The ideal management of glucose concentrations during the perioperative period remains unclear, and hyperglycemia may worsen surgical outcomes because it results in reperfusion injury and suppresses the immune system [1] - [8] . Moreover, postoperative insulin sensitivity is reduced in proportion to the magnitude of the surgical invasion [9] . The state of reduced insulin sensitivity is called insulin resistance, and postoperative insulin resistance may contribute to hyperglycemia [10] . Therefore, glucose administration has been avoided during surgery [11] [12] [13] . However, patients are typically required to fast for several hours before surgery to avoid vomiting during the induction of anesthesia, and patients may experience nutritional stress during long surgeries. In this context, glucose is necessary for activities of the brain, red blood cells, and kidney medulla, and it is stored as glycogen in the muscle and liver. However, the total amount of stored glycogen is insufficient to support the basal energy expenditure for one day, and gluconeogenesis may be increased in fasting patients [14] .

We have previously reported that a 1.5% glucose infusion (average administration rate: 0.15 g/kg/h) during surgery can suppress ketogenesis and attenuate postoperative insulin resistance without causing hyperglycemia [15] . We also found that postoperative glucose infusion (0.08 g/kg/h) effectively suppressed ketogenesis at the next morning [15] . However, there is insufficient evidence regarding the appropriate postoperative glucose dose and administration rate. In addition, overfeeding can result in nutritional stress, such as protein breakdown, edema, and glucotoxicity [16] [17] . Furthermore, refeeding using a high glucose load may result in an abnormal sodium balance, abnormal fluid balance, and even death among patients who have been fasting for a prolonged time [18] [19] . Moreover, rapid variability in blood glucose concentrations may enhance apoptosis in the endothelial cells of the human umbilical vein [20] . Based on our findings regarding the effects of postoperative glucose infusion at a rate of 0.08 g/kg/h, we hypothesized that this rate might suppress intraoperative ketogenesis and attenuate postoperative insulin resistance when the surgical stress is controlled also during surgery. Therefore, the present study prospectively evaluated the serum concentrations of ketone bodies and postoperative insulin resistance among patients who received intraoperative glucose administration at 0.08 g/kg/h during maxillofacial surgery.

This prospective study was performed using methods that were very similar to our previous study [15] . After obtaining approval from the Ethics Committee of Kyushu University Hospital, we obtained written informed consent from patients who were undergoing elective maxillofacial surgery and had an American Society of Anesthesiologists physical status of I?II. We excluded patients with diabetes millitus and/or obesity (a body mass index [BMI] of >25 kg/m²).

This study included 15 patients (13 women and 2 men). All patients underwent osteotomy of the maxilla and/or the mandible, because of a jaw deformity, between February 2013 and August 2015. No patients received insulin or other fluid infusions during the surgery, with the exception of scheduled autologous blood transfusions. The patient characteristics and anesthetic procedures are listed in Table 1, and the hemodynamic and bispectral index data are listed in Table 2.

The serum concentrations of noradrenaline and cortisol were significantly lower at T2 - T4, compared to at T1 (p < 0.01). The blood glucose concentrations exhibited minor variations between 90 mg/dL and 130 mg/dL during the surgery. No hyperglycemia was observed in all patients (Figure 1), although the glucose concentrations at T3 and T4 were significantly higher than those at T1 (p < 0.001 and p = 0.0052, respectively). The plasma insulin concentrations at T2 were significantly lower than those at T1 (p = 0.0023), the concentrations at T3 were significantly higher than those at T1 (p = 0.0109), and the concentrations at T4 were similar to the T1 values (Table 3). We observed no significant

Values are given as mean ± standard deviation. BMI: body mass index.

Values are given as mean ± standard deviation. T1: anesthetic induction; T2: 1 h after anesthetic induction; T3: 3 h after anesthetic induction; T4: at the end of surgery; HR: heart rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; BIS: bispectral index.

T1: anesthetic induction; T2: 1 h after anesthetic induction; T3: 3 h after anesthetic induction; T4: at the end of surgery.

Values are given as mean ± standard deviation. *p < 0.05, **p < 0.01 vs. T1. T1: anesthetic induction; T2: 1 h after anesthetic induction; T3: 3 h after anesthetic induction; T4: at the end of surgery.

differences in total ketone bodies during surgery. The plasma concentrations of acetoacetic acid at T3 and T4 were significantly higher than those at T1 (p = 0.0217 and p = 0.0306, respectively), although there were no significantly differences in the plasma concentrations of 3-hydroxybutyric acid, and no acetone was detected at any measurement (Table 3). The serum FFA concentrations were within the normal limits at all measurements, and we did not observe any significant changes during the surgery (Table 3). Furthermore, no significant changes were observed in the plasma concentrations of noradrenaline and cortisol (Table 3).

