|Year : 2014 | Volume
| Issue : 3 | Page : 274-281
Neuroendocrine stress response and hyperglycemia in children undergoing laparoscopic surgery: a comparative study between remifentanil infusion and fentanyl boluses during sevoflurane-based anesthesia
Hany A Shehab1, Samar A Abdou1, Abdulrhman A Alwassef2, Yasser Shaban3
1 Department of Anesthesia, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Anesthesia, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||20-Jul-2013|
|Date of Acceptance||18-Nov-2013|
|Date of Web Publication||27-Aug-2014|
Samar A Abdou
Department of Anesthesia, Faculty of Medicine, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
The aim of the study was to determine the effect of remifentanil (REM) infusion versus fentanyl (FEN) boluses during sevoflurane-based anesthesia on the frequency and the severity of stress hyperglycemia in children undergoing laparoscopic surgery.
Patients and methods
The study included 64 children randomly allocated into the REM group, receiving REM infusion (0.05-0.5 μg/kg/min), and the FEN group, receiving FEN boluses of 1-2 μg/kg. All patients were maintained by sevoflurane (1-2%) inhalation. Six blood samples were taken for the estimation of random blood glucose (RBG), serum glucagon and insulin, and plasma adrenaline. Hyperglycemia was considered if RBG was more than 140 mg/dl, and was treated with insulin if RBG was more than 200 mg/dl. The frequency and the extent of hyperglycemia were determined in both groups.
In the FEN group, RBG levels were elevated from the start of surgery till second postoperative day with a significant difference compared with baseline levels. Eight patients had RBG less than 140 mg/dl, and 13 patients had temporary and 11 had persistent hyperglycemia, and four of them required insulin therapy. There were significant elevations in the serum glucagon and plasma adrenaline with a significant decrease in the serum insulin. In the REM group, mean RBG levels were significantly elevated from the time of maximal surgical stress till second postoperative day in comparison with baseline levels, but were significantly lower compared with the FEN group. Fourteen patients had RBG less than 140 mg/dl, 12 patients had temporary and six had persistent hyperglycemia, and three of them required insulin therapy with a significantly lower frequency of both temporary and persistent hyperglycemia and a nonsignificantly lower number of patients received insulin therapy in the REM group compared with the FEN group. There were significantly lower plasma adrenaline and glucagon levels, with a nonsignificantly lower serum insulin level in the REM group compared with the FEN group.
REM/sevoflurane anesthesia attenuated the neuroendocrine stress response during laparoscopic surgery and reduced the frequency and the extent of intraoperative and postoperative hyperglycemia, with sparing need for insulin therapy.
Keywords: fentanyl, remifentanil, stress hormones, stress hyperglycemia
|How to cite this article:|
Shehab HA, Abdou SA, Alwassef AA, Shaban Y. Neuroendocrine stress response and hyperglycemia in children undergoing laparoscopic surgery: a comparative study between remifentanil infusion and fentanyl boluses during sevoflurane-based anesthesia. Ain-Shams J Anaesthesiol 2014;7:274-81
|How to cite this URL:|
Shehab HA, Abdou SA, Alwassef AA, Shaban Y. Neuroendocrine stress response and hyperglycemia in children undergoing laparoscopic surgery: a comparative study between remifentanil infusion and fentanyl boluses during sevoflurane-based anesthesia. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 20];7:274-81. Available from: http://www.asja.eg.net/text.asp?2014/7/3/274/139542
| Introduction|| |
Blood glucose is tightly regulated by two types of mechanisms: the hormonal system, which consists of a balance between the hypoglycemic insulin and the hyperglycemic counter-regulatory hormones (i.e. glucagon, epinephrine, and cortisol), and the neural mechanism, which consists of the activation of messages issued from glucose sensors of various organs. These hormonal and neural signals modulate carbohydrate metabolism by controlling glucose fluxes, including endogenous production and the entrance of glucose into the cells. The translocation of glucose transporters (GLUT) is a prominent mechanism for the modulation of glucose transport across cell membranes. Among these transporters, GLUT-1 is the predominant transporter for non-insulin-mediated glucose uptake, GLUT-2 regulates the flow of glucose across liver cell membranes, and GLUT-4 is the main insulin-responsive GLUT and therefore modulates insulin-mediated glucose uptake in the adipose tissue and cardiac and skeletal muscles [1-3].
