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Effect of Intraoperative Glucose Infusion on Catabolism of Adipose Tissue and Muscle Protein in Patients Anesthetized With Remifentanil in Combination With Sevoflurane During Major Surgery: A Randomized Controlled Multicenter Trial

Sawada, Atsushi MD, PhD; Kamada, Yasuhiro MD, PhD; Hayashi, Haruko MD; Ichinose, Hiromichi MD, PhD; Sumita, Shinzo MD, PhD; Yamakage, Michiaki MD, PhD

doi: 10.1213/ANE.0000000000001522
Anesthetic Pharmacology: Original Clinical Research Report
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BACKGROUND: A harmful effect of stress hormone secretion during surgery is lipolysis and proteolysis to maintain normal blood glucose levels. A well-titrated general anesthetic improves blood glucose control by suppressing secretion of these stress hormones. The aim of this study was to explore the effect of intraoperative glucose infusion on lipolysis and proteolysis in patients undergoing a general anesthetic consisting of sevoflurane and remifentanil during long (>6 hours) major surgery.

METHODS: In this prospective, single-blinded, randomized, multicenter trial, 80 patients with an expected duration of anesthesia of >6 hours were allocated to either the glucose group, consisting of 40 patients who were infused with acetated Ringer’s solution with glucose (2 mg/kg/min), or the no glucose group, consisting of 40 patients who were infused with the same solution, but without glucose. After oxygenation, general anesthesia was induced with propofol, fentanyl, and rocuronium and was maintained with sevoflurane, oxygen, rocuronium, and remifentanil infusions. The rates of remifentanil infusion were titrated based on systolic arterial blood pressure, maintaining this parameter within 10% of its postanesthesia values. Seventy-four patients completed the study. Urinary 3-methylhistidine/creatinine (3-MH/Cre) ratio, acetoacetic acid, 3-hydroxybutyric acid, blood glucose, insulin, and cortisol were measured 3 times: at anesthesia induction (0 hour) and at 3 and 6 hours after anesthesia induction. Urinary 3-MH/Cre ratio was the primary study outcome.

RESULTS: In the no glucose group, the urinary 3-MH/Cre ratio at 6 hours was increased compared with that at 0 hour (213 [range, 42–1903] vs 124 [18–672] nmol/μmol; the difference in medians, 89; the 95% confidence interval [CI] of the difference, 82–252; P = .0002). Acetoacetic acid and 3-hydroxybutyric acid levels in the no glucose group were greater than those in the glucose group at 6 hours (110 [8–1036] vs 11 [2–238] μmol/L; the difference in medians, 99; the 95% CI of the difference, 92–196; P < .0001 and 481 [15–2783] vs 19 [4–555] μmol/L; the difference in medians, 462; the 95% CI of the difference, 367–675; P < 0.0001, respectively). Blood glucose and insulin levels in the glucose group were greater than those in the no glucose group at 3 hours (146 [103–190] vs 93 [72–124] mg/dL; the difference in medians, 53; the 95% CI of the difference, 47–55; P < .0001 and 9.8 [1.2–25.4] vs 3.2 [0.4–15.0] μU/mL; the difference in medians, 6.5; the 95% CI of the difference, 4.8–6.8; P < .0001) and 6 hours (139 [92–189] vs 87 [68–126] mg/dL; the difference in medians, 52; the 95% CI of the difference, 44–58; P < .0001 and 8.1 [1.2–22.3] vs 3.2 [0.4–10.1] μU/mL; the difference in medians, 4.9; the 95% CI of the difference, 4.0–5.9; P < .0001). Cortisol levels in both groups were similarly within normal levels at 0, 3, and 6 hours.

CONCLUSIONS: The study showed that intraoperative glucose infusion suppressed lipolysis and proteolysis in patients anesthetized with remifentanil in combination with sevoflurane during surgery of >6 hours in length.

