The metabolic and endocrine response to surgery depends on a variety of factors such as severity (1) and duration (2) of surgical trauma, patient age (3), anesthetic method (4), and surgical technique (5). Whereas inhaled anesthetics exert only minimal inhibitory influence on the surgical stress response (6), propofol anesthesia supplemented with alfentanil attenuates the intraoperative increase in a plasma glucose concentration mediated through a suppression of the hypothalamopituitary-adrenal response (2,3). Because it is well established that opioids are capable of completely obtunding the metabolic endocrine alterations induced by an operation, this inhibitory influence has been mainly ascribed to the action of the opioid. Sufentanil, 5 to 10 times as potent as fentanyl and with a slightly shorter duration of action, abolished the increase in plasma concentration of catecholamines, cortisol, glucose, and free fatty acids during open heart surgery when administered in large doses (7,8). Sufentanil in moderate doses provided similar (9,10) or greater inhibition (11,12) of the sympathoadrenergic and cortisol responses during abdominal and peripheral orthopedic surgical procedures when compared with fentanyl. However, more complete information on the impact of sufentanil alone, or in combination, with propofol on changes in intermediary metabolism is lacking, and comparison with inhaled anesthesia has not yet been made. Furthermore, the impact of IV anesthetics on the metabolic hormonal response in the immediate period after surgery has received little attention.
The purpose of this study was to investigate the effect of propofol anesthesia combined with continuous infusion of sufentanil in moderate doses on perioperative glucose metabolism and the endocrine response to abdominal hysterectomy. To clarify underlying mechanisms of changes in glucose metabolism, endogenous glucose production and glucose clearance were assessed by an isotope dilution technique by using [6,6-2H2] glucose before and 2 h after surgery (2).
The study was approved by the ethics committee of our hospital, and informed consent was obtained from 20 patients undergoing elective abdominal hysterectomy for benign uterine myoma. Biometric and clinical data are presented in Table 1. None of the patients suffered from cardiovascular, renal, hepatic, or hormonal disorders or was receiving any medication.
Patients were randomly allocated to receive either inhaled anesthesia with enflurane (enflurane group, n = 10) or propofol/sufentanil anesthesia (propofol/sufentanil group, n = 10). All patients received oral premedication (chlorazepate 20 mg) on the night before surgery and 3 h before the operation. In the enflurane group, anesthesia was induced with thiopental 5 mg/kg and fentanyl 1.5 μg/kg. Anesthesia was maintained with enflurane at end-tidal concentrations between 0.8% and 1.4%. Patients in the propofol/sufentanil group received propofol 1.5 mg/kg and sufentanil 0.5 μg/kg for the induction of anesthesia followed by continuous infusions of propofol and sufentanil. Propofol initially administered at a rate of 10 mg · kg−1 · h−1 was reduced to 6 mg · kg−1 · h−1 after 10 min and stopped with final skin suture. Sufentanil was infused at 0.01 μg · kg−1 · min−1 and was discontinued approximately 30 min before the end of surgery. Orotracheal intubation in both groups was facilitated by succinylcholine 1.5 mg/kg, and supplemental doses of vecuronium were administered to provide complete muscle relaxation during the surgical procedure. Patient lungs were ventilated with 30% oxygen in nitrous oxide to an end-tidal carbon dioxide concentration of 35–40 mm Hg with capnometric control. Hemodynamic monitoring was performed by using automatic blood pressure measurement and a three-lead electrocardiogram monitor. Cardiac output was measured by thoracic bioimpedance (Non Invasive Continuous Cardiac Output Monitor (NCCOM) Model 3-R7; Biomed Medical Manufacturing Ltd., Irvine, CA). Patients received a balanced electrolyte solution at 8 mL · kg−1 · h−1 (TutoOP, Braun Melsungen, Germany) IV during surgery and 2 mL · kg−1 · h−1 thereafter. Postoperative pain intensity was estimated using a 10-cm visual analog scale, in which 0 = no pain and 10 = unbearable pain. Pain was treated with IV piritramide to achieve a visual analog scale score <4.
