Abstract

Objective

Amino acid administration helps to prevent intraoperative hypothermia but may enhance thermogenesis when combined with glucose infusion. The aim of this study was to examine the effect of intraoperative amino acid administration, with or without glucose infusion, on temperature regulation during laparoscopic colectomy.

Methods

Twenty-one patients whose physical status was classified I or II by the American Society of Anesthesiologists, and who were undergoing elective laparoscopic colectomy were enrolled. The exclusion criteria were a history of diabetes and/or obesity, preoperative high levels of C-reactive protein, high blood glucose and/or body temperature after anesthesia induction, and surgical time >500 minutes. Each patient received an acetate ringer solution and was randomly assigned to one of three groups. Group A patients were given only amino acids. Group AG patients were given amino acids and glucose. Group C patients were given neither amino acids nor glucose. Tympanic membrane temperatures and blood glucose and insulin levels were measured intraoperatively.

Results

Intraoperative amino acid infusion significantly increased body temperature during surgery as compared with either Group AG or C. The blood glucose levels in Group AG were significantly higher than those in Groups A and C. However, there were no significant differences between Groups A and C. Two hours after anesthesia induction, serum insulin levels in Groups A and AG significantly increased compared with Group C. No significant differences in the postoperative complications or patient hospitalization lengths were detected between the groups.

Conclusion

Intraoperative amino acid infusion without glucose administration maintains body temperature more effectively than combined amino acid and glucose infusion in patients undergoing laparoscopic colectomy, despite unaltered intraoperative insulin levels.

Keywords

amino acids; body temperature; glucose; insulin;

1. Introduction

Perioperative hypothermia causes adverse effects, such as shivering, poor wakefulness, bleeding and infection, and worsens morbidity and/or mortality.¹Evidence-based established methods using either a forced air system and/or a fluid warmer are recommended to maintain perioperative body temperature.²Intravenous amino acid administration has also been reported to prevent intraoperative hypothermia and suppress protein catabolism during general anesthesia.3, 4, 5

The mechanisms by which amino acids mediate thermogenic effects are controversial; however, hypermetabolism or central thermoregulatory control may play a pivotal role.3, 4, 5, 6 Hypermetabolism-related heat production likely occurs as a result of an increase in oxidative metabolism from protein synthesis, which requires extra synthesis of ATP. The mechanism of central thermoregulatory control is not clear, but amino acids may produce an increase in major autonomic thermoregulatory defense thresholds. Recently, Yamaoka et al7, 8 reported that amino acids enhanced insulin secretion, stimulated muscle protein synthesis, and enhanced muscle heat accumulation in rats undergoing general anesthesia. Clinically, Moriyama et al⁹ showed that amino acid infusion promotes insulin secretion, which may cause amino-acid-induced thermogenesis. Schricker et al¹⁰ reported that intraoperative glucose infusion promotes insulin secretion. Together, these findings suggest that combined amino acid and glucose nourishment may enhance thermogenesis. However, we did not find a significant effect of amino acids alone or combined with glucose on thermogenesis during knee surgery.¹¹ We speculated that these negative results may be attributed to the short duration of the procedure.

Here, we evaluated the effects of combined glucose and amino acid infusion on body temperature and insulin secretion in laparoscopic colectomy, which is an operation of longer duration than in our previous study (5 hours vs. 2 hours).¹¹ We tested the hypothesis that combined glucose and amino acid administration is more effective than amino acid infusion alone in regulating blood glucose levels and maintaining body temperature.

2. Methods

The study protocol was approved by the Saiseikai Nakatsu Hospital Ethics Committee based on the Declaration of Helsinki and was performed at the Saiseikai Nakatsu Hospital, Osaka, Japan. Written informed consent was obtained from all of the participants.

A total of 28 patients were recruited for this study. Each patient underwent elective laparoscopic colectomy under general anesthesia between September 1, 2010 and July 31, 2011, and had a physical status of Ι or ΙΙ, as classified by the American Society of Anesthesiologists.