From the *Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Anesthesiology, Nikko Memorial Hospital, Muroran, Japan; Department of Anesthesiology, Asahikawa Red Cross Hospital, Asahikawa, Japan; and §Department of Anesthesiology, Obihiro-Kosei General Hospital, Obihiro, Japan.

Accepted for publication June 9, 2016.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Atsushi Sawada, MD, PhD, Department of Anesthesiology, Sapporo Medical University School of Medicine, S 1, W 16, Chuo-ku, Sapporo, Japan. Address e-mail to a.sawada@sapmed.ac.jp.

Intraoperative hyperglycemia caused by surgical stress, the so-called stress-induced hyperglycemia, is a risk factor for postoperative complications and mortality.1–5 Many studies have reported that the stress response to surgery activates the sympathetic nervous system and increases secretion of pituitary hormones.6–10 The overall metabolic effect of the hormonal changes increases catabolism, which mobilizes substrates such as adipose tissue and muscle protein, to provide energy sources. Furthermore, preoperative fasting promotes the catabolism of adipose tissue and muscle protein, resulting in the production of glucose.11 Several studies have shown that remifentanil in combination with inhaled anesthesia improves intraoperative blood glucose control by suppressing stress hormone secretion.12–17

Intraoperative administration of glucose exerts anticatabolic action through the suppression of gluconeogenesis and release of gluconeogenic amino acids from muscle protein.7,18,19 Kambe et al20 demonstrated that low-dose glucose infusion suppresses lipolysis and ketogenesis; furthermore, general anesthesia with remifentanil in combination with sevoflurane suppresses stress hormone secretion during minor surgery. Because the stress response to surgery correlates with the degree of surgical invasion, it is more difficult to suppress perioperative catabolism during major surgery compared with that during minor surgery.21 The excessive stress response associated with major surgery induces postoperative catabolism, increases postoperative complications, and worsens postoperative mortality.22 Hence, we investigated the effect of intraoperative glucose infusion on lipolysis and ketogenesis during prolonged major surgery in patients under general anesthesia.

In this prospective, single-blinded, randomized control, multicenter trial, we assessed the effect of intraoperative glucose infusion on blood glucose levels and catabolism of adipose tissue and muscle protein in patients anesthetized with remifentanil in combination with sevoflurane during prolonged major surgery. We hypothesized that intraoperative glucose infusion maintained normal blood glucose levels and suppressed catabolism of adipose tissue and muscle protein during prolonged major surgery in patients under general anesthesia.

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METHODS

Study Design and Patient Selection

A total of 80 patients were scheduled to participate in this randomized control multicenter trial conducted in 4 centers (Sapporo Medical University Hospital, Japan; Nikko Memorial Hospital, Japan; Asahikawa Red Cross Hospital, Japan; and Obihiro-Kosei General Hospital, Japan). This study was approved by the appropriate institutional review board of each center and registered with the University hospital Medical Information Network clinical trial registry (UMIN000007094). Written informed consent was obtained from all patients before enrollment. Eighty patients were included in this study if they had an American Society of Anesthesiologists physical status I or II, were aged 20 years or older, and had an expected duration of anesthesia of >6 hours for elective surgery. Patients were excluded if they were obese (body mass index >35 kg/m2); had cardiac, hepatic, renal, or metabolic disorders, including diabetes mellitus; were taking any medication affecting metabolism, such as corticosteroids or β-blockers; or were scheduled to undergo hepatic, pancreatic, gallbladder, or cardiac surgery.

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Randomization and Allocation

The randomization protocol was prepared outside the study center. Randomization was performed using a sealed opaque envelope and a computer-generated random allocation created by an independent researcher. We randomly allocated patients to either the glucose group, consisting of 40 patients who were infused with acetated Ringer’s solution with glucose (2 mg/kg/min) or the no glucose group, consisting of 40 patients who were infused with the same solution, but without glucose (1:1 allocation, parallel trial design). The patients were blinded to group assignment. Because the anesthesiologists administering anesthesia could not help being aware of the group allocation, they did not participate in any other parts of this trial.