All patients were studied on the day of surgery after an overnight fast. The rate of appearance of glucose (Ra glucose), i.e., endogenous glucose production, was measured by an isotope dilution technique by using the stable isotope tracer [6,6-2H2] glucose (Mass Trace, Woburn, MA) immediately before and after the operation. A superficial vein in the dorsum of the hand was cannulated and the cannula kept patent with saline (2 mL · kg−1 · h−1). A second cannula was inserted into a superficial vein of the contralateral arm to provide access for the infusion of the isotope. A priming dose of [6,6-2H2] glucose 22 μmol/kg was administered and followed by continuous infusion of [6,6-2H2] glucose 0.22 μmol · kg−1 · min−1 for 120 min. Then, anesthesia was induced and hysterectomy performed. Postoperative [6,6-2H2] glucose infusion commenced immediately after extubation and was continued for 120 min. Three arterialized blood samples (SaO2 > 95%) were collected before both infusion periods to determine baseline 2H enrichment and during 100, 110, and 120 min of pre- and postoperative isotope infusions, when the tracer was assumed to have reached an isotopic steady state. Plasma concentrations of circulating metabolites (glucose, lactate, free fatty acids, triglycerides) and hormones (insulin, glucagon, cortisol, catecholamines) were determined after 110 min of pre- and postoperative isotope infusion and during the operation (5 and 60 min after incision of the peritoneum and at the end of surgery when the skin was closed). Each blood sample that was transferred immediately to a heparinized tube and centrifuged at 4°C was stored at −70°C. A schematic representation of the procedure is shown in Figure 1.
The isotopic enrichment of [6,6-2H2] glucose in plasma was determined by gas chromatography-mass spectrometry (Models GC 5890, MS 5971; Hewlett Packard, Munich, Germany) in the selected-ion monitoring mode by using electron impact ionization as previously described (2).
When there is an isotopic steady state, the Ra of unlabeled substrate in plasma can be derived from the plasma enrichment, atom percentage excess (APE) calculated by:MATH in which F is the infusion rate of the labeled tracer (μmol · kg−1 · min−1) and APEpl the tracer enrichment in plasma at steady state. The APE value used in this calculation was the mean of the three APE values determined during isotopic plateau obtained after 100, 110, and 120 min pre- and postoperative isotope infusion. The accuracy of the isotopic enrichments at isotopic plateau was tested by evaluating the scatter of the three APE values greater than their mean, expressed as coefficient of variation. A coefficient of variation <5% was used as a confirmation of a valid plateau. The clearance rate of glucose was calculated as Ra glucose divided by the corresponding plasma glucose concentration obtained after 110 min of isotope infusion.
Plasma concentration of glucose, lactate, free fatty acids, and triglycerides were measured by using enzymatic kits (Boehringer Mannheim GmbH, Mannheim, Germany). Insulin (INS-RIA-100; Medgenix Diagnostics, Brussels, Belgium), glucagon (Double Antibody Glucagon RIA; Diagnostic Products Corporation, Los Angeles, CA) and cortisol (DSL-2000 SP Aktive® Cortisol; Diagnostic System Laboratories, Sinsheim, Germany) were analyzed with radioimmunoassays. For the analysis of epinephrine and norepinephrine, blood was drawn in lithium-heparinate monovettes containing 10 μL/mL of a solution of 61 g/L glutathione and 76 g/L ethylenglykol-bis(β-aminoethylether)-N,N-tetraacetate for stabilization. Catecholamine concentrations were quantified by means of reversed phase high performance liquid chromatography (Model HPLC, Chromakon 500; Kontron, Eiching, Germany) with electrochemical detection as described earlier (13).
