Background:
It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients.
Objective:
To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management.
Design:
A randomized, open-label, controlled trial with blinded end point assessment.
Setting:
Tertiary care center.
Patients:
Adults with and without diabetes who were undergoing on-pump cardiac surgery.
Measurements:
The primary outcome was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital.
Intervention:
Patients were randomly assigned to receive continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) or conventional treatment (n = 201). Patients in the conventional treatment group were not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). Both groups were treated with insulin infusion to maintain normoglycemia after surgery.
Results:
Mean glucose concentrations were statistically significantly lower in the intensive treatment group at the end of surgery (6.3 mmol/L [SD, 1.6] [114 mg/dL {SD, 29}] in the intensive treatment group vs. 8.7 mmol/L [SD, 2.3] [157 mg/dL {SD, 42}] in the conventional treatment group; difference, −2.4 mmol/L [95% CI, −2.8 to −1.9 mmol/L] [−43 mg/dL {CI, −50 to −35 mg/dL}]). Eighty two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, −1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, −1 to 0 days]) was similar for both groups.
Limitations:
This single-center study used a composite end point and could not examine whether outcomes differed by diabetes status.
Conclusions:
Intensive insulin therapy during cardiac surgery does not reduce perioperative death or morbidity. The increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention.
References
- 1.
Carvalho G ,Moore A ,Qizilbash B ,Lachapelle K ,Schricker T . Maintenance of normoglycemia during cardiac surgery. Anesth Analg. 2004;99:319-24. [PMID:15271698 ] CrossrefMedlineGoogle Scholar - 2.
Schricker T ,Lattermann R ,Schreiber M ,Geisser W ,Georgieff M ,Radermacher P . The hyperglycemic response to surgery: pathophysiology, clinical implications and modification by the anesthetic technique. Clin Intensive Care. 1998;9:118-28. CrossrefGoogle Scholar - 3.
Van den Berghe G ,Wouters P ,Weekers F ,Verwaest C ,Bruyninckx F ,Schetz M ,et al . Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-67. [PMID:11794168 ] CrossrefMedlineGoogle Scholar - 4.
Garber AJ ,Moghissi ES ,Bransome ED ,Clark NG ,Clement S ,Cobin RH ,et al . American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;10Suppl 2 4-9. [PMID:15251633 ] CrossrefMedlineGoogle Scholar - 5.
Lazar HL ,Chipkin SR ,Fitzgerald CA ,Bao Y ,Cabral H ,Apstein CS . Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004;109:1497-502. [PMID:15006999 ] CrossrefMedlineGoogle Scholar - 6.
Furnary AP ,Gao G ,Grunkemeier GL ,Wu Y ,Zerr KJ ,Bookin SO ,et al . Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:1007-21. [PMID:12771873 ] CrossrefMedlineGoogle Scholar - 7.
Krinsley JS . Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79:992-1000. [PMID:15301325 ] CrossrefMedlineGoogle Scholar - 8.
Gandhi GY ,Nuttall GA ,Abel MD ,Mullany CJ ,Schaff HV ,Williams BA ,et al . Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc. 2005;80:862-6. [PMID:16007890 ] CrossrefMedlineGoogle Scholar - 9.
Ouattara A ,Lecomte P ,Le Manach Y ,Landi M ,Jacqueminet S ,Platonov I ,et al . Poor intraoperative blood glucose control is associated with a worsened hospital outcome after cardiac surgery in diabetic patients. Anesthesiology. 2005;103:687-94. [PMID:16192760 ] CrossrefMedlineGoogle Scholar - 10.
Doenst T ,Wijeysundera D ,Karkouti K ,Zechner C ,Maganti M ,Rao V ,et al . Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2005;130:1144. [PMID:16214532 ] CrossrefMedlineGoogle Scholar - 11.
Montori VM ,Bistrian BR ,McMahon MM . Hyperglycemia in acutely ill patients. JAMA. 2002;288:2167-9. [PMID:12413377 ] CrossrefMedlineGoogle Scholar - 12. Black CT, Hennessey PJ, Andrassy RJ. Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin. J Trauma. 1990;30:830-2; discussion 832-3. [PMID: 2380999] Google Scholar
- 13.
Hostetter MK . Handicaps to host defense. Effects of hyperglycemia on C3 and Candida albicans. Diabetes. 1990;39:271-5. [PMID:2407580 ] CrossrefMedlineGoogle Scholar - 14.
McMahon MM ,Bistrian BR . Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am. 1995;9:1-9. [PMID:7769211 ] CrossrefMedlineGoogle Scholar - 15.
McCowen KC ,Malhotra A ,Bistrian BR . Stress-induced hyperglycemia. Crit Care Clin. 2001;17:107-24. [PMID:11219223 ] CrossrefMedlineGoogle Scholar - 16.
Delamaire M ,Maugendre D ,Moreno M ,Le Goff MC ,Allannic H ,Genetet B . Impaired leucocyte functions in diabetic patients. Diabet Med. 1997;14:29-34. [PMID:9017350 ] CrossrefMedlineGoogle Scholar - 17.