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Anesthesia Management and Study Protocol

Patients fasted from 9:00 PM on the night before surgery and were allowed to drink a sugarless beverage until 2 hours before entering the operating room. None of the patients received premedication before surgery. On arriving at the operating room, standard monitoring of electrocardiogram, pulse oximetry, and noninvasive blood pressure was established. After the placement of a venous cannula in each patient, patients in the glucose group were infused with acetated Ringer’s solution (Veen-F Inj., Kowa Co. Ltd., Tokyo, Japan; 6–10 mL/kg/h) with glucose (2 mg/kg/min), whereas those in the no glucose group were infused with the same solution, but without glucose. Although epidural anesthesia was performed in patients in whom it was indicated, epidural anesthesia was only used for postoperative analgesia to equalize intraoperative analgesic effects between patients who did and did not receive epidural anesthesia. After oxygenation, general anesthesia was induced with propofol (1.5 mg/kg), fentanyl (100 μg), and rocuronium (0.6 mg/kg). After anesthesia induction, an arterial cannula was placed in a radial artery for measurement of invasive arterial blood pressure and obtaining blood samples. A urethral catheter was placed for measurement of urine volume and simultaneously obtaining urine samples. Tracheal intubation was performed after the placement of an arterial cannula. General anesthesia was maintained with sevoflurane (1.0%–1.5%), oxygen (35%–45%), rocuronium, and remifentanil infusion (0.1–0.5 μg/kg/min). The rates of remifentanil infusion were titrated based on systolic arterial blood pressure, maintaining this parameter within 10% of its postanesthesia values. Additional boluses of fentanyl were administered as needed during surgery. If systolic arterial blood pressure decreased to <80 mm Hg, 5 mg ephedrine was administered intravenously. Because of their influence on blood glucose, other fluids, such as acetated Ringer’s solution containing glucose, hydroxyethyl starch solutions, and any blood products, were not permitted until we obtained blood and urine samples at 6 hours after anesthesia induction. Corticosteroids were not permitted for the same reason. Saline for dilution of antibiotics was permitted at any time. We administered other fluids as necessary after obtaining blood and urine samples at 6 hours. In case of an emergency, such as accidental massive hemorrhage, hydroxyethyl starch solutions and blood products were appropriately administered, and the patients were excluded from analysis.

Figure 1

Figure 1

Figure 1 shows the study protocol. Blood samples for analysis were obtained 3 times: at anesthesia induction (0 hour) and at 3 and 6 hours after anesthesia induction. Blood glucose levels were measured at the same time. If blood glucose increased to >200 mg/dL, 2 U of insulin was administered intravenously. If blood glucose decreased to <60 mg/dL, 20 mL of 50% glucose was administered intravenously. Urine samples were obtained 2 times: at 0 and 6 hours after anesthesia induction. We measured blood glucose, insulin, cortisol, acetoacetic acid, 3-hydroxybutyric acid, and urinary 3-methylhistidine/creatinine (3-MH/Cre) ratio. Acetoacetic acid and 3-hydroxybutyric acid were used as an index of catabolism of adipose tissue. Urinary 3-MH/Cre ratio was used as an index of catabolism of muscle protein.

