Perioperative Glucose Management

1. Perioperative Glucose Management An Evolving Standard of Care Charles E. Smith, MD, FRCPC Professor, Case Western Reserve University Director, Cardiothoracic and Trauma Anesthesia MetroHealth Medical Center Cleveland, OH

2. Objectives • Harmful effects of hyperglycemia • Beneficial effects of insulin + glycemic control • Observational studies • Interventional studies • Protocol implementation

3. Surgery • Stress + fasting associated with surgery leads to relative insulin deficiency • ↑ insulin resistance • ↓ insulin secretion • Insulin deficiency leads to hyperglycemia + excess circulating free fatty acids Gandhi GY et al. Mayo Clin Proc 2008;83:418-30

4. Surgical stress • Degree of hyperglycemia depends on severity + extent of tissue trauma; anesthesia factors • Elective intraperitoneal surgery +nondiabetics: ↑ 126-180 mg/dL (7-10 mmol/L) • Cardiac surgery: impressive disturbance of glucose homeostasis. • > 270 mg/dL (15 mmol/L) in nondiabetics • > 360 mg/dL (20 mmol/L) in diabetics Schricker + Carvalho. J CTVA 2005;19:684-8

5. Surgical stress + hyperglycemia • Typical metabolic + endocrine alterations • ↑ glucose production • ↓ glucose utilization • ↑ renal absorption of filtered glucose • ↓ insulin activity • Cardiac surgery: pancreatic hypoperfusion, excess glucose in prime + cardioplegia, hypothermia Schricker + Carvalho J CTVA 2005. Smith et al: JCTVA 2005;19:201-8

6. Immune system + hyperglycemia • Impaired microvascular response • Adhesion + transmigration of leucocytes • Complement cascade • Cytokine network • Chemokine formation • Chemotaxis, phagocytosis • Generation of reactive O2 species • Neutrophil apoptosis Turina M. CCM 2005;33:1624

7. Beneficial effects of glycemic control • Protects hepatocytic mitochondria • Improved PMN neutrophil function • Better bactericidal + opsonic activity • Partial correction of abnormal serum lipids • Counteracts catabolism of critical illness • ↑ endothelial function + myocardial protection • ↓ inflammation + apoptosis Brindley et al. CJA 2006;53:947-9

8. Beneficial effects of insulin • Stimulates glucose uptake + lipogenesis • Inhibits lipolysis, proteolysis +glycogenolysis • Multiple nonmetablic effects: • ↓ levels circulating adhesion molecule + E-selectin • ↓ circulating NO levels by suppressing inducible nitric oxide synthetase gene expression • Protects vascular endothelium from injury • Prevents organ system dysfunction Schricker J CTVA 2005. Langouche et al. J Clin Invest 2005.

9. Insulin infusion + glycemic control • Avoids sustained cellular glucose overload + toxicity in many cell types • ↓ likelihood for vital organ dysfunction • Prevents damage to mitochondrion • Blunts stress response to CPB Van den Berghe Ann Int Med 2007;146;307-8 Albacker et al. Ann Thorac Surg 2008;86:20-7

10. Observational studies • Relationship of hyperglycemia + adverse outcomes well investigated • Neurologic illness, trauma • Myocardial infarction • Burns • Cardiac surgery • Critical care • Kidney transplant donors Gandhi et al Mayo Clin Proc 2008;83:418-30. Blasi-Ibanez et al. Anesthesiology 2009;110:333

11. Interventional studies • DCCT + EDIC 1993+ 2003; UKPDS 1998 + 2008 ↓ complications + mortality in diabetics • DIGAMI 2: ↓ mortality in diabetics w AMI [Eur Heart J 2005] • Leuven trial 2001: 34% ↓ mortality + 40-50% ↓ in important co-morbidities [NEJM 2001, postop surgical pts] • Krinsley: 29% ↓ mortality + ↓ renal insufficiency [Mayo Clin Proc 2004, postop ICU]

12. Cardiac Surgery + Intraop Insulin • Furnary et al: ↓ mortality + deep sternal wound infections in diabetics [Ann Thor Surg 1999 + J TCVS 2003] • Lazar et al: ↓ infection, Afib, ischemia, inotropes, LOS, mortality in diabetics [Circulation 2004]

13. Portland Diabetic Project • 23,619 cardiac surgery pts, 1987-2005 • 5510 had diabetes, 40% on insulin • 1987-92: subcut regular insulin, target 150-200 • 1992-05: continuous regular insulin, target ↓ over time, currently 70-110 in ICU • 3-BG= average value of all glucose measures on each of 3 days: POD 0, 1, 2 [24-72 measures] • Current 3- BG = 121 mg/dl Furnary AP. Endocrine Practice 2006;12[Supp 3]:22-6. http://www.providence.org/protocoldownload

14. Portland Diabetic Project, results • ↓ risk of death by 60%, mainly pump failure + afib (4.4% vs 1.1%) • Annual CABG mortality < nondiabetics • ↓ risk of deep sternal wound infection by 77% (2% to 0.6%) • Other effects: ↓ transfusion, afib, inotropes, infections, LOS Furnary AP, Wu YX. Endocrine Practice 2006;12 (Supp 3) :22-6

15. Boston GIK Study • 149 diabetic pts, CABG • Randomized to GIK vs std therapy • GIK started before anesthesia induction + continued until 12 hr postop. • GIK: insulin 4.8 u/hr+ dextrose 1.5 g/h + KCL 2.4 mEq//h. Target: 125-200. • Std therapy: sliding scale subcut insulin if > 250 Lazar et al. Circulation 2004;109:1497-1502

