The Association Between Peri-Operative Hyperglycemia and Major Morbidity and Mortality
The Association Between Peri-Operative Hyperglycemia and Major Morbidity and Mortality
Surgery induces a stress effect on the body partially through a catabolic energy state. In
 turn, glucose levels may rise to levels which have been associated with major morbidity
 (Golden, 1999) and mortality (Ouattara, 2005). An increasing body of evidence suggests that
 intensive insulin therapy for tight control of blood glucose levels in certain surgical and
 critical care patient populations may improve mortality and selected morbidity outcomes when
 compared to those patients receiving conventional insulin therapy and blood glucose
 management. More specifically, poor intra-operative blood glucose control is associated with
 worse outcome after cardiac surgery. Intensive insulin therapy with tight blood glucose
 control in surgical patients while in the ICU may reduce morbidity and mortality. Such
 outcome improvements would clearly provide benefits to patients, providers and payers. To
 date, there is scant research examining whether intensive insulin therapy for tight control
 of blood glucose in the perioperative period can alter outcomes for the non cardiac surgery
 population. The purpose of this study is to determine whether intensive insulin therapy for
 tight control of blood glucose in the perioperative period in non cardiac major surgery
 patients is associated with altered morbidity and mortality rates.
Intensive insulin therapy to control blood glucose levels reduces morbidity and mortality in
 intensive care unit patients and in cardiac surgical patients but its role in patients
 undergoing non-emergent non-cardiac surgery is unknown. Benefits of glucose control may
 result from prevention of immune system dysfunction, reduction in systemic inflammation, and
 protection of endothelium and mitochondrial structure and function, all of which are known to
 be altered by high stress states such as that induced by surgical procedures.

 In a prospective, randomized, controlled study of adult patients admitted to our operating
 suite for non-emergent non-cardiac surgery, we propose to correlate in-hospital morbidity and
 mortality with blood glucose levels of patients who are expected to have moderate to high
 levels of physiologic stress as a result of their pre-existing medical conditions or as a
 result of the proposed surgical procedure. Specifically, patients who are deemed to be
 American Society of Anesthesiologists Risk Classification 1-3 or higher, or patients
 undergoing intermediate and high risk procedures shall be considered to have moderate to high
 physiologic stress.

 Determination of intermediate / high risk procedures shall be according to the American
 College of Cardiology / American Heart Association 2002 Guidelines for Perioperative
 Cardiovascular Evaluation for Noncardiac Surgery as outlined in Table 1.

 Table 1. Cardiac Event Risk Stratification for Noncardiac Surgical Procedures High (Reported
 cardiac risk often >5%)

 -  Emergent major operations, particularly in the elderly

 -  Aortic and other major vascular surgery

 -  Peripheral vascular surgery

 -  Anticipated prolonged surgical procedures associated with large fluid shifts and/or
 blood loss Combined incidence of cardiac death and nonfatal myocardial infarction.
 Further preoperative cardiac testing is not generally required. Intermediate (Reported
 cardiac risk generally <5%)

 -  Intraperitoneal and intrathoracic surgery

 -  Carotid endarterectomy surgery

 -  Head and neck surgery

 -  Orthopedic surgery

 -  Prostate surgery Low (Reported cardiac risk generally <1%):

 -  Endoscopic procedures

 -  Superficial procedures

 -  Cataract surgery

 -  Breast surgery

 Prior to entering the operating suite for surgery, patients will be randomly assigned to
 receive either intensive insulin treatment or conventional insulin treatment. Treatment
 assignment will be performed using sealed envelopes, and patients stratified according to
 Table 2.

 TABLE 2. Baseline Characteristics of Patients. Variable Intention to Treat Group P Value Male
 sex (%) Age (Years) Type of Surgery

 -  Intracranial (%)

 -  Head & Neck (%)

 -  Thoracic (%)

 -  Vascular (%)

 -  Gastrointestinal (%)

 -  Urologic (%)

 -  Orthopedic (%)

 -  Gynecologic (%)

 -  Myocutaneous (%) History of Cancer (%) History of Organ Failure before Surgery (%) Organ
 Failure After Surgery (%) History of Diabetes (%)

 -  Treated with insulin

 -  Treated with oral diabetic agent, diet or both

 Inclusion criteria:

 -  Patients scheduled for non emergent surgery under either general or regional anesthesia
 deemed to have moderate to high physiologic stress

 -  Male and female subjects over the age of 18 with or without a diagnosis of diabetes
 mellitus

 -  Patients must be able to provide informed consent

 Exclusion criteria:

 -  Cognitively impaired

 -  Non-English or Spanish speaking with no relative present who is fluent in reading and
 comprehending English or Spanish.