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Statistical Analysis

For this trial, our primary objective was to investigate the effect of intraoperative glucose infusion on catabolism of muscle protein. On the basis of previous data for urinary 3-MH/Cre ratio,23 a total of 35 patients was necessary to detect a 30 nmol/μmol difference in urinary 3-MH/Cre ratio with an standard deviation of 40 nmol/μmol, a significance level of 5%, and a power of 80%. We estimated that 80 patients should be included in this trial, with 40 patients in each intervention group, because of possible dropouts and complications during surgery. Statmate 2 (GraphPad Software, La Jolla, CA) was used to calculate the sample size. Blinding to the allocation of patients was removed only after the analysis phase. The D’Agostino-Pearson omnibus normality test was performed to assess the normality of distribution. Parametric data (basic patient characteristics) were compared using the 2-tailed Student t test. Nonparametric data at the same time points between 2 groups were compared by the Mann-Whitney U test. Nonparametric data at 2 points (at 0 and 6 hours) in each group were compared by the Wilcoxon signed rank test. Nonparametric data at 3 points (at 0, 3, and 6 hours) in each group were compared by the Kruskal-Wallis test followed by Dunn multiple comparisons test, and their confidence intervals (CIs) are the 95% Dunn-adjusted CIs. The median differences and the 95% CI for the median differences between groups were calculated by the Hodges-Lehmann estimator. JMP software (SAS Institute Inc, Cary, NC) was used to calculate the 95% CI for the median differences. Differences were considered significant at P < .05. Prism 6 (GraphPad Software) was used to analyze all data.

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RESULTS

Patient recruitment and flow through the protocol are described in the Consolidated Standards of Reporting Trials diagram (Figure. 2). Of the 80 patients enrolled, 1 patient in the no glucose group was excluded from follow-up because of declining participation before arriving at the operating room. Four patients in the glucose group were excluded from analysis because of insufficient duration of anesthesia or administration of fluids that were not permitted. One patient in the no glucose group was excluded because of intraoperative administration of corticosteroids. Overall, 74 patients completed the trial: 36 (90%) in the glucose group and 38 (95%) in the no glucose group. The patient characteristics are summarized in Table 1. There were no significant differences between the 2 groups. Type of surgery and perioperative data are summarized in Table 2. Patients in both groups underwent similar surgical procedures. The perioperative data were similar between the 2 groups. The total amounts of all anesthetic agents were similar between the 2 groups during surgery. All 74 patients successfully awoke from general anesthesia and were extubated after surgery. No complications were observed in either group by the day after surgery.

Table 1

Table 1

Table 2

Table 2

Figure 2

Figure 2

Figure 3A shows the urinary 3-MH/Cre ratio in both groups. In the no glucose group, the urinary 3-MH/Cre ratio at 6 hours was greater than that at 0 hour (Figure 3A; median [range], 213 [42–1903] vs 124 [18–672] nmol/μmol; the difference in medians, 89; the 95% CI of the difference, 82–252; P = .0002). In the glucose group, the urinary 3-MH/Cre ratio was similar at 0 and 6 hours. Figure 3B shows the plasma acetoacetic acid levels in both groups. In the no glucose group, plasma acetoacetic acid levels at 6 hours were greater than those at 0 hour (Figure 3B; median [range], 110 [8–1036] vs 18 [3–267] μmol/l; the difference in medians, 93; the 95% CI of the difference, 77–170; P < .0001). Plasma acetoacetic acid levels in the no glucose group were greater than those in the glucose group at 6 hours (Figure 3B; median [range], 110 [8–1036] vs 11 [2–238] μmol/L; the difference in medians, 100; the 95% CI of the difference, 92–196; P < .0001). Figure 3C shows plasma 3-hydroxybutyric acid levels in both groups. In the glucose group, plasma 3-hydroxybutyric acid levels at 6 hours were lesser than those at 0 hour (Figure 3C; median [range], 19 [4–555] vs 204 [26–1016] μmol/L; the difference in medians, 186; the 95% CI of the difference, 145–242; P < .0001), whereas in the no glucose group, plasma 3-hydroxybutyric acid levels at 6 hours were greater than those at 0 hour (Figure 3C; median [range], 481 [15–2782] vs 124 [13–1149] μmol/L; the difference in medians, 357; the 95% CI of the difference, 225–400; P < .0001). Plasma 3-hydroxybutyric acid levels in the no glucose group were greater than those in the glucose group at 6 hours (Figure 3C; median [range], 481 [15–2782] vs 19 [4–555] μmol/L; the difference in medians, 462; the 95% CI of the difference, 367–675; P < .0001).