Ferguson TB ,Dziuban SW ,Edwards FH ,Eiken MC ,Shroyer AL ,Pairolero PC ,et al . The STS National Database: current changes and challenges for the new millennium. Committee to Establish a National Database in Cardiothoracic Surgery, The Society of Thoracic Surgeons. Ann Thorac Surg. 2000;69:680-91. [PMID:10750744 ] CrossrefMedlineGoogle Scholar - 18.
O'Brien PC ,Fleming TR . A multiple testing procedure for clinical trials. Biometrics. 1979;35:549-56. [PMID:497341 ] CrossrefMedlineGoogle Scholar - 19.
Chaney MA ,Nikolov MP ,Blakeman BP ,Bakhos M . Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg. 1999;89:1091-5. [PMID:10553817 ] CrossrefMedlineGoogle Scholar - 20. Rassias AJ, Givan AL, Marrin CA, Whalen K, Pahl J, Yeager MP. Insulin increases neutrophil count and phagocytic capacity after cardiac surgery. Anesth Analg. 2002;94:1113-9, table of contents. [PMID: 11973171] Google Scholar
- 21.
Groban L ,Butterworth J ,Legault C ,Rogers AT ,Kon ND ,Hammon JW . Intraoperative insulin therapy does not reduce the need for inotropic or antiarrhythmic therapy after cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2002;16:405-12. [PMID:12154416 ] CrossrefMedlineGoogle Scholar - 22.
Mitrakou A ,Ryan C ,Veneman T ,Mokan M ,Jenssen T ,Kiss I ,et al . Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991;260:67-74. [PMID:1987794 ] MedlineGoogle Scholar - 23.
Montori VM ,Permanyer-Miralda G ,Ferreira-González I ,Busse JW ,Pacheco-Huergo V ,Bryant D ,et al . Validity of composite end points in clinical trials. BMJ. 2005;330:594-6. [PMID:15761002 ] CrossrefMedlineGoogle Scholar - 24.
Freemantle N ,Calvert M ,Wood J ,Eastaugh J ,Griffin C . Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289:2554-9. [PMID:12759327 ] CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
From the Mayo Clinic College of Medicine, Rochester, Minnesota.
ClinicalTrials.gov registration number: NCT00282698.
Acknowledgments: The authors thank Nicole Henderson, Laurie Olsen, and Lisa Schrader for recruitment of study participants, data collection and entry, and project management; Victor Montori, MD, MSc, for providing methodological expertise; and Darrell Schroeder, MS, for statistical support.
Disclosures:Consultancies: R.A. Rizza (Abbott, Takeda, Symphony Capital, Eli Lilly Inc.), M.M. McMahon (Baxter Healthcare); Honoraria: R.A. Rizza (Merck & Co. Inc., Novo Nordisk, Takeda, Mankind, Eli Lilly Inc.); Stock ownership or options (other than mutual funds): R.A. Rizza (Diobex); Grants received: H.V. Schaff (AstraZeneca, Atricure Inc., Avant Immunotherapeutics Inc., Baxter, Boston Scientific, Cryolife Inc., Edwards Lifesciences, Jarvik Heart Inc., Medtronic Inc., Sorin Group/Carbomedics, St. Jude Medical, Thoratec Corporation, TransTech Pharma Inc., W.L. Gore and Associates Inc.).
Corresponding Author: Gunjan Y. Gandhi, MD, MSc, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905; e-mail, gandhi.
Current Author Addresses: Drs. Gandhi, Nuttall, Abel, Mullany, Schaff, O'Brien, Williams, Rizza, and McMahon; Mr. Johnson, Ms. Cutshall, and Ms. Mundy: Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905.
Author Contributions: Conception and design: G.Y. Gandhi, G.A. Nuttall, M.D. Abel, P.C. O'Brien, A.R. Williams, S.M. Cutshall, L.M. Mundy, R.A. Rizza, M.M. McMahon.
Analysis and interpretation of the data: G.Y. Gandhi, G.A. Nuttall, P.C. O'Brien, R.A. Rizza, M.M. McMahon.
Drafting of the article: G.Y. Gandhi, R.A. Rizza, M.M. McMahon.
Critical revision of the article for important intellectual content: G.Y. Gandhi, G.A. Nuttall, M.D. Abel, C.J. Mullany, P.C. O'Brien, A.R. Williams, R.A. Rizza, M.M. McMahon.
Final approval of the article: G.Y. Gandhi, R.A. Rizza, M.M. McMahon.
Provision of study materials or patients: C.J. Mullany, H.V. Schaff.
Statistical expertise: P.C. O'Brien, M.G. Johnson.
Obtaining of funding: A.R. Williams, R.A. Rizza, M.M. McMahon.
Administrative, technical, or logistic support: G.A. Nuttall, M.D. Abel, C.J. Mullany, H.V. Schaff, S.M. Cutshall, L.M. Mundy.
Collection and assembly of data: G.Y. Gandhi.
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