16. Boston GIK Study, results • ↓ glucose: 138 vs 260 [12 hr postop] • ↓ afib: 17 vs 42% • ↓ LOS 6.5 vs 9.2 days • ↓ infections: 0 vs 13 pts [pneumonia, wound] • Other: postop: ↑ CI, ↓ pacing, ↓ inotropes • Other: 2yrs: improved outcome, ↓ ischemia, ↓ wound infections Lazar et al. Circulation 2004;109:1497-1502

17. Mayo Intraop Cardiac Surgery Study • 400 pts: 20% diabetics, Hg A1C 7% • Randomized to intraop intensive vs std therapy • Intensive: • Insulin started > if 100 mg/dl. Target 80-100 • Std therapy: • sliding scale IV insulin 200-250, or IV insulin if > 250 • Postop: • Both groups had intensive IV insulin, target 80-100 Gandhi GY et al. Ann Intern Med 2007;146:233-43

18. Mayo Intraop Cardiac Surgery Study • ↓ glucose after CPB: 123 vs 148 [19 u insulin] • ↓ glucose ICU arrival: 114 vs 157 • All pts normoglycemic afterwards by protocol design (103-104 mg/dl, 72-73 u insulin/ 24 h) • No difference in 1o or 2o outcomes: • death, sternal wound infection, cardiac arrest, arrhythmias, ARF, > 24h intubation, LOS • More deaths + strokes in treatment gp (4 vs 0, P =0.06; 8 vs 1, P = 0.02) Gandhi GY et al. Ann Intern Med 2007;146:233-43

19. Neurosurgical Patients • RCT 483 adult pts admitted to neuro ICU postop [20% head trauma]: IIT, target gluc 80-110, vs control (gluc < 200). Excluded pts w diabetes • LOS shorter + infection rate lower with IIT • More hypoglycemic (gluc < 50) episodes in IIT • 94% of IIT gp had hypoglycemic episodes • No difference in mortality + Glasgow outcome scale between gps Bilotta et al. Anesthesiology 2009;110:611

20. Rethinking Glucose Control • Tight glucose control did not prevent CV deaths + macrovascular complications in type 2 diabetes • ADVANCE • VADT • ACCORD • Tight glucose control leads to hypoglycemia • VISEP • Glucontrol ADA 2008: 68th Annual Scientific Sessions

21. Meta-analysis of IIT • 29 RCTs, 8432 pts • No mortality difference • Tightness of control • Surgical, medical, med/surg • ↓ sepsis (10.9 vs 13.4%) • ↑ hypoglycemia (< 40 mg/dL, 13.7 vs 2.5%) Wiener et al. JAMA. 2008;300(8):933-944

22. Consensus recommendations *ADA. **SCCM. ***AHA. Loh-Trivedi + Rothenberg, 2008

23. Protocol Implementation • Periop glycemic control depends on: • nature of surgery • severity of illness, age • sensitivity to insulin • modality used to achieve glycemic control • body temp, caloric intake, infection • Preop diabetes + treatment

24. Protocol Implementation, cont’ • Interaction between glucose metabolism + surgical trauma + CPB is complex • Optimal intraop glycemic control cannot be achieved by occasional measurements of glucose + reactive adjustments of insulin infusion Schricker + Carvalho. J CTVA 2005

25. Cardiac surgery + intraop glycemic control • Hyperinsulinemic, normoglycemic clamp • Infuse insulin at constant rate • Infuse dextrose to clamp blood glucose at a specific level Carvalho et al. Anesth Analg 2004 Smith et al. J CTVA 2005 Van Wezel at al. J Clin Endocrinol Metab 2006

26. Cardiac surgery + intraop glycemic control • IV insulin • IV GIK • Sliding scale insulin • Adjust rate + dose based on glucose levels Furnary et al. Ann Thorac Surg 1999 + J TCVS 2003 Lazar et al. Circulation 2004 Gandhi et al. Ann Int Med 2007

27. Iatrogenic hypoglycemia • Brain cannot synthesize glucose or store more than a few min supply as glycogen • Brain is critically dependent on continuous supply of glucose from circulation • Signs + symptoms masked by anesthesia: • anxiety, palpitations, tremor, sweating, hunger, paresthesias, cognitive dysfct, seizures, coma, brain damage Cryer et al. Diabetes Care 2003;26:1902-12

28. Glycemic thresholds • 72-108 mg/dL (4.0-6.0 mmol/L) : • normal range • ~ 65-70 mg/dL (3.6-3.9 mmol/L): • neuroendocrine response (↑ glucagon + epinephrine) • ~ 50-55 mg/dL (2.8-3.0 mmol/L): • neurologic symptoms, cognitive impairment • Thresholds may be shifted in poorly controlled diabetics Cryer et al. Diabetes Care 2003;26:1902-12

29. My Perspective • Current treatment does not provide plasma glucose-regulated insulin replacement or secretion • Pharmacokinetics of insulin are imperfect • Time course of short acting analogues measured in hrs • Time course of endogenous insulin in nondiabetics measured in min • Iatrogenic hypoglycemia can be minimized but not eliminated if goal of treatment is near- euglycemia

30. Glycemic control: future directions • Glucose – regulated insulin replacement via pancreatic islet transplant (diabetics) • Bio-engineered artificial β-cell (diabetics) • Closed loop insulin replacement systems: • reliable glucose sensor necessary • CGMS gold: measures subcut glucose q 10 s • CGMS guardian: measures interstitial glucose q 5min • CSII: continuous subcut insulin infusion • IV-intraperitoneal systems Cryer et al. Diabetes Care 2003. Ferrari. Curr Opin Anaesthesiol 2008

31. Summary • Glycemic control of benefit in pts with diabetes, + in nondiabetic critically ill patients • Optimal periop glycemic control will carry risk of iatrogenic hypoglycemia • Periop control can be achieved in most pts through coordinated protocols, but ideal glucose level not known