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.
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.
The authors thank Maiko Honma, MD, Department of Anesthesiology, Nikko Memorial Hospital, Muroran, Japan, for assistance with patient enrollment and data entry.
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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© 2016 International Anesthesia Research Society
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