 -  Female patients of child bearing age who have a positive pregnancy test on admission.

 In all patients, whole blood hemoglobin A1C and glucose levels will be drawn prior to
 induction of anesthesia. Additional whole blood glucose levels will be drawn at the time of
 induction of anesthesia, at skin incision, hourly throughout the operation, at emergence from
 anesthesia, every hour up to three hours after the completion of surgery, and then once per
 day until the patient is discharged from the hospital.

 In the intensive treatment group, continuous insulin infusion (50 IU of Novolin R [Novo
 Nordisk]) in 50mL of 0.9% saline via infusion pump will be started when the blood glucose
 level exceeds 110 mg/dL and will be adjusted to maintain the blood glucose level between 80
 and 110 mg/dL. Adjustments will be made according to the University Hospital's ICU Adult
 Insulin Infusion Protocol. When the blood glucose level falls below 80 mg/dL, the insulin
 infusion will be tapered and discontinued. For patients going to the ICU after surgery,
 insulin infusions will be continued according to the University Hospital's ICU Adult Insulin
 Infusion Protocol under the direction of the ICU staff. For patients not being to the ICU
 after surgery, insulin infusions will be tapered to off after the final hourly blood glucose
 determination at three hours after the completion of surgery. The University Hospital's Blood
 Glucose Management Order Set for Medical and Surgical Patients will then be adopted for
 continued glucose management.

 In the conventional treatment group, continuous insulin infusion will be started when the
 blood glucose level exceeds 200 mg/dL and will be adjusted to maintain the blood glucose
 level between 180 and 200 mg/dL. Adjustments will be made according to a modified ICU Adult
 Insulin Infusion Protocol. When the blood glucose level falls below 180mg/dL, the insulin
 infusion will be tapered and discontinued. For patients transferred to an ICU after surgery,
 insulin infusions will be continued according to the University Hospital's ICU Adult Insulin
 Infusion Protocol under the direction of the ICU staff. For patients not being transferred to
 an ICU after surgery, insulin infusions will be tapered to off after the final hourly blood
 glucose determination at three hours after the completion of surgery. The University
 Hospital's Blood Glucose Management Order Set for Medical and Surgical Patients will then be
 adopted for continued glucose management.

 How will the study be analyzed?

 At baseline, data on demographic and clinical characteristics of the patients (see Table 1)
 will be obtained. Blood will be systematically sampled and whole blood glucose levels
 determined as described above. All blood glucose values will be tabulated from baseline
 through end of study.

 A research associate blinded to the treatment groups will determine morbidity and mortality
 by reviewing the patient's medical record upon discharge from the hospital and recording the
 occurrence of morbidity and mortality by the following criteria:

 1. Post-operative surgical wound infection - a clinical condition requiring antibiotic
 treatment beyond the UH Surgical Infection Prevention (SIP) protocol and / or subsequent
 wound drainage / debridement

 2. Systemic infection - presence of bacteremia or prolonged (i.e. greater than 10 days) use
 of antibiotics

 3. Myocardial Injury - postoperative EKG changes that reveal new Q waves or S-T segment
 elevations greater than 1mm in any lead(s) or serum troponin levels that exceed….

 4. Malignant arrhythmia - asystole, ventricular tachycardia or fibrillation requiring
 cardiopulmonary resuscitation, antiarrhythmia therapy, or defibrillator implantation

 5. Respiratory Injury - mechanical ventilation for more than 48 hours, reintubation, or
 planned tracheostomy

 6. Neurological Injury - focal brain injury with permanent functional deficit, irreversible
 encephalopathy

 7. Renal Injury - a level of serum creatinine twice that present on admission to the
 hospital or acute renal failure requiring dialysis

 8. Hepatic Injury - bilirubin level of >3mg per deciliter

 9. Venous Thromboembolism - deposition of thrombus in peripheral or central veins as
 determined by Doppler ultrasonography, angiography or computed tomography.
Inclusion Criteria:

 -  Patients scheduled for non emergent surgery under either general or regional
 anesthesia deemed to have moderate to high physiologic stress

 -  Male and female subjects over the age of 18 with or without a diagnosis of diabetes
 mellitus

 -  Patients must be able to provide informed consent

 Exclusion Criteria:

 -  Cognitively impaired

 -  Non-English or Spanish speaking with no relative present who is fluent in reading and
 comprehending English or Spanish.

 -  Female patients of child bearing age who have a positive pregnancy test on admission.