Surgical intervention and anesthesia procedures lead to a series of hormonal changes, which is mainly attributed to the catecholamine response to stress. The postoperative status is associated with so-called stress-induced hyperglycemia, defined as transient intraoperative and/or postoperative hyperglycemia in patients without previous evidence of diabetes mellitus [4-6].
Remifentanil (REM) is a fentanyl (FEN) derivative with methyl ester linkage. It is a synthetic, esterase-metabolized opioid, with a side-branch susceptible to rapid hydrolysis by nonspecific tissue and plasma esterases. Rapid biotransformation to REM acid, which is a minimally active metabolite, was associated with a short, predictable duration of action with no accumulation of effect on repeated dosing or with continuous infusion. These pharmacokinetic properties could explain the rapid onset and the short duration of action of REM. REM is an effective agonist at the µ-opioid receptor and produces profound analgesia. Preliminary investigations in human volunteers and anesthetized patients have shown that REM has a rapid onset of effect (blood-brain equilibration time of 1 min), a small central volume of distribution, rapid clearance and rapid offset of effect (context sensitive half-time of 3 min) and a terminal elimination half-life of about 10 min [7-10].
The unique pharmacokinetics of REM and the few drug-related side effects allow its application as an adjuvant anesthetic for various surgical procedures. The current prospective comparative study aimed to determine the effect of REM infusion versus FEN boluses during sevoflurane-based anesthesia on the frequency and the severity of acute stress hyperglycemia in children undergoing laparoscopic surgery.
| Patients and methods|| |
The current prospective randomized comparative study was conducted at Departments of Anesthesia and Clinical Pathology at Madinah Maternity and Children Hospital, KSA, from December 2011 to April 2013. After approval of the study protocol by the local ethical committee and obtaining written fully informed parents' consent, all American Society of Anesthesiologists (ASA) grade I and II patients assigned for laparoscopic surgery were enrolled in the study. The study included 64 patients: 41 male and 23 female, with a mean age of 4.7 ± 1.5 years (range 2-8 years) and a mean body weight of 14.4 ± 3.3 kg (range 10-26 kg). Only eight patients were ASA grade II, whereas 56 patients were ASA grade I. All patients received ondansetron at a dose of 1.3 ± 0.35 mg (range 0.6-2.4 mg).
All surgeries were performed by the same surgical team using pneumoperitoneum with an inflation pressure in the range of 12-14 mmHg. Patients were randomly allocated into two study groups using sealed envelopes: the REM group included patients maintained on a REM infusion and the FEN group included patients received FEN intermittent boluses. Patients with known allergy to the study drugs and those who had any endocrinopathy or congenital metabolic disorders were excluded from the study.
All patients were premedicated with intravenous midazolam at a dose of 0.05 mg/kg, and 2 min thereafter, anesthesia was induced with intravenous sodium thiopental at a dose of 5 mg/kg and rocuronium was given at dose of 0.6 mg/kg to facilitate tracheal intubation. Muscle relaxation throughout the duration of surgery was maintained with rocuronium.
Patients included in the REM group received a slow REM infusion (2 mg in 40 ml of physiological saline) at a dose of 0.05-0.5 mg/kg/min together with 1-2% sevoflurane in 60% oxygen in air. Patients included in the FEN group received doses of FEN 1-2 mg/kg together with sevoflurane 1-2% in 60% oxygen in air. The REM infusion rate, FEN doses and the MAC of sevoflurane were adapted according to hemodynamic responses. Intraoperative fluid therapy was provided as glucose 5% in half normal saline for fluid maintenance, and intraoperative fluid loss was replaced by lactate ringer solution. REM infusion was stopped immediately at the end of surgery. Rescue postoperative analgesia in the form of pethidine 1-2 mg/kg intramuscular injection was given 10 min before the end of the surgery.
Before surgical manipulation, ondansetron (100 μg/kg, maximal dose 4 mg) was administered intravenously to prevent postoperative nausea and vomiting. Throughout the operative procedure, the heart rate and systolic and diastolic blood pressures were monitored noninvasively and recorded before the induction of anesthesia (baseline), at the time of induction of anesthesia, 1 and 5 min after intubation, at the time of skin incision and closure, and after transfer to the postanesthetic care unit.
