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Anesthetic Pharmacology: Research Reports

The Effects of Sevoflurane and Propofol on Glucose Metabolism Under Aerobic Conditions in Fed Rats

Kitamura, Takayuki MD; Ogawa, Makoto MD; Kawamura, Gaku MD; Sato, Kanako MD; Yamada, Yoshitsugu MD, PhD

Author Information
doi: 10.1213/ANE.0b013e3181b8554a

Abstract

Surgery under general anesthesia exaggerates endocrine metabolic responses.1,2 Insulin secretion is impaired, resulting in decreased glucose use. Blood concentrations of catabolic hormones, such as cortisol, growth hormone, and norepinephrine, are increased, resulting in enhancement of glucose production. Because of the changes in glucose metabolism, hyperglycemia occurs during surgery. Several studies reported that intraoperative hyperglycemia is an independent risk factor for mortality and morbidity related to surgery.3–5 Today, both sevoflurane and propofol are widely used as general anesthetics in clinical settings. Several studies reported that volatile anesthetics such as sevoflurane impair glucose use, thus suggesting a possible contribution to intraoperative hyperglycemia.2,6–8 However, to our knowledge, the effects of IV anesthetics, such as propofol, on glucose metabolism are poorly understood. Thus, we compared the effects of sevoflurane and propofol on glucose metabolism under aerobic conditions using 2 experimental models of fed rats.

METHODS

Subjects

All experimental protocols in this study were approved by the animal care committee of our institute. We used adult, male, Sprague-Dawley rats weighing 350–400 g (Nippon Bio-Supp. Center, Tokyo, Japan). Rats were housed separately in a regulated environment; room temperature was maintained at 25°C, and a 12-h light-dark cycle (7 am and 7 pm) was applied. Food (24% protein, 5% fat, 6% ash, 3% fiber, 8% water, and 54% nitrogen-free extract) and water were provided ad libitum until the experiments. All experiments were performed between 9 am and 5 pm. To prevent hypothermia during experiments, we used a heat lamp, and rats were placed on a heating pad during general anesthesia.

Surgical Stress: Sigmoid Colostomy

Seventy-two rats were divided into 2 groups: rats undergoing sigmoid colostomy under sevoflurane anesthesia (group surgery/S) and under propofol anesthesia (group surgery/P).

Immediately before surgical preparation, baseline blood glucose levels (baseline values) were measured using blood obtained by puncturing the tail vein. Anesthesia for surgical preparation was with sevoflurane (3% in 1 L/min oxygen) via a tightly fitting mask. All rats underwent tracheotomy. After tracheal intubation, sevoflurane (3% in 1 L/min oxygen) was administered via a tracheal tube, and the lungs were ventilated mechanically. A 19-gauge catheter was inserted into the right jugular vein for administration of drugs and maintenance fluid, and it was inserted into the right carotid artery for blood sampling. The arterial catheter was connected to a low volume pressure transducer for monitoring hemodynamics.

After surgical preparation, sevoflurane anesthesia was maintained at 3 different concentrations for rats in group surgery/S: 1.5% (group surgery/SL, 8 rats), 2% (group surgery/SM, 8 rats), and 3% (group surgery/SH, 8 rats) in 1 L/min oxygen. For rats in group surgery/P, sevoflurane administration was discontinued, but propofol was administered IV: bolus dose of 20 mg/kg followed by continuous infusion at a rate of 20 mg · kg−1 · h−1 (group surgery/PL, 8 rats), bolus dose of 30 mg/kg followed by continuous infusion at a rate of 30 mg · kg−1 · h−1 (group surgery/ PM, 8 rats), and bolus dose of 40 mg/kg followed by continuous infusion at a rate of 40 mg · kg−1 · h−1 (group surgery/PH, 8 rats). Additionally, we coadministered buprenorphine (Sigma-Aldrich Japan, Tokyo, Japan) at doses of 50 and 200 μg/kg IV in 8 rats anesthetized using the same protocol as rats in group surgery/PM (group surgery/PMB50 and group surgery/PMB200, respectively), and coadministered 200 μg/kg buprenorphine IV in 8 rats anesthetized by the same protocol as rats in group surgery/SM (group surgery/SMB200). Buprenorphine was dissolved in physiological saline using a solution with a concentration of 200 μg/mL. Total fluid administration after surgical preparation was adjusted to 10 mL · kg−1 · h−1 for all rats using physiological saline. Thirty minutes after surgical preparation, we measured arterial blood glucose levels (presurgery values). All rats then underwent sigmoid colostomy. At the end of sigmoid colostomy, arterial blood glucose levels (postsurgery values) were measured.

