000, 2004. Hospital Mortality (%) Glucose management group (n = 800)
Benefits of Tight Glycemic Control: Observational Studies and Early Intervention Trials 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% mortality After 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.
Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study • Randomized controlled trial: • 1548 patients admitted to a surgical ICU, receiving mechanical ventilation. Patients were assigned to receive either: • Conventional therapy: IV insulin only if BG >215 mg/dL • Target BG levels: 180-200 mg/dL • Mean daily BG: 153 mg/dL • Intensive 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 34% * 46% * * * * 41% * *P<0.01 Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. Relative Risk Reduction (%)
Intensive Glucose Management in RCT Primary Outcome Trial N Setting Van den Berghe 2006 HI-5 2006 1200 MICU Hospital mortality 240 CCU AMI 6-mo mortality Glucontrol 2007 1101 ICU ICU mortality -1.5% Ghandi 2007 399 OR Composite VISEP 2008 537 ICU 28-d mortality De La Rosa 2008 504 SICU MICU 28-d mortality NICE-SUGAR 2009 6104 ICU 3-mo mortality *not significant ARR RRR 2.7% 7.0% Odds Ratio (95% CI) P-value 0.94* (0.84-1.06) N.S. NR N.S. -10% 1.10* (0.84-1.44) N.S. 2% 4.3% 1.0* (0.8-1.2) N.S. 1.3% 5.0% 0.89* (0.58-1.38) NR N.S. 1.14 (1.02-1.28) < 0.05 -1.8%* -30%* -4.2% * -13%* -2.6% -10.6 N.S.
What is NICE-SUGAR? N Normoglycaemia I C E S U Survival G Intensive Using Care Glucose Evaluation Algorithm Regulation A R
NICE – SUGAR March 26, 2009 NEJM Vol 360 (13) • Open Label RCT, Multinational • 6104 critically ill patients • Intensive infusion (81-108 mg/dL) vs “Conventional” control (144 – 180 mg/dL) • 90 day survival – primary end point
Description • 3054 patients were assigned to the intensive control group and 3050 to the conventional control group. • 829 patients(27.5%) died in the intensive control group and 751(24.9%) in the conventional-control group which is a difference between surgical vs. medical ICU patients. • Severe hypoglycemia (<40 mg/dL) was recorded in 6.8% of patients in the intensive control group, vs. 0.5% in the conventional group.
Blood Glucose Values, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
Probability of Survival Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
Probability of Survival and Odds Ratios for Death, According to Treatment Group Operative Admission Diabetes Severe Sepsis Trauma Apache Score Corticosteroids All deaths at day 90 Favors Favors IIT Conventional Nice Sugar, NEJM 2009;360:1283
NICE - SUGAR • • • • 90 day mortality Severe hypoglycemia Glucose control (median) Insulin infusion 27.5% vs 24.9% 6.8% vs 0.5% 107 vs 141 mg/dL 97% vs 69%
No difference •30 day mortality •ICU days •Hospital days •Days of mechanical ventilation •Days of renal replacement •Organ failures
Discussion • • • • • • Positives: Large multi-center study. Robust statistical analysis. Use of a uniform insulin protocol between sites. The primary outcome in this in unbiased. Good representation od critically ill patients Enrolled more patients than trials that preceded it.
Discussion • • • • • Limitations: More patients in the IIT group received corticosteroids which could effect the variable were studying 10% if the IIT discontinued prematurely. No significant difference in the primary outcome, death. Inclusion criteria ,i.e., length of stay is a subjective parameter. The study was not blinded to the treating personnel
Why the differences? When all the available data are considered, an important step is to establish reasons for the discrepancies in the published literature.
Reasons for discrepancies • Differences in populations of patients (for example, reasons for admittance to the ICU), • Insulin-treatment protocols, • Mortality, • Glucose goals, • Glucose concentrations actually achieved • The use of parenteral nutrition • The expertise and experience of nursing staff at a particular institution could also influence the outcome
Methods used to measure glucose • Another critical, but frequently overlooked, factor is the method used to measure glucose levels. • Arterial blood gas analyzer • Capillary blood with point of care meters • Differences among precesion of different glucometers
Patient-specific factors • Some glucose meters are affected by partial pressure of oxygen and hematocrit. • Reduced tissue perfusion in hypotensive patients results in large differences in glucose concentrations in capillary blood samples, despite minimal alterations in arterial blood samples. • Another variable is that the glucose concentrations in arterial, venous and capillary blood all differ. • Although these differences are minimal in fasting individuals, postprandial capillary glucose values are 1.1–1.4 mmol/l higher than those in venous blood. • Finally, as a consequence of differences in water content, glucose concentrations in plasma are ~11% higher than those in whole blood if the hematocrit is normal. • Some, or perhaps all, of these factors might have contributed to the results reported by the NICE-SUGAR investigators.
Questions 1. What is the optimal target for the glucose therapy. 2. Does a particular sub-set of patients benefits from tight glucose control 3. What about hypoglycemia? 4. Strategies for the future management of blood glucose in the ICU
AACE - Consensus Conference Blood Glucose Targets • Upper Limit Inpatient Glycemic Targets: ICU: 110 mg/dl (6.1 mmol/L) Non-critical care (limited data) • Pre-prandial: 110 mg/dl (6.1 mM) • Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose is now < 126 mg/dL AACE- Endocrine Practice 10 (1): 77-82, 2004 ADA- Diabetes Care 27: 553-591, 2004 Diabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.
Is Hypoglycemia Life-threatening?
Hypoglycemic events Favors IIT Griesdale et al., CMAJ 2009;180:821 Favors Control
Favors IIT All Mixed ICU 0.99 (0.87-1.12) All Medical ICU 1.00 (0.78-1.28) All Surgical ICU 0.63 (0.44-0.91) ALL ICU 0.93 (0.83-1.04) Favors Control
Points to ponder • The NICE-SUGAR trial adds to the accumulating data on the use of tight glucose control protocols in patients in the ICU; however, this study does not 'close the case' on these protocols. • Further large trials are necessary if the question of whether intensive insulin therapy improves the outcomes of selected ICU patients is to be unequivocally resolved. • As the dose of insulin used in critically ill patients is determined exclusively by their blood glucose value, accurate measurement of glucose concentration is essential to achieve the desired targets and to avoid hypoglycemia. • In multicenter trials, a particularly important issue is that glucose measurements among institutions are standardized to avoid variability among patients. • Highly accurate measurements of glucose concentration will, therefore, be necessary in future research
Practice Points • Intensive insulin therapy to maintain blood glucose concentrations <6.0 mmol/l in patients hospitalized in the intensive-care unit might increase mortality • Patients enrolled in NICE-SUGAR who received intensive insulin therapy had increased hypoglycemia and cardiovascular mortality compared with patients who received conventional insulin therapy • Accurate measurement of blood glucose concentration is necessary to achieve the desired target and avoid hypoglycemia
Thank you very much
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