Figure 3

Figure 3

Figure 4

Figure 4

Figure 4A shows blood glucose levels in both groups. In the glucose group, blood glucose levels at 3 and 6 h were greater than those at 0 hour (Figure 4A; median [range], 146 [103–190], 139 [92–189], and 103 [80–132] mg/dL, respectively; the difference in medians, 42; the 95% CI of the difference, 41–44; P < 0.0001). Blood glucose levels in the glucose group were greater than those in the no glucose group at 3 hours (Figure 4A; median [range], 146 [103–190] vs 93 [72–124] mg/dL; the difference in medians, 53; the 95% CI of the difference, 47–55; P < .0001) and 6 hours (Figure 4A; median [range], 139 [92–189] vs 87 [68–126] mg/dL; the difference in medians, 52; the 95% CI of the difference, 44–58; P < .0001). In the no glucose group, blood glucose levels at 6 hours were lesser than those at 0 hour (Figure 4A; median [range], 87 [68–126] vs 96 [72–147] mg/dL; the difference in medians, 9; the 95% CI of the difference, 8–10; P = .005). The highest blood glucose level was 190 mg/dL in the glucose group. The lowest blood glucose level was 68 mg/dL in the no glucose group. None of the patients in both groups required intravenous administrations of insulin or 50% glucose. Figure 4B shows plasma insulin levels in both groups. In the glucose group, plasma insulin levels at 3 and 6 hours were greater than those at 0 hour (Figure 4B; median [range], 9.8 [1.2–25.4], 8.1 [1.2–22.3], and 4.5 [0.4–18.3] μU/mL, respectively; the difference in medians, 5.3; the 95% CI of the difference, 3.8–5.6; P < .001). Plasma insulin levels in the glucose group were greater than those in the no glucose group at 3 hours (Figure 4B; median [range], 9.8 [1.2–25.4] vs 3.2 [0.4–15.0] μU/mL; the difference in medians, 6.5; the 95% CI of the difference, 4.8–6.8; P < .0001) and 6 hours (Figure 4B; median [range], 8.1 [1.2–22.3] vs 3.2 [0.4–10.1] μU/mL; the difference in medians, 4.9; the 95% CI of the difference, 4.0–5.9; P < .0001). Figure 4C shows plasma cortisol levels in both groups. In the glucose group, plasma cortisol levels at 3 and 6 hours were lesser than those at 0 hour (Figure 4C; median [range], 4.6 [1.6–22.7], 5.3 [1.0–32.3], and 14.4 [7.2–27.6] μg/dL, respectively; the difference in medians, 9.8; the 95% CI of the difference, 9.1–10.3; P < .0001). In the no glucose group as well, plasma cortisol levels at 3 and 6 hours were lesser than those at 0 hour (Figure 4C; median [range], 4.4 [2.0–17.8], 6.2 [1.2–23.9], and 13.2 [2.9–23.3] μg/dL, respectively; the difference in medians, 8.8; the 95% CI of the difference, 7.2–9.3; P < .0001). Plasma cortisol levels in both groups were similarly within normal levels at 0, 3, and 6 hours.

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DISCUSSION

In this randomized control, multicenter trial comparing blood glucose control and protein catabolism in patients anesthetized with remifentanil in combination with sevoflurane who did and did not receive glucose supplementation during major surgery, urinary 3-MH/Cre ratio, serum acetoacetic acid, and 3-hydroxybutyric acid, as measures of protein catabolism and lipolysis, increased in the no glucose group, but not in the glucose group. In previous studies, intraoperative infusion of acetated Ringer’s solution with 1% glucose has been shown to suppress protein catabolism during minor surgery.19 Furthermore, infusion of a low dose of glucose attenuated fat catabolism without causing hyperglycemia in patients anesthetized with remifentanil in combination with sevoflurane during minor surgery.20 However, the influence of intraoperative glucose infusion on proteolysis and lipolysis during surgeries of >6 hours has not been previously evaluated. In this study, we showed that intraoperative glucose infusion suppresses the catabolism of muscle protein and adipose tissue without causing hyperglycemia in patients anesthetized with remifentanil in combination with sevoflurane during long-duration surgery.