Intravenous Glucose Tolerance Test

Another set of rats (56 rats) were divided into 3 groups: awake rats undergoing intravenous glucose tolerance test (IVGTT) (group IVGTT/A), rats undergoing IVGTT under sevoflurane anesthesia (group IVGTT/S), and rats undergoing IVGTT under propofol anesthesia (group IVGTT/P).

After measuring baseline blood glucose levels, sevoflurane anesthesia was used for surgical preparation (3% in 1 L/min oxygen) via a tightly fitting mask. Rats assigned to groups IVGTT/S and IVGTT/P underwent tracheotomy. After tracheal intubation, sevoflurane (3% in 1 L/min oxygen) was administered via a tracheal tube, and the lungs were ventilated mechanically. All rats underwent catheterization to the right jugular vein and the right carotid artery. Catheters were tunneled subcutaneously and externalized at the back of the neck in rats assigned to group IVGTT/A.

After surgical preparation, 8 rats assigned to group IVGTT/A were allowed to recover from anesthesia by discontinuing sevoflurane administration. For rats in group IVGTT/S, sevoflurane anesthesia was maintained at 3 different concentrations: 1.5% (group IVGTT/SL, 8 rats), 2% (group IVGTT/SM, 8 rats), and 3% (group IVGTT/SH, 8 rats) in 1 L/min oxygen. For rats in group IVGTT/P, sevoflurane administration was discontinued, but propofol was administered IV: bolus dose of 20 mg/kg followed by continuous infusion at a rate of 20 mg · kg−1 · h−1 (group IVGTT/PL, 8 rats), bolus dose of 30 mg/kg followed by continuous infusion at a rate of 30 mg · kg−1 · h−1 (group IVGTT/PM, 8 rats), and bolus dose of 40 mg/kg followed by continuous infusion at a rate of 40 mg · kg−1 · h−1 (group IVGTT/PH, 8 rats). Thirty minutes after surgical preparation, we measured arterial blood glucose levels (pre-IVGTT values). Glucose 0.5 g/kg was then administered IV, and arterial blood glucose levels were measured every 5 min for 30 min. We used a sterile glucose solution with a concentration of 0.5 g/mL in distilled water (Ohtsuka Pharmaceutical Co., Tokyo, Japan).

Analysis of Blood Glucose Levels

Blood glucose levels were measured by the glucose oxidase method using a blood glucose meter (Medisafe, Terumo, Tokyo, Japan). We withdrew 0.2 mL of blood via the arterial catheter for each measurement.

Calculated Values and Statistics

The area under the time-response curve (AUC) for blood glucose levels above the pre-IVGTT value during IVGTT in each rat was calculated and used to evaluate the effects of anesthetics on changes in blood glucose levels after glucose administration.

Data are shown as means± sd. Statistical analyses were performed using StatView version 5.0 (SAS Institute, Cary, NC) and JMP version 7.0.2. (SAS Institute). Homogeneity of the variance was examined using Bartlett test. For overall comparisons of serial data among groups, we used 2-way repeated-measures analysis of variance (ANOVA), with group and time point as the factors. For overall comparisons of serial data within each group, we used 1-way repeated-measures ANOVA. We used 1-way ANOVA with Scheffé F test as a post hoc test for comparisons of blood glucose levels at each time point among groups and for comparisons of the AUC among groups. We used 1-way ANOVA with Dunnett test as a post hoc test for comparisons of hemodynamic variables at each time point among groups. Statistical significance was set at P < 0.05.