The following exclusion criteria applied: a history of diabetes and/or obesity (body mass index > 30); preoperative receipt of sedatives, analgesics, or antidepressants; preoperative C-reactive protein level > 1.0 mg/dL; blood glucose level > 126 mg/dL, and/or body temperature > 37.5°C after anesthetic induction; or surgical time > 500 minutes.

The following values were recorded: white blood cell count, C-reactive protein, sodium, total protein, albumin, hemoglobin, and hematocrit levels, as well as glucose level, the day before, the day of, and the day after surgery.

All patients were given 2 L polyethylene glycol electrolyte lavage solution, 200 mL magnesium citrate solution, and 24 mg sennoside 1 day before surgery, and were also given 120 mL glycerin enema on the day of surgery. All the patients were maintained as nothing per orem status at least 24 hours prior to surgery, but were given 1 L of electrolyte solution with 4.3% glucose and 500 mL Ringer's acetate solution with 5% glucose intravenously until the start of surgery.

General anesthesia was induced with propofol (1.2–2 mg/kg), fentanyl (2–4 μg/kg), and rocuronium (0.9 mg/kg), and it was maintained with sevoflurane (1–1.5%) and continuous remifentanil infusion (0.05–0.25 μg/kg/minute) throughout surgery. An epidural catheter was inserted between the 10^th and 11^th thoracic lumbar vertebrae or 11^th and 12^th thoracic lumbar vertebrae. For intraoperative pain control, a 5–7-mL bolus of 0.375% ropivacaine was given followed by continuous infusion of 2 mL/hour beginning 10 minutes before skin incision, and lasting until the end of surgery. A 22 G catheter was inserted into the left radial artery for continuous arterial blood pressure monitoring and blood withdrawal throughout the study.

The patients were randomly assigned to the amino acid (A), amino acid and glucose (AG), or control (C) groups. The patients were given intravenous Ringer's acetate solution (Veen-F Inj., Kowa Co. Ltd., Tokyo, Japan) at 5 mL/kg/hour, and Groups A and AG were both given amino acids at 200 mL/hour (300 mL, Amiparen; Otsuka Pharmaceutical Factory, Tokushima, Japan; Table 1) for 1.5 hours after surgery initiation. In Group AG, glucose was infused at 2 mg/kg/minute with an infuser pump; it was administered at anesthesia induction and for the duration of surgery. All infusions were given at room temperature.

Table 1. Composition of amino acid mixture fluid (Amiparen).

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Blood glucose levels were measured every hour from anesthesia induction (beginning, t = 0) until the end of the surgery, with a portable glucose self-monitoring device (Glutest Neo Super and Sensor; Sanwa Kagaku Kenkyusho Co. Ltd., Nagoya, Japan). Insulin levels were measured three times: at anesthesia induction (t = 0), 2 hours after anesthesia induction, and at the end of surgery.

After taking the first blood sample, 300 mL amino acids was infused in Groups A and AG, and glucose was also administered continuously in Group AG until surgery ended. Mean blood pressure and heart rate were maintained at 70–100% of the baseline values with ephedrine (5 mg as indicated). After surgery, patients received up to 200 mg sugammadex to antagonize neuromuscular blockade and facilitate emergence from general anesthesia. For postoperative pain control, ropivacaine (8 mg/hour) and fentanyl (0.4–0.55 μg/hour) were administered together through the epidural catheter; the treatment was discontinued on Postoperative Day (POD) 2.

The operating room temperature was maintained at 26°C until anesthesia induction; the room was cooled to ∼23°C during surgery, and warmed to 26°C near the end of surgery. Patients were placed in the lithotomy position during surgery and covered with a single sheet. A forced-air warming system (Bair-Hugger; Arizant Healthcare, Eden Prairie, MN, USA) was set to 38°C during surgery and positioned over the precordium and upper limbs. The tympanic membrane temperature was measured as the core temperature every 15 minutes throughout the procedure because an esophageal probe was not available in our operating room.

Our institute has the following protocol for initiating the measurement of body temperature and blood glucose during surgery: (1) when blood glucose is < 70 mg/dL, 20 mL of 20% glucose is given; (2) when blood glucose is > 200 mg/dL, 2 U insulin is administered; (3) when the core temperature is > 38°C, the forced-air warming system is suspended until the body temperature drops below 38°C; and (4) when the body temperature is < 35°C, the target temperature of the forced-air warming system increases to 43°C until the body temperature increases above 35°C.