Hyperglycemia was considered according to contemporary medical practice, which stated that hyperglycemia was present under stress conditions if random blood glucose (RBG) was more than 140 mg/dl and it should be treated with insulin only if blood glucose levels are more than 200 mg/dl . The frequency and the extent of hyperglycemia were determined in both groups. Insulin therapy was provided as a continuous infusion of insulin 50 IU of Actrapid HM (Novo Nordisk A/S, Bagsvaerd, Denmark) in 50 ml of 0.9% sodium chloride using a pump (Perfusor-FM; B. Braun, Melsungen, Germany) and was adjusted to achieve a blood glucose level in the range of 180-200 mg/dl.
Blood sampling and stress hormone assay
In both groups, six blood samples were taken: at baseline (before the induction of anesthesia), after tracheal intubation, at maximum surgical trauma (maximum stress), defined intraoperatively by the attending surgeon, at 1 h after surgery, and on the first and the second days postoperatively (1-DPO, 2-DPO). Blood samples were divided into three parts:
(1) The first part was placed in a tube containing sodium fluoride (2 mg sodium fluoride/ml blood) to prevent glycolysis. Plasma was separated by centrifugation and used for the estimation of glucose by the glucose oxidase method .
(2) The second part was immediately placed into iced-water, cool-centrifuged within 15 min, and stored at −25°C until further analysis for the measurement of plasma epinephrine. An improved reversed-phase high-performance liquid chromatography technique was used for analysis [autosampler: AS 2000 (Merck Hitachi, Darmstadt, Germany); pump: L-6200 Intelligent Pump (Merck Hitachi); detector: ECD (Merck LaChrom L 3500 A; Merck Hitachi); analytical column for separation: RP 18 - equilibrated and tested (Bio-Rad Diagnostics, Munchen, Germany); software: D 7000-HPLC-System (Merck Hitachi] .
(3) The third part was allowed to clot, and then the serum was separated by centrifugation at 3000 rpm for 10 min; the serum was removed and divided into two parts:
The first part was placed in a plain tube and stored at −70°C till it was used for radioimmunoassay determination of the serum level of insulin [13,14].
The second part was placed in a tube containing 250 kIU Trasylol (aprotinin)/ml of whole blood to yield a final concentration of ˜500 kIU Trasylol/ml of serum to protect glucagon from proteolysis during assay procedures. Samples were stored at -20 to -70°C till further use for radioimmunoassay determination of the serum level of glucagon [13,15].
The sample power calculated according to Kraemer and Theimann  using the proposed figure showed that the sample size for 60% power would require an N of 31/group and 80% power would require an N of 51/group. This hypothesis was documented by Murphy and Myors . Thus, the current study sample size was chosen to be 32 patients per group. The data obtained were presented as mean ± SD, ranges, numbers, and ratios. Results were analyzed using the Wilcoxon ranked test for unrelated data (Z-test) and the χ2 -test. Statistical analysis was conducted using the SPSS (version 15, 2006; SPSS Inc., Chicago, Illinois, USA) for Windows statistical package. A P value of less than 0.05 was considered statistically significant.
| Results|| |
There was a nonsignificant difference between the study groups with regard to patient characteristics [Table 1].
The mean operative time for the REM group was 124.5 ± 16.2 min (range 90-150 min), whereas that for the FEN group was 118.4 ± 13 min (range 100-135 min) with a nonsignificant difference between both groups. Both anesthetic modalities provided hemodynamic stability throughout the operative time without significant difference between both groups [Table 2].