The primary outcome measure of our study was the effect of intraoperative glucose infusion on catabolism of muscle protein. 3-MH is an amino acid derived from the skeletal muscle protein. Although other amino acids are reutilized for new protein synthesis, 3-MH is not reutilized and is quantitatively excreted by the kidney in urine. Because there is a gender gap in urinary 3-MH levels, because of the difference in the quantity of total muscle protein, urinary 3-MH/Cre ratio has been proposed as an index of catabolism of muscle protein that is not affected by this gender gap.23–25 Glucose administration after surgery has been well established to have protein-sparing properties26; however, little is known about the effect of intraoperative glucose infusion on protein catabolism during prolonged and major surgery. Kambe et al20 demonstrated that intraoperative glucose infusion did not suppress protein catabolism during minor surgery; glucose was infused for only the first 2 hours of surgery in their study. In this study, the urinary 3-MH/Cre ratio in the no glucose group was significantly increased during surgery, with no such increase in the glucose group. Conversely, plasma insulin levels in the glucose group were significantly increased compared with those in the no glucose group. Our results suggest that, in healthy subjects without altered glucose utilization, intraoperative glucose infusion is not associated with the risk of hyperglycemia and that it additionally suppresses starvation-induced protein breakdown in patients anesthetized with remifentanil in combination with sevoflurane during prolonged and major surgery.

Starvation-induced physiologic changes occur with short-term fasting. Starvation-induced physiologic adaptations in the human body include the promotion of lipolysis, ketone body synthesis, and endogenous glucose production and uptake.27 Adipose tissue is a major alternative fuel source that is used to meet the body’s energy demands during periods of starvation. Starvation promotes the metabolism of triglycerides to fatty acids. Fatty acids can be used as the major fuel to yield energy, producing ketone bodies, such as acetoacetic acid and 3-hydroxybutyric acid. The levels of these ketone bodies have been reported to increase during starvation.27 Furthermore, plasma insulin levels have been reported to decrease during starvation.28 Because insulin intensely inhibits lipolysis through phosphodiesterase-3B stimulation, which results in the inactivation of protein kinase A and a reduction in the phosphorylation of hormone-sensitive lipase, this decrease in plasma insulin levels enables lipolysis during starvation.28 In this study, plasma insulin levels in the no glucose group were significantly decreased compared with those in the glucose group during surgery. At the same time, plasma ketone body levels in the no glucose group were significantly increased compared with those in the glucose group. These results suggest that patients who do not receive intraoperative glucose infusions during major surgery react in a similar manner as starved patients.

In previous studies, a glucose infusion of 2 mg/kg/min reportedly did not lead to excess hyperglycemia during surgery.29,30 Therefore, we infused glucose at a rate of 2 mg/kg/min in this study, which resulted in a significant increase in intraoperative blood glucose levels without causing hyperglycemia during major surgery. These results are consistent with the previous findings.29,30 Most clinical studies concluded that hyperglycemia is associated with a worse stroke outcome.31,32 Although 14 neurosurgical patients received intraoperative glucose infusion in this study, none of them experienced hyperglycemia during surgery or had complications after surgery.

Plasma insulin levels in the glucose group were significantly increased in parallel with the increase in blood glucose levels during surgery. Insulin is synthesized and secreted by the β cells of the pancreas in response to an increase in blood glucose levels. Insulin promotes the uptake of glucose into the skeletal muscle and adipose tissue. Furthermore, it also inhibits lipolysis and proteolysis.18,33 The higher insulin levels induced by intraoperative glucose infusion in the glucose group may have suppressed the catabolism of muscle protein and adipose tissue. Adrenergic hormone secretion, which also affects the catabolism of muscle protein and adipose tissue during surgery, is inhibited by remifentanil anesthesia. However, we did not measure adrenergic hormone levels in this study. Hence, we cannot ignore the fact that the suppression of catabolism in this study may have been because of the decreased levels of adrenergic hormones resulting from the intraoperative use of remifentanil.