In the post-anesthesia care unit, 50 mg intravenous flurbiprofen axetil or 50 mg intrarectal diclofenac sodium was administered as necessary for pain relief. We recorded the need of these two drugs for 7 days post-surgery. Twenty-four hours after surgery, the visual analog scale was used to evaluate postoperative pain. We also recorded any adverse effects, such as postoperative shivering, nausea or vomiting, oral intake, and hospital stay.

Blood samples were centrifuged at 3500 rpm for 5 minutes, and plasma was stored at 2–8°C until analysis. Serum insulin levels were measured as immune-reactive insulin using the chemiluminescence immunoassay method.

2.1. Statistical analysis

The nonsteroidal anti-inflammatory drug (NSAID) administration frequency is shown as the median and the range, whereas the other data are presented as the mean ± standard deviation. Body temperature changes, serum insulin levels, and blood glucose levels throughout surgery were analyzed with two-way analysis of variance, followed by post hoc analysis with Tukey's test. The interval data were assessed with the Kruskal–Wallis analysis of variance median test, followed by post hoc analysis with the Mann–Whitney U test. A statistics software package (STATISTICA 5.5; StatSoft Inc., Tulsa, OK, USA) was used, and statistical significance was accepted at p < 0.05.

3. Results

We recruited 28 patients for the study. Five patients were excluded based on our exclusion criteria, and two patients from Group A were excluded because of the need for temporary administration of glucose solution. Therefore, a total of 21 patients (13 men and 8 women) were enrolled. The patient characteristics are summarized in Table 2. There were no significant differences in body height, body weight, or body mass index between the three groups.

Table 2. Basic patient characteristics.

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Table 3 illustrates the perioperative data for all the groups. The patients from each group received similar operations. Total volumes administered in each group were 31.8 ± 9.1 mL/kg in Group C, 39.7 ± 2.8 mL/kg in Group A, and 34.3 ± 10.0 mL/kg in Group AG respectively. The anesthesia time, fluid, and blood balance were similar. The intravenous remifentanil and ephedrine doses were similar between the groups.

Table 3. Perioperative time, fluid balance, body temperature, and intraoperative dose of remifentanil and ephedrine in all groups.

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Fig. 1 and Table 4 show body temperature changes compared to baseline values before surgery. Body temperatures in Group A rose continuously and increased gradually above the baseline, and were significantly increased compared with baseline and with Groups AG and C in each period (p < 0.05). Although the patients in Group AG displayed significant temporary body temperature reductions that recovered gradually throughout surgery, the patients in Group C displayed significantly decreased body temperatures throughout surgery. Insulin levels 2 hours after anesthesia induction were similar between Groups A and AG, but were significantly higher in Groups A and AG than in Group C (Group C, n = 6; Group A, n = 5; Group AG, n = 6; p < 0.05; Fig. 2 and Table 4). Blood glucose levels in Group AG were significantly higher than those in Groups A and C at 1 hour, 2 hours, 3 hours, or 4 hours after anesthesia induction and at the end of surgery (p < 0.05; Fig. 3and Table 4).

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Fig. 1. Body temperature changes throughout surgery compared with baseline. Values are presented as the mean ± standard deviation. A p value <0.05 by two-way analysis of variance and Tukey's test. a Versus Groups AG and C at each time period. b Versus baseline. c Anesthesia induction.

Table 4. Perioperative body temperature change, serum insulin levels, and blood glucose levels for patients in all groups.*

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Fig. 2. Serum insulin levels during surgery. Values are presented as the mean ± standard deviation. a Versus Group C 2 hours after baseline. b Versus Group C at baseline. c Versus Group A at baseline and end of surgery. d Versus Group AG at baseline and end of surgery. e Versus Group C at baseline. p < 0.05, two-way analysis of variance and Tukey's test. f Anesthesia induction.