In all cases, the glucose infusion rate decreased after surgery. The preoperative glucose infusion rate of 6.62 ± 1.65 mg/kg/min decreased significantly to 3.31 ± 0.98 mg/kg/min (p < 0.001), which corresponded to a 48.0% ± 17.9% reduction.

Intraoperative glucose administration is necessary for achieving perioperative metabolic homeostasis, and may contribute to better surgical outcomes [15] [24] . However, there is insufficient information regarding the appropriate intraoperative glucose dose and infusion rate, and especially regarding the lower limits of these values. We also found that postoperative glucose infusion (0.08 g/kg/h) effectively suppressed ketogenesis at the next morning. Therefore, the present study aimed to evaluate the effects of intraoperative continuous glucose administration at 0.08 g/kg/h on blood glucose concentrations, ketogenesis, and postoperative insulin resistance.

Surgical stress affects glucose concentrations and glucose metabolism [25] . In this context, catecholamine and cortisol are secreted in response to various stresses, such as surgical invasion and pain [26] . However, we found that the intraoperative serum concentrations of noradrenaline and cortisol were significantly lower than the baseline concentrations.

Although our previous study revealed that Ringer’s solution with 1.5% glucose increased the mean blood glucose concentrations from approximately 100 mg/dL to 150 mg/dL at the induction of anesthesia, because of the rapid infusion rate (20 mL/kg/h) [11] , no intraoperative hyperglycemia was detected in the present study. In this context, Risso et al. have reported that fluctuating glucose concentrations exert more negative effects on vein endothelial cells, compared to stably high glucose concentrations [20] . However, a sharp increase in the glucose concentrations was not detected in the present study, which was maintained at 90 - 130 mg/dL during the surgery. Similar to the changes in blood glucose concentrations, the insulin concentrations were increased at T3 and subsequently returned to near baseline values at the end of the surgery.

In our previous study, overnight fasting and glucose-free fluid therapy induces ketogenesis [15] [27] . However, intraoperative low-dose glucose (approximately 43% of basal energy expenditure) effectively suppressed ketogenesis during orthopedic surgery [27] . Furthermore, intraoperative glucose administration (0.15 g/kg/h) effectively suppressed serum ketone body concentrations during maxillofacial surgery [15] . Those results suggest that, during periods with no dietary or infused glucose, the necessary glucose is supplied from fat by gluconeogenesis. Serum acetoacetic acid concentrations at T3 and T4 were higher than those at T1. However, there were not significant differences in serum concentration of total ketone bodies during surgery. Therefore, we compared the present study’s patients (G2 group) with patients from our previous study who had only received Ringer’s solution without glucose (R group) or who had received Ringer’s solution with 1.5% glucose (G1 group). Based on this comparison, there is a tendency that the serum ketone bodies concentrations were lower in G2 group than those of R group, although the trend was not statistically significant. On the other hand, the concentrations in G2 group were significantly lower than those in R group at T4 (Figure 2). Therefore, these results may suggest that continuous glucose infusions at a rate of 0.08 g/kg/h are the lower limit for suppressing ketogenesis during surgery.

In the present study, the glucose clamp technique was used for quantifying insulin sensitivity before and after surgery. The homeostasis model assessment (HOMA) index is another inexpensive and simply method for quantifying insulin sensitivity [28] [29] [30] , however, the HOMA method provides a crude and potentially inaccurate measure of postoperative insulin resistance [22] [31] . In contrast, the glucose clamp technique uses the glucose infusion rate as the indicator of insulin sensitivity, and its value decreased after surgery for all patients in the present study. Furthermore, in our previous study, postoperative insulin resistance in G1 group was effectively attenuated to a level that was comparable to that in the R group. Moreover, G2 group from the present study exhibited a non-significant trend towards a lower reduction rate compared to R group (p = 0.197), and a trend towards a higher reduction rate compared to G1 group (p = 0.44) (Figure 3). These results suggest that intraoperative glucose infusion at a rate of 0.08 g/kg/h may be insufficient for attenuating postoperative insulin resistance.