The Portland Diabetic Project: Hyperglycemia/Mortality Hypothesis

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Lucy Jacobs
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1 The Portland Diabetic Project: Hyperglycemia/Mortality Hypothesis Perioperative Hyperglycemia increases the risk of mortality in patients undergoing CABG.

2 (n = 3956) 6.1% 4.9% The Portland Diabetic Project CABG Only Mortality vs. Hyperglycemia 6.0% P< % 2.4% 1.2% 0.0% 1.6% (n= 2886) (n= 1073) BG <200 BG >200

3 CABG Mortality by glucose sextile Mortality 15% 12% 9% 6% 3% 0% N= < 150 P< / / 200 mg / dl / / >250

4 Cardiac-related Mortality by BG quantile 15% 10% Cardiac-Related Non-Cardiac 5% 0% < / / / / 250 >250 mg / dl

5 MVA of CABG Mortality Variable P value Odds Ratio 3-BG < (mg/dl) Epinephrine < Cardiogenic Shock Renal failure Reoperation Operative Status Age / yr Unstable Angina Ejection Fraction / % PVD / CVD Hx Atrial Fibrillation N = 2895 Area under the ROC curve = 0.891

6 Conclusion: AHA 1999 Intraoperative and postoperative hyperglycemia in diabetics, adversely effects postoperative cardiacrelated mortality in diabetic CABG patients Perioperative CABG mortality in diabetics might be reduced to that of the non-dm population through a CII infusion protocol which substantially and safely eliminates hyperglycemia.

7 Independent association of Isolated BG Measurements on Mortality Hgb A-1C BG-Preop 3-BG BG-DOS BG-POD1 BG-POD2 BG-POD Odds Ratio

8 Is Hyperglycemia in the peri-operative period associated with increased mortality in patients undergoing CABG? Yes -- Independently associated: Beyond 3rd POD in ICU and until 3rd POD on the floor Mortality directly rises with 3-BG > 150 mg/dl mg/dl mg/dl mg/dl 8x@ mg/dl > 250 mg/dl

9 The Portland Diabetic Project: CII / Mortality Hypothesis The Portland Protocol (Continuous Intravenous Insulin -- CII) lowers the incidence of mortality in patients undergoing CABG.

10 Insulin Infusions Reduce Mortality in Diabetic CABG Patients Anthony P. Furnary, MD; Guangqiang Gao, MD; Gary L. Grunkemeier, PhD; Kathryn J. Zerr, RN, MBA; H. Storm Floten, MD; Albert Starr, MD St Vincent Medical Center Providence Health Systems J Thorac Cardiovasc Surg 2003; 125: nd Meeting of the American Association for Thoracic Surgery Washington, DC; May 7, 2002

11 DM CABG Patient Population Total CABG Patients : 13,649 Diabetic: 26% Mean Age: 65 Sex: 65% male Redo : 12% n= 3,554 11% 5% 51% 33% DM Control Insulin Oral Diet None

12 Two sequential groups: Control n = 942: Subcutaneous Insulin (SQI) q 4 hrs Target blood glucose < 200 mg/dl Study n = 2612: Continuous Intravenous Insulin (CII) The Portland CII Protocol Titrated to target BG q 1-2 hrs Endpoint: Hospital mortality Study Design Non-randomized, Prospective interventional study

13 Overall Mortality = 3.2% 5% 3% 1% Cause of Death 19% 54% Pump Failure Arrythmia Neurologic Respiratory Renal Failure Infection Hemorrhage 17% Median = 11 days (0-68)

14 CABG Mortality: SQI vs. CII 6.0% 5.0% 4.0% 3.0% 2.0% 5.3% P < % 1.0% 0.0% (n= 942) (n= 2612) SQI CII

15 Multivariable Analysis of Mortality Variable P value Odds Ratio Insulin Infusion Cardiogenic Shock < Renal failure < Reoperation < Operative Status < Age / yr Unstable Angina Ejection Fraction / % PVD / CVD Hx Atrial Fibrillation N = 2933 Area under the ROC curve = 0.874

16 MVA of Risk-Adjusted Mortality* Variable P value Odds Ratio STS Risk score < (35 Risk Factors) Insulin Infusion Area under the ROC curve = *External Risk Adjustment (n = 2834)

17 CABG Mortality by BG quantile 15% 10% P< % % < / / / / 250 >250 mg / dl

18 Ischemic DM Myocardial Metabolism BG Glycolysis 90% FFA Utilization Membrane dysfunction Negatively Inotropic Free Radicals Direct Toxicity Arrythmogenic Endothelial dysfunction MVO 2 O 2 Accumulation of B-Oxidized FFA Intermediaries

19 Cardiac-related Mortality by BG quantile 15% 10% Cardiac-Related Non-Cardiac 5% 0% < / / / / 250 >250 mg / dl

20 Cardiac-Related Mortality:SQI vs. CII 5.0% 4.0% 3.0% 4.4% P < % 1.0% 1.6% 0.0% (n= 942) (n= 2612) SQI CII

21 Summary: AATS 2002 CII independently reduced absolute CABG mortality by 57% as compared to SQI controls CII lowers the incidence of cardiac related mortality. CII reduced risk-adjusted mortality by 50%. CII adds an independently protective effect on mortality to the constellation of risk factors in the STS risk model.

22 Conclusions: AATS 2002 DM not the true risk factor for death following CABG Myocardial glyco-metabolic state influences mortality. The protective effect of CII may stem from improved glyco-metabolic control which enhances the effective utilization of excess glucose to improve myocardial energetics. Insulin infusions should become the standard of care for glycometabolic control in DM CABG patients.

23 MVA of CABG Mortality Variable P value Odds Ratio CII Cardiogenic Shock < Renal failure Reoperation < Operative Status < Age / yr Unstable Angina Ejection Fraction / % Hx PVD / CVD Hx Atrial Fibrillation N = 3293 Area under the ROC curve = 0.868

24 DM CABG Mortality: Non-DM LOS 9% 9.6% 7.6% 5.7% 3.8% 1.9% 0.0% CII Non-DM DM Pts Year

25 Do Continuous intravenous insulin infusions (CII) in DM CABG patients reduce postoperative mortality? Yes -- CII independently reduce mortality by 60%

Diabetes mellitus (DM) is a well-established risk factor for death

Diabetes mellitus (DM) is a well-established risk factor for death Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting Anthony P. Furnary, MD, a,d Guangqiang Gao, MD, a Gary L. Grunkemeier, PhD, b YingXing