Thirty-nine patients diagnosed with oral malignant tumors who were aged ≥ 60 years and scheduled for radical operation with tissue reconstruction (scheduled time required ≥ 8 h) from February 2013 to May 2016 were enrolled following approval of the Clinical Ethical Committee of Kagoshima University Hospital. The study was further registered with the UMIN Clinical Trials Registry (UMIN-CTR), UMIN000015522. Written informed consent was obtained from all patients. Patients were category I (normal healthy patients, no organic, physiological, or psychiatric disturbances) or II (patients with mild systemic disease, no functional limitations) of the American Society of Anesthesiologists physical status classification [13]. Patients were randomly allocated to the GI and control groups using computer software that generated random whole numbers, where odd numbers were assigned to the control group and even numbers to the GI group. Patients who had diabetes mellitus, who were not able to continue GI infusion due to hypoglycemia, or whose actual operation time was less than 8 h, were excluded from the analysis.
Anesthesia was induced by propofol (2 mg/kg) or thiopental sodium (5 mg/kg) and inhalation of sevoflurane with 66% nitrous oxide in oxygen. Tracheal intubation was then facilitated by intravenous vecuronium (0.1 mg/kg) or rocuronium (1 mg/kg). In some cases, tracheotomy was performed under local anesthesia and then general anesthesia was induced using the same anesthetics that were described above. Anesthesia was maintained by sevoflurane and nitrous oxide in oxygen combined with an opioid analgesic, remifentanil (0.05–0.3 μg/kg/min). Patients were ventilated to maintain an end-tidal concentration of carbon dioxide at 35–40 mmHg. Routine patient monitoring included non-invasive blood pressure, invasive blood pressure through the radial artery, electrocardiogram, pulse oximetry, and an inspired/expired anesthetic gas and carbon dioxide, which were included in a patient monitor SOLAR 8000 (GE Marquette Medical Systems). Adequate analgesia was achieved by remifentanil, keeping the blood pressure of around 100 mmHg and heart rate of 80 beats/min; hypertension > 140 mmHg and tachycardia > 100 beats/min were avoided. Blood transfusion was performed when the hemoglobin concentration was < 8.0 g/dL or unstable systolic blood pressure was < 80 mmHg.
In the control group, combination of acetate Ringer’s solution which contains 1% (W/V) glucose and lactate Ringer’s solution, which contains no glucose, was infused. Regular insulin was subcutaneously applied each time when a blood glucose concentration of ≥ 180 mg/dL occurred. In the GI group, 1–4 U/h of regular insulin was continuously applied with infusion of glucose-containing acetate Ringer’s solution (5–10 g glucose per 500 mL) during surgery. In the GI group, blood glucose was adjusted within the target concentration of 80–120 mg/dL. Measurement of blood glucose concentrations was performed every 30 min during the operation. When the infusion rate of insulin was changed, blood glucose concentrations were measured every 15 min to avoid hypoglycemia. Briefly, in most cases, insulin was infused at 1–3 U/h for maintaining target glucose concentrations when acetate Ringer’s solution, in which 10 g glucose was contained, was infused at a constant speed (e.g., 250 mL/h for 50 kg body weight) throughout surgery. A second venous route was used to provide additional fluid (containing no glucose) when volume load was required. In both groups, low-dose dopamine (3 μg/kg/min) was simultaneously administered to maintain renal blood flow and to obtain constant urine output. Arterial blood samples were analyzed every 2–3 h to prevent hypokalemia. Potassium chloride was supplemented (approximately 20 mEq/h) to achieve a target plasma concentration of 4–4.5 mEq/L when hypokalemia (< 3.5 mEq/L) was observed.
Pre- and postoperative C-reactive protein (CRP), body temperature measured in the armpit, total protein (TP) and serum albumin concentration, days until discharge, and incidence of postoperative hypoalbuminemia and complications were compared. Postoperative complications, i.e., surgical site infection (SSI) including methicillin-resistant Staphylococcus aureus (MRSA), necrosis of a reconstructed flap, bacteremia, hypotension, or pneumonia, indicated those which required additional therapeutic interventions. The highest body temperature was used when multiple measurements were performed within a day. Values of blood examinations at postoperative day 4 (Day4) or Day5 are represented as Day4/5, using the higher values of CRP and body temperature and the lower values of TP and serum albumin, when data at both days were available.
Statistical analysis
Data are expressed as means with standard deviation (SD). One-way analysis of variance was used to test significance between the two groups in the baseline numerical items, in the CRP concentration and body temperature for each time point, and days required until discharge. The chi-square test was used to test differences between the groups for baseline categorical items (sex, history of hypertension, dyslipidemia, and smoking habit), incidence of each postoperative complication, and number of patients who had postoperative complications. Correlations between the mean infusion rate of glucose applied during surgery (X) and TP and serum albumin concentrations (Y) were analyzed by Pearson’s correlation coefficient, and relations were fitted by simple regression. Multiple linear regression analysis was performed to estimate the dependence of age, body mass index (BMI), mean infusion rate of glucose (mg/kg/h) and insulin (mU/kg/h) during surgery, operation time, total fluid volume, intraoperative blood loss, and intraoperative blood transfusion on the reduction of TP and albumin concentrations from the control to Day1 values. P < 0.05 was considered statistically significant.