RESULTS

Changes in Blood Glucose Levels and Hemodynamics During Sigmoid Colostomy Under Sevoflurane and Propofol Anesthesia

The time course of blood glucose levels during sigmoid colostomy under sevoflurane anesthesia and propofol anesthesia are shown in Figure 1. There were significant differences in the time course of blood glucose levels among the 6 groups (P < 0.0001).

Figure 1
Figure 1:
Figure 1.

In group surgery/SL, group surgery/SM, and group surgery/SH, blood glucose levels increased significantly during the experimental period (P < 0.0001, P = 0.0002, and P = 0.0009, respectively); both presurgery and postsurgery values were significantly higher than baseline values (P < 0.05 for each comparison). Whereas blood glucose levels increased significantly during the experimental period in group surgery/PL and group surgery/PM (P = 0.0191 and 0.0011, respectively), there were no significant changes in blood glucose levels during the experimental period in group surgery/PH. Presurgery values in group surgery/PL, group surgery/PM, and group surgery/ PH were similar to baseline values. Although postsurgery values in group surgery/PL and group surgery/PM were slightly but significantly higher than baseline values (P < 0.05 for each comparison), postsurgery values in group surgery/PH were similar to baseline values.

There were no significant differences in baseline values among the 6 groups. Both presurgery and postsurgery values in group surgery/SM and group surgery/SH were similar to those in group surgery/SL. Presurgery values in group surgery/PL, group surgery/PM, and group surgery/PH were significantly lower than in group surgery/SL (P = 0.0022, 0.0003, and 0.0003, respectively), and postsurgery values in group surgery/PL, group surgery/PM, and group surgery/PH were significantly lower than in group surgery/SL (P < 0.0001 for each comparison).

Hemodynamic variables during sigmoid colostomy in the 6 groups are shown in Table 1. There were no significant differences in the time course of mean arterial blood pressure among groups; however, there were significant differences in the time course of heart rate (HR) among groups (P = 0.0069). The HR in group surgery/PM was significantly more rapid than that in group surgery/SL before and after sigmoid colostomy (P = 0.0003 and P < 0.0001, respectively), and the HR in group surgery/PL was significantly more rapid than that in group surgery/SL after sigmoid colostomy (P < 0.0001).

Table 1
Table 1:
Hemodynamic Variables During Sigmoid Colostomy Under Sevoflurane and Propofol Anesthesia

Effects of the Coadministration of Buprenorphine on Changes in Blood Glucose Levels and Hemodynamics During Sigmoid Colostomy Under Propofol and Sevoflurane Anesthesia

The time course of blood glucose levels during sigmoid colostomy under propofol anesthesia with or without buprenorphine is shown in Figure 2. There were significant differences in the time course of blood glucose levels among group surgery/PM, group surgery/PMB50, and group surgery/PMB200 (P = 0.0224). There were no significant differences in baseline and presurgery values among the 3 groups. Postsurgery values were significantly decreased by the coadministration of buprenorphine in a dose-dependent manner (P = 0.0429). The time course of blood glucose levels during sigmoid colostomy under sevoflurane anesthesia with or without buprenorphine is also shown in Figure 2. There were no significant differences in the time course of blood glucose levels between group surgery/SM and group surgery/SMB200.

Figure 2
Figure 2:
Figure 2.

Hemodynamic variables during sigmoid colostomy under propofol anesthesia with or without buprenorphine are shown in Table 2. There were no significant differences in the time course of mean arterial blood pressure among group surgery/PM, group surgery/ PMB50, and group surgery/PMB200. There were significant differences in the time course of HR among the 3 groups (P = 0.0096); although HR decreased significantly during sigmoid colostomy in group surgery/ PM (P = 0.0199), no significant changes in HR were detected during sigmoid colostomy in group surgery/ PMB50 and group surgery/PMB200. Hemodynamic variables during sigmoid colostomy under sevoflurane anesthesia with or without buprenorphine are also shown in Table 2. There were no significant differences in the time course of hemodynamic variables between group surgery/SM and group surgery/SMB200.

Table 2
Table 2:
Hemodynamic Variables During Sigmoid Colostomy Under Propofol/Buprenorphine Anesthesia and Sevoflurane/Buprenorphine Anesthesia

Changes in Blood Glucose Levels and Hemodynamics During IVGTT

The time course of blood glucose levels during IVGTT is shown in Figure 3. There were significant differences in the time course of blood glucose levels among the 7 groups (P < 0.0001).