|Table 2 The mean heart rate and systolic and diastolic blood pressures determined throughout the observation period in both groups|
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All patients showed stress elevation of blood glucose in at least one estimation time, irrespective of the anesthetic modality used; however, the blood glucose level was less than 140 mg/dl (the predetermined level for hyperglycemia) in 22 (33.8%) patients, 14 in the REM group and eight in the FEN group, and more than 140 mg/dl in 42 patients, 18 in the REM group and 24 in the FEN group, with a significantly (P < 0.05) higher frequency of hyperglycemia in the FEN group compared with the REM group. Twenty-five (39.1%) patients, 12 in the REM group and 13 in the FEN group, had blood glucose level of more than 140 mg/dl, but less than 200 mg/dl once during the observation time (temporary hyperglycemia), whereas 17 (27.1%) patients, six in the REM group and 11 in the FEN group, had persistent hyperglycemia for a blood glucose level of more than 140 mg/dl for more than one estimation throughout the observation period, with a significantly (P < 0.05) higher frequency of persistent hyperglycemia in the FEN group compared with the REM group. Seven patients, three in the REM group and four in the FEN group, who had persistent hyperglycemia had blood glucose more than 200 mg/dl and were controlled using conventional insulin therapy and were normalized on the 2-DPO with a nonsignificantly (P > 0.05) lower frequency of patients requiring insulin therapy in the REM group compared with the FEN group ([Table 3] and [Figure 1].
|Figure 1: Patient distribution according to the frequency and the type of hyperglycemia detected throughout the observation period in both groups. FEN, fentanyl; REM, remi fentanil.|
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|Table 3 Patient distribution according to the frequency and the type of hyperglycemia detected throughout the observation period in both groups|
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Mean baseline and postintubation blood glucose levels were nonsignificantly (P > 0.05) different between both study groups, with nonsignificantly higher (P > 0.05) postintubation RBG levels compared with baseline levels. However, other RBG estimations were significantly (P < 0.001) higher in both groups compared with baseline levels. Mean RBG levels estimated at maximal surgical stress, 1-h, 1-DPO and 2-DPO were significantly higher in the FEN group compared with REM group ([Table 4] and [Figure 2]).
|Table 4 Mean random blood glucose levels estimated and the frequency of episodes of elevated random blood glucose level|
detected throughout the observation period in both groups
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|Figure 2: Mean random blood glucose (RBG) levels estimated throughout the study period in both study groups. DPO, day postoperatively; FEN, fentanyl; REM, remi fentanil.|
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Mean estimated baseline and postintubation serum levels of insulin and glucagon showed a nonsignificant difference (P > 0.05) between both groups. Patients receiving REM showed a fluctuation in the serum glucagon in comparison with the baseline level, which was significantly (P < 0.05) lower at maximum surgical stress, nonsignificantly (P > 0.05) lower at 1-h postoperatively, significantly (P < 0.05) higher at 1-DPO and then nonsignificantly (P > 0.05) higher at 2-DPO. In contrast, in the FEN group, mean serum glucagon levels showed a steady elevation, which was significant (P < 0.05) in comparison with baseline levels and peaked at 1-DPO and slightly decreased at 2-DPO, but was still significantly (P < 0.05) higher compared with baseline levels. Intergroup comparison showed significantly (P < 0.05) higher levels in the FEN group compared with the REM group ([Table 5] and [Figure 3]).
|Figure 3: Mean serum levels of glucagon and insulin estimated throughout the study period in both groups. DPO, day postoperatively; FEN, fentanyl; REM, remi fentanil.|
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|Table 5 Mean levels of stress hormones estimated in both groups throughout the study period|
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In the FEN group, the mean serum insulin was significantly (P < 0.05) lower at the time of maximal surgical stress compared with baseline levels, and it started to elevate thereafter with nonsignificantly (P > 0.05) lower levels at 1-h postoperatively, 1-DPO, and 2-DPO. In contrast, serum insulin levels estimated in the REM group were nonsignificantly (P > 0.05) lower compared with baseline levels throughout the observation period. Both study groups showed a nonsignificant (P > 0.05) difference in serum insulin levels until 1-DPO, but the difference became significantly higher (P < 0.05) in favor of the REM group at 2-DPO ([Table 5] and [Figure 3]).
In the FEN group, plasma adrenaline levels were significantly (P < 0.05) higher throughout the study period till 1-DPO and became nonsignificantly (P > 0.05) higher at 2-DPO compared with baseline levels, whereas in the REM group, plasma adrenaline started to elevate at maximal surgical stress, at 1-h postoperatively and at 1-DPO and was nonsignificantly higher (P > 0.05) at 2-DPO compared with baseline levels. Intergroup comparison showed significantly (P < 0.05) lower plasma adrenaline levels estimated at maximal surgical stress and at 1-h postoperatively in the REM group compared with the FEN group ([Table 5] and [Figure 4].