Differences between and within groups for repeated measures were analyzed by two-way analysis of variance and post hoc analysis by Student-Newman-Keuls test. A probability of <0.05 was accepted as significant. Data are presented as mean ± SD.
There were no differences between the two groups regarding age, height, and weight of patients. Preoperative fasting time, duration of surgery and anesthesia, and the postoperative amount of piritramide administered for pain treatment were similar in both groups. Patients in the propofol/sufentanil group received a mean total amount of 97 ± 9 μg sufentanil and 851 ± 59 mg propofol. Estimated blood loss never exceeded 300 mL, and no patient received blood transfusion.
Hemodynamic variables are displayed in Table 2. Heart rate and mean arterial pressure did not change within the two groups; however, the former was 5 min lower after peritoneal incision in patients with propofol/sufentanil anesthesia when compared with the enflurane group (P < 0.05). Cardiac output similarly decreased in both groups during hysterectomy (P < 0.05) and postoperatively increased to a higher value than before surgery (P < 0.05).
Plasma glucose concentrations in the enflurane group increased 5 min after peritoneal incision and remained elevated throughout the study (Table 3). Plasma glucose concentrations in patients receiving propofol/sufentanil increased 60 minutes after incision of the peritoneum and were lower than during inhaled anesthesia (P < 0.05). No significant difference between groups was detected 2 h after hysterectomy. Lactate plasma concentrations did not change significantly during or after surgery (Table 3). Plasma concentrations of free fatty acids increased during and after hysterectomy in the enflurane group (P < 0.05) and only after surgery in the propofol/sufentanil group (P < 0.05) (Table 3). Plasma triglyceride concentrations increased during propofol/sufentanil anesthesia (P < 0.05) without showing any difference between the groups.
Plateau enrichment of [6,6-2H2] glucose was achieved in all infusions and the mean coefficient of variation was 2.5% ± 2.5% before and 2.3% ± 1.6% after surgery. Glucose kinetics are shown in Figure 2. Endogenous glucose production increased in both groups after surgery when compared with preoperative values (P < 0.05) and was significantly more pronounced in the propofol/sufentanil than in the enflurane group (P < 0.05). Glucose clearance revealed no significant changes within and between the two groups:preoperative, propofol/sufentanil group (2.7 ± 0.3 mL · kg−1 · min−1) and enflurane group (2.6 ± 0.8 mL · kg−1 · min−1); and postoperative, propofol/sufentanil group (2.4 ± 0.3 mL · kg−1 · min−1) and enflurane group (2.2 ± 0.5 mL · kg−1 · min−1).
Plasma concentrations of hormones are displayed in Table 4. There was an increase in the intraoperative values of plasma cortisol, epinephrine, and norepinephrine concentrations in the enflurane group (P < 0.05). In contrast, plasma cortisol and catecholamine concentrations in the propofol/sufentanil group did not change during surgery and were lower than in the enflurane group (P < 0.05). Plasma concentrations of cortisol and catecholamines increased in all patients after surgery (P < 0.05) without showing any differences between the two groups. Plasma glucagon and insulin concentrations did not change significantly throughout the study period. The glucagon/insulin ratio, however, postoperatively increased in the propofol/sufentanil group from 9 ± 4 to 15 ± 7 pg/μU (P < 0.05), which was higher than in the enflurane group (8 ± 4 pg/μU, P < 0.05).
Propofol anesthesia supplemented with sufentanil, in contrast to inhaled anesthesia, completely suppressed the intraoperative endocrine stress response and attenuated the increase in plasma glucose concentration. Two hours after surgery, however, patients in the propofol/sufentanil group exhibited a more pronounced increase in endogenous glucose production accompanied by a significantly higher glucagon/insulin ratio.