Figure 3
Figure 3:
Figure 3.

Significant differences were detected by overall comparisons within each group of blood glucose levels during the experimental period in groups IVGTT/SL, IVGTT/SM, and IVGTT/SH (P = 0.0339, 0.0318, and 0.0381, respectively), but not in groups IVGTT/A, IVGTT/PL, IVGTT/PM, or IVGTT/PH. In group IVGTT/A, blood glucose levels before and 5, 10, 15, 20, and 25 min after glucose administration were significantly higher than baseline values (P < 0.05 for each comparison); however, blood glucose levels 30 min after glucose administration were similar to baseline values. In groups IVGTT/SL, IVGTT/SM, and IVGTT/SH, blood glucose levels before and 5, 10, 15, 20, 25, and 30 min after glucose administration were significantly higher than baseline values (P < 0.05 for each comparison). In groups IVGTT/PL, IVGTT/PM, and IVGTT/PH, blood glucose levels 5, 10, and 15 min after glucose administration were significantly higher than baseline values (P < 0.05 for each comparison); however, blood glucose levels before and 20, 25, and 30 min after glucose administration were similar to baseline values.

There were no significant differences in baseline values among groups. Pre-IVGTT values in group IVGTT/SH were significantly higher than those in group IVGTT/A (P = 0.0171); however, pre-IVGTT values in the other 5 groups were similar to those in group IVGTT/A. In groups IVGTT/SL, IVGTT/SM, and IVGTT/SH, blood glucose levels after glucose administration were significantly higher than those in group IVGTT/A throughout the experimental period (P < 0.05 for each comparison). In groups IVGTT/PL, IVGTT/PM, and IVGTT/PH, blood glucose levels after glucose administration were similar to those in group IVGTT/A throughout the experimental period.

There were significant differences in the AUC among groups (Fig. 4, P < 0.0001). The AUC in groups IVGTT/SL, IVGTT/SM, and IVGTT/SH was significantly greater than that in group IVGTT/A (P = 0.0012, 0.0096, and 0.0166, respectively); however, the AUC in groups IVGTT/PL, IVGTT/PM, and IVGTT/ PH was similar to that in group IVGTT/A.

Figure 4
Figure 4:
Figure 4.

Hemodynamic variables during IVGTT in all groups except for group IVGTT/A are shown in Table 3. We could not evaluate hemodynamics of rats in group IVGTT/A because these rats were allowed to move freely during IVGTT. There were no significant differences in the time course of hemodynamic variables among the 6 groups.

Table 3
Table 3:
Hemodynamic Variables During IV Glucose Tolerance Test (IVGTT)

DISCUSSION

Glucose metabolism can be modified by several factors during the perioperative period. Surgical stress increases sympathetic nerve activity, increases the plasma concentration of catabolic hormones, and decreases insulin secretion, resulting in increased glucose production as well as decreased glucose use.1,2 Changes in blood glucose levels after sigmoid colostomy observed in this study reflect the effects of general anesthetics on glucose metabolism during surgery. Blood glucose levels increased markedly during sigmoid colostomy under sevoflurane anesthesia; however, blood glucose levels were relatively stable during sigmoid colostomy under propofol anesthesia. In addition, whereas the slight increases in blood glucose levels after sigmoid colostomy under propofol anesthesia were completely prevented by the coadministration of buprenorphine, there were no significant effects of the coadministration of buprenorphine on blood glucose levels after sigmoid colostomy under sevoflurane anesthesia. These results suggest that glucose metabolism during surgery under propofol anesthesia is considerably different from that under sevoflurane anesthesia.

It is unclear whether the increase in glucose production or the impairment of glucose use is the major effect of sevoflurane on glucose metabolism during surgery. However, studies in pigs7 and humans8 have shown that sevoflurane decreases insulin secretion, resulting in impaired glucose use. Changes in blood glucose levels during IVGTT in this study reflect the effects of sevoflurane and propofol on glucose use, suggesting that sevoflurane impairs glucose use, but it is not significantly affected by propofol. We suppose that these findings can be one of the possible explanations for the differences in the effects of sevoflurane and propofol on glucose metabolism during surgery.

