What Should Be the Therapeutic Glycemic Target in Intensive Care Units?

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Lee Greene
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1 What Should Be the Therapeutic Glycemic Target in Intensive Care Units? Irl B. Hirsch, M.D. Professor of Medicine University of Washington School of Medicine

2 Disclosures Research/Grants: Sanofi, Halozyme Consultant: Abbott, Roche, BD My perception of the preparation of this talk with the U of Colorado College of Nursing, Office of Lifelong Learning

3 U of Colorado Watching Me Prepare This Talk

4 Conclusion of This Talk If the facts don t fit the theory, change the theory. Albert Einstein

5 Understanding The Problem Retrospective data are complex and extrapolation can be misleading resulting in inaccurate conclusions

6 Diagnoses with a Significant Association Between Hyperglycemia and Mortality Mean Glucose (mg/dl) > ACUTE MI 17, Odds Ratio Falciglia M, Freyberg RW, Almenoff PL, et al: Crit Care Med 2009;37:

7 Magnitude of Mortality Risk Varies with Admission Diagnosis Mean Glucose (mg/dl) > ISCHEMIC STROKE 2,558 P < Odds Ratio Mean Glucose (mg/dl) > Odds Ratio PNEUMONIA 8,122 P < Mean Glucose (mg/dl) Falciglia M, Freyberg RW, Almenoff PL, et al: Crit Care Med 2009;37: > Odds Ratio SEPSIS 3,933 P <

8 Hyperglycemia Associated with Mortality Independent of Diabetes: Greater Risk in Those Without Diabetes 78,142 Mean Glucose (mg/dl) > No Diabetes 180, Odds Ratio Falciglia M, Freyberg RW, Almenoff PL, et al: Crit Care Med 2009;37:

9 Mortality in Inpatients with New Hyperglycemia In-hospital 10 Mortality Rate (%) Patients With Normoglycemia P <.01 3 Patients With History of Diabetes P < Newly Discovered Hyperglycemia Umpierrez GE et al. J Clin Endocrinol Metab. 87: , 2002.

10 Is Diabetes, Insulin Use, or Both Protective? This Isn t What We Were Taught in Medical School! Kotagal M, Symons RG, Hirsch IB, Ann Surg 2014: in press N=40,836, 19% w/dm Progressive hyperglycemia results in increased risk of each AE, which are higher than with DM Hyperglycemia > 180 mg/dl did not impact AEs

11 So THAT begs the question: Was Albert right? Why are those with diabetes having better outcomes than those without?

12 Potential Explanations For This Paradoxical Finding Those with known diabetes are treated more aggressively with insulin Those with diabetes are more adaptive to hyperglycemia while those without poorly tolerate the high glucose levels More insulin deficiency with diabetes (anesthesia also inhibits insulin secretion) is protective from the inflammatory activation that occurs with hyperglycemia

13 LUCIFERASE ACTIVITY (fold stimulation) Could insulin deficiency in those with diabetes explain the protective effect of diabetes? Did the hospitals in WA State undertreat or overtreat the diabetes? * * * Hyperglycemia + hyperinsulinemia = 7X increase in NF-κβ activation 0 C INS GLUC INS + GLUC INS + GLUC + GGTI C3 + GLUC INS + MAN Golovchenko I, Goalstone ML, Watson P, Brownlee M, Draznin B. Circ Res. 2000;87:

14 Clarity? NICE- SUGAR

15 NICE-SUGAR Patients Heterogeneous patient population-likely indicative of typical ICU populations around the world However Population did not include certain other populations, both common and uncommon MI CT Surgery BMT But what did we learn from the NICE-SUGAR results?

16 NICE SUGAR: OUTCOMES VARIABILE INT CON OR (95%CI) P DEATH 90d 27.5% 24.9% 1.14 ( ) d 22.3% 20.8% 1.09 ( ) 0.17 SEVERE HYPO* 6.8% 0.5% 14.7 ( ) <0.01 NEJM 360:1283, 2009 Does metabolic memory and the phenomenon of epigenetics apply to hypoglycemia too?