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Fig. 3. Blood glucose levels throughout surgery. Values are presented as the mean ± standard deviation. a Versus Groups A and C at each time period and Group AG at baseline. p < 0.05, two-way analysis of variance and Tukey's test. b Anesthesia induction.

One patient each in Groups C and AG required warming system adjustments during surgery because of hypothermia. Although there was a significant difference in visual analog scale scores at POD1 in Group C compared with the other groups, the frequency of the patient analgesic drug requirement up to POD7 was not significantly different between the groups (Table 5). Postoperative complications did not vary between the groups. There was no change in serum sodium concentration after infusion (Group C, 138 ± 2 mEq/L; Group A, 138 ± 2 mEq/L; and Group AG, 137 ± 2 mEq/L). There were no significant differences in the laboratory data between the groups throughout the preoperative and postoperative periods (data not shown).

Table 5. Postoperative NSAID administration frequency, VAS score, and postoperative hospital outcome for patients in all groups.

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4. Discussion

To the best of our knowledge, this is the first study to evaluate the effect of amino acids with and without glucose on insulin secretion and body temperature during surgery. This study revealed two new findings. First, intraoperative amino acid infusion significantly increased body temperature during surgery as compared with either combined amino acid and glucose infusion or the control. Second, amino acid infusion alone or in combination with glucose significantly enhanced insulin secretion as compared with the control.

Our results are consistent with previous studies in which intraoperative amino acid infusion prevented hypothermia during surgery.3, 4, 6 The mechanism of amino-acid-mediated thermogenic effects likely involves hypermetabolism and central thermoregulatory control.3, 6

Recently, Yamaoka et al7, 8 reported that amino acids enhanced insulin secretion and stimulated muscle protein synthesis and heat accumulation under general anesthesia in rats. Therefore, we attributed the amino-acid-induced hypermetabolism to the simultaneously enhanced insulin secretion, which was consistent with the previous study. However, co-infusion of amino acids and glucose did not significantly increase body temperature compared with the control group. These results suggest that the inhibitory effect of glucose on amino-acid-induced hyperthermia may not be related to insulin secretion. Schricker et al¹² reported that protein synthesis decreases during surgery independently of the anesthetic technique. Furthermore, Nakajima et al⁶ suggested that amino-acid-induced hyperthermia results from a set point increase rather than an augmented metabolic rate. Our findings suggest that the relationship between amino-acid-induced thermogenesis and insulin is mild and/or that additional glucose infusion aggravates central thermoregulatory control. Conversely, Obata et al¹³ reported that glucose administration suppresses protein catabolism by decreasing leucine and isoleucine. Schricker et al¹⁴ reported that combined amino acid and glucose infusion increased protein balance as well as amino acids alone, although insulin levels during the combined infusion were higher than those of patients who were infused with amino acids alone postoperatively. Therefore, excessive glucose administration may disturb amino-acid-mediated thermogenesis through alterations in amino acid levels.

We have previously reported that there were no differences in the thermogenic effects induced by the intraoperative infusion of simple amino acids versus the combined infusion of amino acids and glucose in patients undergoing total knee arthroplasty.¹¹ Compared with our previous report, the patients in this study underwent laparoscopic abdominal surgery for a longer duration. Our present findings suggest that amino-acid-induced thermogenic effects are associated with the duration of surgery.

In the current study, although there were no significant differences in the glucose levels of the patients in Groups A and C, two patients in Group A who had been excluded were administered additional glucose because of hypoglycemia. Doi et al¹⁵ reported that isoleucine administration stimulates muscle glucose uptake and causes hypoglycemia. Our findings suggest that insulin secretion promotes muscle glucose uptake and causes hypoglycemia. Furthermore, the surgical stress response is attenuated by laparoscopic surgery, although surgical-stress-induced insulin secretion inhibition and enhanced insulin resistance result in gluconeogenesis-mediated hyperglycemia.16, 17 Note that blood glucose level monitoring is mandatory for detecting insulin-induced hypoglycemia when a patient is given simple amino acid infusion during prolonged surgery.