Volatile anesthetics inhibit insulin secretion.6–9 Insulin secretion is regulated by 2 pathways: KATP channel-dependent pathways and KATP channel-independent pathways, such as α2-adrenergic signaling.10,11 A recent study reported that pancreatic sarcolemmal KATP channels are involved in hyperglycemia induced by isoflurane, but neither mitochondrial KATP channels nor α2-adrenergic receptors are involved.11 Because the effects of propofol on insulin secretion have not been elucidated, the pancreatic sarcolemmal KATP channel can be an object of future studies for investigating the mechanisms underlying the differences in the effects of sevoflurane and propofol on glucose metabolism.

Propofol reduces sympathetic nerve activity,12 and it was reported that plasma concentrations of catecholamines during surgery under propofol/sufentanil anesthesia are significantly lower than those under enflurane anesthesia.13 However, there seemed to be no obvious correlation between hemodynamics and blood glucose levels during sigmoid colostomy and IVGTT in this study. Therefore, it is possible that sympathetic nerve activity is not responsible for the differences in the effects of sevoflurane and propofol on glucose metabolism observed in this study, although we did not measure plasma concentrations of catecholamines.

Several studies reported that plasma concentrations of cortisol and growth hormone under general anesthesia using volatile anesthetics are decreased or not altered without surgical stress but are increased with surgical stress.1,7,9,13,14 Some studies reported that the plasma concentration of cortisol under propofol anesthesia is decreased without surgical stress.13,15 Changes in the plasma concentration of cortisol during surgery under propofol/opioid anesthesia have been controversial.13,14 Further investigations are required to clarify whether catabolic hormones are involved in the differences in the effects of sevoflurane and propofol on glucose metabolism.

Several studies have shown that intraoperative hyperglycemia is associated with a frequent incidence of complications in the postoperative period, and that strict control of blood glucose levels during surgery may minimize the risk of morbidity and mortality.3–5 The results of this study clearly show that propofol and propofol/opioid anesthesia can prevent hyperglycemia related to surgery, but sevoflurane and sevoflurane/opioid anesthesia cannot prevent it, implying the possibility that anesthetic management using propofol and opioids might be better for the management of blood glucose levels during surgery. However, we evaluated the effects of general anesthetics on glucose metabolism during surgery under aerobic conditions but not under anaerobic conditions in this study using rats. Therefore, we cannot simply extrapolate these results to clinical anesthetic practice. Several studies reported the beneficial effects of volatile anesthetics on myocardial ischemia/reperfusion injury.16–18 It was also reported that sevoflurane anesthesia provides better availability of interstitial glycolysis metabolites in the skeletal muscle during tourniquet-induced ischemia/reperfusion than propofol anesthesia,19 and clinical outcome after coronary surgery with cardiopulmonary bypass under sevoflurane anesthesia is better than that under propofol anesthesia.20 Therefore, it is possible to speculate that sevoflurane anesthesia is a better choice than propofol anesthesia as an anesthetic regimen for surgery associated with ischemia/reperfusion, and the protective effects of sevoflurane on ischemia/reperfusion injury may overcome the harmful effects of hyperglycemia induced by sevoflurane.

We used fed rats to examine the effects of general anesthetics on glucose metabolism. The time required for surgical preparation in this study was about 30 min; we consider that 30 min is too short to create a fasting equivalent situation. The main reason why we did not use fasted rats was to avoid the possible effects of fasting on glucose metabolism. However, in clinical settings, patients are usually fasted before the induction of anesthesia. Therefore, further studies using fasted animals to compare the effects of sevoflurane and propofol on glucose metabolism are necessary.

In conclusion, although intraoperative hyperglycemia and impairment of glucose use were observed under sevoflurane anesthesia, propofol anesthesia provided relatively stable glucose homeostasis during surgery and produced no significant effects on glucose use, implying that the effects of these anesthetics on glucose metabolism are markedly different.