17 Subsequent Analysis: Hypoglycemia IS Associated With Mortaltiy N Engl J Med 2012:367: HR for death from shock: moderate hypoglycemia-2.34 (p<0.001) severe hypoglycemia: 4.35 (p<0.001)

18 Arrhythmia Neuroglycopenia Acute Hypoglycemia Effects Inflammation Why is hypoglycemia so dangerous in the ICU patient? ROS

19 My Thoughts About NICE-SUGAR 45% with moderate hypoglycemia, 3.7% with severe Are these under-estimates? BG measured q 2.5 hours; is that sufficient? ORDERED were hourly BG measurements Although it is tempting to criticize the NICE-SUGAR ICU teams for inadequate monitoring of glucose levels, it is difficult to imagine many hospitals doing better. How would the NICE-SUGAR results have differed if CGM were available? Hirsch IB: N Engl J Med 2012; 367:

20 Thoughts of the NICE-SUGAR Authors On the basis of our results, we do not recommend use of the lower target in critically ill adults N Engl J Med 360:1283, 2009

Griesdale et al. CMAJ. 180:821-827, 2009.

21 Griesdale et al. CMAJ. 180: , Tight Glycemic Control in Critically Ill Adults A Meta-analysis of 26 Randomized Controlled Trials (13,567 patients) All-cause Mortality

22 But in These Studies, Consider Standard Control! Is control in the hospital (esp. the ICU) as good as the control groups in your hospital in these studies?

23 Glucose Levels Achieved (mg/dl; mean ± SD) Trial Intensive Standard Δ DIGAMI I (24h) (1) 173 ± ± Leuven I (2) 103 ± ± Leuven II (3) 111 ± ± Krinsley* (4) 119 ± ± VISEP (5) 112 ± ± De La Rosa** (6) 117 ( ) 148 ( ) 31 NICE-SUGAR (7) 115 ± ± * Not RCT ** Median (interquartile range) 1. JACC 26:57-65, N Engl J Med 345: , N Engl J Med 354: , Semin Thorac Cardiovasc Surg 18: N Engl J Med 358: , Crit Care 12:R120, N Engl J Med 360: , 2009

24 Bottom Line NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) and all RCT s except the Van den Berghe SICU Study (NEJM, 2001) have not shown intensive insulin therapy to improve major outcomes, including mortality in ICU patients Still, all epidemiological data consistently shows hyperglycemia associated with increased mortality

25 ADA/AACE Target Glucose Level 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 ( mg/dl) may be appropriate in selected patients Targets <110 mg/dl or >180 mg/dl are not recommended Not recommended < 110 Acceptable Recommended Not recommended >180 Diabetes Care 32:1119, 2009

26 More Thoughts In many hospitals, maintaining blood glucose levels similar to those in the conventional-control group of the NICE-SUGAR population is safe and similar to other recommendations ( mg/dl) the use of more conservative glucose targets is unacceptable and older, nonchalant attitudes need to be abandoned. For surgical patients, especially those who have undergone cardiac procedures, hospitals that can safely achieve lower targets should do so. Continued improvements in technology for continuous glucose monitoring should both answer the questions raised by NICE-SUGAR and expand opportunities for better control Hirsch IB: N Engl J Med 2012;367:

27 Or Stated Differently: We have no evidence to keep blood glucose levels in the hospital above 200 mg/dl

28 Where Is This All Going? 225 subjects randomized to intermediate control ( mg/dl) 222 subjects randomized to intensive control ( mg/dl) All subjects on closed-loop system in SICU with hepato-biliarypancreatic surgery No hypoglycemia reported while on closed-loop mg/dl mg/dl Bile Leakage 12.7% 10.8% Panc. Fistula 26.5% 12.3% SSI* 9.8% 4.1% LOS (Days) *SSI = surgical site infection Diabetes Care 2014;37:

29 Conclusions Retrospective in-patient outcomes comparing those with to without diabetes is consistent, seems paradoxical, and is not understood Hypoglycemia appears more dangerous in this population than we appreciated Standard control in the clinical trials would be a vast improvement to how hyperglycemia is generally managed in the hospital in the US It is unlikely we will see improved outcomes (documented with clinical trial data) until CGM (SC or intravascular) or AP is used in the ICU population

30 My Sympathies to Satish (and Our Prediction in Seattle)

31 Thank You For You Attention

Deepika Reddy MD Department of Endocrinology

Deepika Reddy MD Department of Endocrinology Management of hyperglycemic crisis Review need for inpatient glycemic control Brief overview of relevant trials Case based review of diabetes management strategies/review