In the present study, we observed that glucose levels of patients in Group AG increased significantly during surgery without any postoperative complication. Schricker et al¹⁰ reported that infusing small amounts of glucose (2 mg/kg/minute) did not lead to excessive hyperglycemia during colorectal surgery, although Akhtar et al¹⁸ recommended that glucose levels should be <180 mg/dL in the perioperative period to prevent poor outcomes due to hyperglycemia. Therefore, we used the infusion rate of glucose (2 mg/kg/minute) in our study. Donatelli et al⁵ also demonstrated that intraoperative amino acid and glucose infusion in combination increased glucose levels significantly (but not excessively) in patients undergoing colorectal surgery. These findings suggest that intraoperative moderate amounts of glucose infusion may not lead to excessive hyperglycemia in abdominal surgery. The Enhanced Recovery After Surgery (ERAS) group has recommended preoperative carbohydrates intake for improving insulin resistance and preventing a decline in immunity.² Moreover, intraoperative exogenous glucose suppresses protein catabolism¹⁹ and gluconeogenesis, which reduces the need for muscle protein breakdown to supply gluconeogenic amino acids and decrease insulin resistance.¹⁰ Okabayashi et al²⁰ reported that preoperative oral carbohydrates and branched chain amino acid reduce postoperative insulin resistance. In the current study, we measured the insulin levels during surgery as an index of surgical stress, and the insulin secretion and thermogenesis were enhanced without excessive increases in the blood glucose levels of Groups A and AG. However, a significant body temperature decrease was noted in the control group throughout surgery. We do not have a clear consensus of intraoperative nutrition; however, these results suggest that intraoperative amino acid infusion, with or without glucose, suppresses insulin resistance and benefits thermogenesis in surgery of a long duration.

In the current study, there were no significant differences in the length of postoperative hospital stay or complications among the groups. The Study of Wound Infection and Temperature Group reported that normothermia during surgery decreases not only the infectious complication incidence in patients undergoing colorectal resection, but also shortens hospitalization.¹Sato et al²¹ reported that intraoperative insulin resistance was associated with an increased risk of complications. However, that study utilized invasive techniques, such as open abdominal and cardiac surgery, and patients in the present study underwent laparoscopic surgery, which minimizes surgical stress. Another difference could be the usage of postoperative NSAIDs for postoperative pain relief in our study. We therefore surmise that minimizing surgical invasive procedure and/or the postoperative administration of NSAIDs may inhibit amino-acid-induced thermoregulation effect.

Several limitations must be considered when interpreting the results of the present study. First, we did not measure protein synthesis. Second, we infused a predetermined nutritional dose and time course in each patient. Future studies to evaluate the effects of different doses and time courses of amino acid administration with or without glucose should be considered. Third, we used the branched chain amino acid enriched solution because it was commercially available in Japan. However, there is a possibility that different amino acids may have different insulin-activating properties. Fourth, patients in this study had a longer length of hospital stay in each group compared with those in Europe and the United States, due to the nature of the health care system in Japan. The discharge guidelines in Europe and the US may affect the length of hospital stay in patients in each group. Finally, this preliminary study revealed a statistically significant increase in body temperature during amino acid infusion. However, because of the relatively small (n = 6–8) sample size, we did not detect a difference between amino acid infusion and amino acid infusion combined with glucose. In order to detect a difference of 0.5°C between amino acid infusion and amino acid infusion combined with glucose (assuming a common standard deviation of 0.5°C, the minimum power 0.90, and α = 0.05), a sample size of 22 patients in each group is needed. Therefore, a larger study is mandatory to draw conclusions on whether intraoperative nutrition affects body temperature and hospital outcomes. Nevertheless, this preliminary study may emphasize the importance of intraoperative nutrition management in the maintenance of body temperature.

In conclusion, we have described the effect of amino acid administration with or without glucose infusion on insulin secretion and temperature regulation during laparoscopic colectomy. Intraoperative amino acid infusion without glucose administration appears to be more effective for body temperature maintenance in patients undergoing laparoscopic colectomy than combined amino acid and glucose infusion, despite unaltered intraoperative insulin levels between the two infusion methods.

Acknowledgments

This research was funded by Departmental Sources.