REFERENCES

1. Oyama T, Takazawa T. Effects of halothane anaesthesia and surgery on human growth hormone and insulin level in plasma. Br J Anaesth 1971;43:573–80
2. Diltoer M, Camu F. Glucose homeostasis and insulin secretion during isoflurane anesthesia in humans. Anesthesiology 1988; 68:880–6
3. Gandhi GY, Nuttall GA, Abel MD, Mullany C, Schaff HV, Williams BA, Schrader LM, Rizza RA, McMahon MM. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005;80:862–7
4. McGirt MJ, Woodworth GF, Brooke BS, Coon AL, Jain S, Buck D, Huang J, Clatterbuck RE, Tamargo RJ, Perler BA. Hyperglycemia independently increases the risk of perioperative stroke, myocardial infarction, and death after carotid endarterectomy. Neurosurgery 2006;58:1066–73
5. Ammori JB, Sigakis M, Englesbe MJ, O'Reilly M, Pelletier SJ. Effects of intraoperative hyperglycemia during liver transplantation. J Surg Res 2007;140:227–33
6. Sbai D, Jouvet P, Soulier A, Penicaud L, Merckx J, Bresson JL. Effects of halothane anesthesia on glucose utilization and production in adolescents. Anesthesiology 1995;82:1154–9
7. Saho S, Kadota Y, Sameshima T, Miyao J, Tsurumaru T, Yoshimura N. The effects of sevoflurane anesthesia in insulin secretion and glucose metabolism in pigs. Anesth Analg 1997;84:1359–65
8. Tanaka T, Nabatame H, Tanifuji Y. Insulin secretion and glucose utilization are impaired under general anesthesia with sevoflurane as well as isoflurane in a concentration-independent manner. J Anesth 2005;19:277–81
9. Carli F, Ronzoni G, Webster J, Khan K, Elia M. The independent metabolic effects of halothane and isoflurane anaesthesia. Acta Anaesthesiol Scand 1993;37:672–8
10. Maechler P, Wollheim CB. Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J Physiol 2000;529:49–56
11. Zuubier CJ, Keijzers PJM, Koeman A, Van Wezel HB, Hollmann MW. Anesthesia's effects on plasma glucose and insulin and cardiac hexokinase at similar hemodynamics and without major surgical stress in fed rats. Anesth Analg 2008;106:135–42
12. Ebert TJ, Muzi M, Berens R, Goff D, Kampine JP. Symoathetic responses to induction of anesthesia in humans with propofol or etomidate. Anesthesiology 1992;76:725–33
13. Schricker T, Carli F, Schreiber M, Wachter U, Geisser W, Lattermann R, Georieff M. Propofol/sufentanil anesthesia suppresses the metabolic and endocrine responses during, not after, lower abdominal surgery. Anesth Analg 2000;90:450–5
14. Schricker T, Lattermann R, Fiset P, Wykes L, Carli F. Integrated analysis of protein and glucose metabolism during surgery: effects of anesthesia. J Appl Physiol 2001;91:2523–30
15. Schricker T, Klubien K, Carli F. The independent effect of propofol anesthesia on whole body protein metabolism in humans. Anesthesiology 1999;90:1636–42
16. Belhomme D, Peynet J, Louzy M, Launay J-M, Kitakaze M, Menasche P. Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation 1999;100: II340–4
17. De Hert SG, ten Broecke PW, Mertens E, Van Sommeren EW, De Blier IG, Stockman BA, Rodrigus IE. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology 2002;97:42–9
18. De Hert SG, Turani F, Mathur S, Stowe DF. Cardioprotection with volatile anesthetics: mechanisms and clinical implications. Anesth Analg 2005;100:1584–93
19. Carles M, Dellamonica J, Roux J, Lena D, Levraut J, Pittet JF, Boileau P, Raucoules-Aime M. Sevoflurane but not propofol increases interstitial glycolysis metabolites availability during tourniquet-induced ischaemia-reperfusion. Br J Anaesth 2008;100:29–35
20. De Hert SG, Van der Linden PJ, Cromheecke S, Meeus R, ten Broecke PW, De Blier IG, Stockman BA, Rodrigus IE. Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 2004;101:9–20
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