|Figure 4: Mean plasma adrenaline levels estimated throughout the study period in both study groups. DPO, day postoperatively; FEN, fentanyl; REM, remi fentanil.|
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| Discussion|| |
The rationale of the current study is the implementation of combined anesthesia using inhalational anesthesia plus intravenous anesthesia using REM infusion or FEN repeated boluses, and both provided hemodynamic stability throughout the duration of surgery without significant difference. In line with the use of combined anesthesia, Goldmann et al.  found that a combination of epidural and general anesthesia reduces the intraoperative stress response, but moderate hemodynamic instability is relatively common and has to be compensated for by adequate volume replacement and vasopressor support. Bozza et al.  compared inhalatory/epidural anesthesia versus inhalatory/endovenous anesthesia in infants undergoing correction of anorectal malformations and found that both are effective in the intraoperative and the postoperative period.
Patients enrolled in the FEN group represent a typical example of the neuroendocrine body response to surgical injury with significantly higher RBG levels since the start of surgery till 2-DPO, in comparison with baseline levels with significantly elevated serum glucagons and plasma adrenalin and low serum insulin throughout the study period. In contrast, REM showed ameliorative effects of surgical injury stress on the neuroendocrine body responses, wherein despite the significantly higher RBG in comparison with the baseline level, mean RBG levels estimated were significantly lower in the REM group compared with the FEN group. These effects could be attributed to the blunting effect of REM on the sympathetic nervous system manifested as a significantly lower plasma adrenaline, and on release of glucogenic hormones, glucagon with nonsignificantly lower serum insulin.
Changes in the hormonal milieu and the glycemic status could be explained by the facts that hormonal response to injury is diffuse and includes the release of ACTH, cortisol, growth hormone, glucagon, epinephrine, and norepinephrine with a decreased or an unchanged release of insulin. Another important mechanism for hyperglycemia is that immediately after injury, the plasma insulin concentration is depressed in relation to hyperglycemia due to reduced β-cell sensitivity to glucose that is mediated by an increased sympathetic tone and an increased level of catecholamine with a concomitant decrease in the blood flow to the splanchnic area including the pancreas; an intact adrenal gland is also necessary for this effect of blunted insulin release, leading to delayed assimilation of the glucose load [20-25].
The reported better endocrine response to surgery with REM-based TIVA supports that reported previously in the literature; Liu et al.  reported that different anesthetic methods and drugs had different effects on stress hormones during surgical operation; blood glucose was lowered slightly at induction and intubation, and was increased distinctly at the end of operation in all studied patients, but glucagon and blood glucose of the REM/propofol and the REM/inhalational groups were lower than those of the epidural/general and the epidural/general/laryngeal mask groups. Ihn et al.  found that adrenaline, noradrenalin, cortisol, and glucose levels were significantly lower with TIVA than with volatile induction and maintenance of anesthesia, and concluded that TIVA with propofol and REM may be preferable to volatile induction and maintenance of anesthesia with sevoflurane alone because it leads to smoother, more rapid induction, more rapid awakening and lower stress responses to surgical stimuli.
Marana et al. [28,29] compared intraoperative and postoperative neuroendocrine stress responses during TIVA using propofol and REM versus sevoflurane anesthesia during laparoscopic surgery, and reported that with TIVA, perioperative levels of norepinephrine, epinephrine, ACTH, cortisol, and growth hormone were significantly decreased compared with their preoperative values; however, with sevoflurane, all markers were significantly increased compared with TIVA.
In support of the superiority of REM infusion over intermittent FEN, Winterhalter et al.  found stress hormones 30 min after the start of cardiopulmonary bypass to be higher in patients who received intermittent FEN compared with those who received REM infusion and concluded that the perioperative endocrine stress response was attenuated in patients supplemented with continuous REM infusion as compared with intermittent FEN. Sato et al.  reported that the maximum blood glucose was lower and less insulin was administered during cardiopulmonary bypass under REM anesthesia than under low-dose FEN anesthesia, and concluded that REM reduces the stress response to surgical stimulation in cardiac surgery.
The results obtained and a review of the literature led to the conclusion that REM/sevoflurane anesthesia attenuated the neuroendocrine stress response during laparoscopic surgery and reduced the frequency and the extent of intraoperative and postoperative hyperglycemia with sparing need for insulin therapy.
| Acknowledgements|| |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]