Surgical invasion activates the sympathetic nervous system and promotes the secretion of stress hormones.33 Furthermore, stress-induced hyperglycemia because of surgical invasion is implicated in the development of postoperative complications.1–5 A previous study reported that intraoperative use of high-dose remifentanil (0.5 μg/kg/min) with propofol improved intraoperative blood glucose control and insulin resistance by suppressing stress hormone secretion, whereas intraoperative use of low-dose remifentanil (0.1 μg/kg/min) did not.16 In this study, the total amount of remifentanil infused was similar between the glucose group and the no glucose group (0.30 ± 0.11 and 0.27 ± 0.10 μg/kg/min, respectively). We measured plasma cortisol levels as an indication of the degree of surgical stress. We observed that plasma cortisol levels in both groups were similarly within normal levels during surgery. Our results indicate that intraoperative use of >0.25 μg/kg/min remifentanil in combination with sevoflurane could suppress surgical stress in patients undergoing major surgery.

This study has several limitations. First, this study did not include subjects with significant comorbidity or those with altered glucose metabolism. Our results would apply to only healthy subjects. Furthermore, we followed up patients only on the day after surgery and did not measure values for adrenocorticotropic hormone, cortisol, glucose, and insulin on the day after surgery. Kambe et al20 measured these parameters and demonstrated that intraoperative infusion of glucose for 2 hours did not affect their values on the day after surgery. The effect of intraoperative glucose infusion during major surgery on the duration of increased lipolysis and proteolysis should be investigated in a future study. Although we speculated that intraoperative glucose infusion could enhance recovery after surgery in patients undergoing prolonged and major surgery, we did not investigate other end points, such as the length of hospital stay and the occurrence of postoperative complications and mortality, in this study. Hence, we were unable to conclude with certainty that intraoperative glucose infusion might improve postoperative outcome in patients anesthetized with remifentanil in combination with sevoflurane during long-duration and major surgery. Second, this study included many types of surgery. We analyzed the effect of intraoperative glucose infusion according to each surgical procedure category (craniotomy, laparoscopic gastrointestinal tract surgery, and otorhinolaryngologic surgery). In each surgical procedure category, blood glucose and cortisol levels in the glucose group were significantly higher than those in the no glucose group at 3 and 6 hours (data not shown). In craniotomy and laparoscopic gastrointestinal tract surgery, acetoacetic acid and 3-hydroxybutyric acid levels in the no glucose group were greater than those in the glucose group at 6 hours (data not shown). There were no differences in 3-MH/Cre ratios because of the small numbers of samples in each surgical procedure category. We observed no differences in terms of the type of surgery in this study. To investigate the influence of the type of surgery on the effects of intraoperative glucose infusion, a larger number of samples in each surgical procedure category is required.

In conclusion, our findings suggest that patients who do not receive a glucose infusion intraoperatively during major surgery react similarly to starved patients. Intraoperative glucose infusion suppresses the catabolism of adipose tissue and muscle protein in patients anesthetized with remifentanil in combination with sevoflurane during major surgery.

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ACKNOWLEDGMENTS

The authors thank Maiko Honma, MD, Department of Anesthesiology, Nikko Memorial Hospital, Muroran, Japan, for assistance with patient enrollment and data entry.

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DISCLOSURES

Name: Atsushi Sawada, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Name: Yasuhiro Kamada, MD, PhD.

Contribution: This author helped conduct the study.

Name: Haruko Hayashi, MD.

Contribution: This author helped conduct the study.

Name: Hiromichi Ichinose, MD, PhD.

Contribution: This author helped conduct the study.

Name: Shinzo Sumita, MD, PhD.

Contribution: This author helped conduct the study.

Name: Michiaki Yamakage, MD, PhD.

Contribution: This author helped design the study and write the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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