The inhibitory influence of IV anesthesia using sufentanil on the metabolic and hormonal changes during abdominal hysterectomy is in accordance with the previous finding that opioids are able to obtund or delay the hyperglycemic and endocrine response to different types of surgery (4). Large-dose morphine (14), fentanyl (15), alfentanil (16), and sufentanil anesthesia (7) prevented the increase in the plasma concentrations of glucose and counter-regulatoryhormones during upper abdominal and cardiac surgery. Sufentanil administered in the same doses as those used in the current study produced equivalent inhibition of the sympathoadrenergic and cortisol response in geriatric patients undergoing major abdominal surgery (9) and during lower abdominal and peripheral orthopedic surgical procedures (10). The results of recent studies have suggested that sufentanil provides even more profound suppression of the endocrine stress response than fentanyl, morphine, and meperidine, as reflected by lower increases in catecholamine plasma concentrations during minor general surgical or gynecological operations (11,12).
Although the suppressory effect on the intraoperative metabolic and endocrine stress response in this study was most likely caused by sufentanil, there is evidence that propofol, at least in part, might have contributed. Inhibitory effects of propofol on the sympathoadrenal system have been documented in patients undergoing cardiac surgery (17) and documented in vitro when propofol concentrations, similar to concentrations observed during the induction of anesthesia, decreased the basal and nicotine-stimulated release of catecholamines from chromaffine cells. 1 In addition, propofol in contrast to thiopentone prevented the increase of plasma epinephrine concentration after endotracheal intubation (19). The experimental design of the current study, however, did not allow identification of the independent metabolic and endocrine effects of propofol and sufentanil, respectively.
The modifying influence on the stress response achieved by propofol/sufentanil anesthesia was restricted to the intraoperative period. Two hours after hysterectomy, increases in the plasma concentra- tions of glucose, free fatty acids, cortisol, and cat- echolamines were comparable in the two groups. This finding is in agreement with the previous observation that intraoperative block of the stress response by alfentanil and sufentanil had no impact on circulating concentrations of metabolic substrates and hormones beyond one hour after the completion of the administration of the drug (10,16). Furthermore, the magnitude of the postoperative increase in endogenous glucose production in our study was significantly higher in the propofol/sufentanil than in the enflurane group. It should be noted that the total amount of narcotics administered for postoperative pain treatment and pain relief was similar in the two groups, further supporting the concept that nociceptive pathways are only partially responsible for the activation of the stress response (20).
After 10 hours of fasting, glycogenolysis accounts for approximately 60% of total endogenous glucose production, the remaining 40% being derived from gluconeogenesis (21). As a result of increased concentrations of counter-regulatory hormones, perioperative hepatic gluconeogenesis is stimulated to a greater degree (22). Gluconeogenesis in the liver is an energy-consuming process and accounts for 50% of hepatic oxygen consumption (23). Thus, any modification of hepatic gluconeogenesis by anesthetic interventions may have an effect on the energy balance of the liver. In the current study, the gluconeogenic contribution to total glucose production could not be quantified because tracer kinetics do not separately allow the identification of the two biochemical pathways.
The pronounced postsurgical increase in glucose production after propofol/sufentanil anesthesia was associated with a significantly increased glucagon/insulin ratio. Because glucagon, by counteracting the action of insulin, is considered the major gluconeogenic hormone, accelerated endogenous glucose production in the propofol/sufentanil group presumably was mediated through this increase in the glucagon/insulin ratio (24).
In conclusion, our results demonstrate that the concept of stress-free anesthesia using propofol combined with moderate doses of sufentanil is valid only for the intraoperative period. Propofol/sufentanil did not inhibit the metabolic endocrine changes two hours after surgery, which were even more pronounced than after inhaled anesthesia, possibly because of the shorter half-life of both IV anesthetics. Based on the hypothesis that intra-and postoperative block of the stress response might favorably influence postoperative morbidity (25), it is questionable whether patients undergoing lower abdominal surgery can benefit from propofol/sufentanil anesthesia.
We thank Dr. Ulrich Bothner for his help in the statistical analysis of the data.
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