Sufentanil, a new synthetic opiate agonist with the highest mu-opiate receptor affinity, reliably blunts the intraoperative hemodynamic variations consecutive to noxious surgical stimulations, reduces the anesthetic requirements, and alleviates postoperative pain when administered by systemic or spinal route [1-4]. The alpha (2-adrenoceptor) agonist clonidine also effectively reduces the intraoperative variations in heart rate and arterial blood pressure . It possesses anesthetic-sparing effects and alleviates postoperative pain [6,7]. These two effects seem to be more important when clonidine is administered by the spinal route [5,8]. Epidural clonidine induces relative hypotension, but unlike the opiates, it is devoid of major respiratory depressant effects [7,9].
The present study contrasts these two drugs on a clinical basis in order to determine which is the most appropriate use of these substances in the perioperative period.
This double-blind study was approved by the Institutional Ethics Committee and all subjects gave informed consent. Forty adult patients between 18 and 50 yr of age scheduled for extensive intestinal resection for inflammatory bowel disease or second stage reanastomosis participated in this study. Exclusion criteria were: chronic use of any antiinflammatory, opiate, cardiovascular, or psychotropic medications including benzodiazepines; any renal or hepatic dysfunction; acute inflammatory bowel process at the time of surgery; inability to understand the study protocol; and a history of allergic reaction to any of the study drugs. A previous abdominal procedure was a required inclusion criterion because of the previous experience of postoperative pain.
The day before surgery, the study protocol was explained to the patients. They were instructed to push the analgesic demand button of the patientcontrolled analgesia (PCA) device (Abbott LifeCare Registered Trademark 4200; Abbott Laboratories, N. Chicago, IL) any time they experienced pain and until pain was relieved. The pain visual analog scale was clearly explained. Arterial blood pressure and heart rate at rest were recorded.
The night before surgery all patients received 2 mg lormetazepam. Another 2 mg was given sublingually 1 h before the procedure, followed 30 min later by atropine 7 micro gram/kg intramuscularly.
An epidural catheter was then inserted in all patients at the L1-L2 level using the loss-of-resistance technique. At this time, patients were randomly assigned to receive either epidural clonidine (Group 1) or epidural sufentanil (Group 2). An initial dose of clonidine (4 micro gram/kg in 10 mL saline) was given in 20 min and followed immediately by a continuous infusion of 2 micro gram centered dot kg (-1) centered dot h-1 (5 mL/h) during 12 h. A loading dose of sufentanil (0.5 micro gram/kg in 10 mL) was given in 20 min, followed by an 0.2 micro gram centered dot kg-1 centered dot h-1 infusion (5 mL/h) during 12 h.
Intraoperative monitoring included an intraarterial catheter for systemic blood pressure monitoring, a central venous catheter for central venous pressure monitoring, electrocardiogram, and other normal monitoring.
General anesthesia was induced at the same time the epidural infusion was started. Anesthetic management consisted of intravenous (IV) sufentanil 2.5 micro gram, propofol titrated until loss of consciousness (+/- 2 mg/kg), and atracurium (0.5 mg/kg) for induction of anesthesia. Anesthesia was maintained with a propofol infusion of 3 mg centered dot kg-1 centered dot h-1 and 50% nitrous oxide in oxygen. Neuromuscular block was maintained with a continuous infusion of atracurium (5 micro gram centered dot kg-1 centered dot min-1). Mechanical ventilation was adjusted to maintain a carbon dioxide end-expiratory concentration of +/- 36 mm Hg.
Additional doses of propofol (0.5 mg/kg in bolus) were given in response to a 20% increase of the mean arterial pressure and/or heart rate recorded after the initial dose of the epidural drugs and before skin incision (epidural baseline). The absence of return of both heart rate and mean arterial blood pressure to this epidural baseline 3 min after an additional dose of propofol prompted the injection of an IV bolus of sufentanil 2.5 micro gram.
The atracurium infusion was discontinued at the beginning of the closure of the peritoneum. The propofol infusion and nitrous oxide were discontinued at the last skin suture.
The following assessments were made:
1. Intraoperative anesthetic (propofol) and analgesic (sufentanil) requirements according to the hemodynamic variables were recorded.
2. Intraoperative hemodynamics were continuously monitored throughout the study period, especially during the first 2 h after epidural infusion when values were recorded at 2-min intervals.
3. Time to awakening from anesthesia was determined as the time from discontinuation of the nitrous oxide and propofol until the time the patients first opened their eyes in response to verbal command.
4. PaO2, PaCO2, and pHa were measured (Corning blood gas analyzer; Corning, Medfield, MA) at arrival in the recovery room and 3 h after tracheal extubation. Central venous PCO2 was measured at 6 and 12 postoperative hours.
5. Postoperative sedation was assessed according to a three-point sedation scale at 0, 1.5, 3, 6, 12, 18, 24, and 36 h (0 = alert or drowsy, but easily aroused to an alert state by verbal command; 1 = sleeping and arousable by verbal command; 2 = sleeping and not arousable by verbal stimuli, but arousable to a drowsy state by tactile stimulation).
6. Postoperative analgesic requirements were assessed using a PCA delivery system that the patient activated to deliver a preset bolus of sufentanil. The PCA settings were a sufentanil bolus dose of 5 micro gram (0.5 mL) at a lockout interval of 8 min with a 4-h limit of 80 micro gram. Both the met and unmet demands were considered.
7. Pain was evaluated using a 10-cm visual analog scale (VAS) at rest after 3, 6, 12, 18, 24, 36, and 48 h and during mobilization from the supine position in bed to the sitting position in the armchair at 12, 18, 24, 36, and 48 h.
8. Plasma sufentanil concentration was determined in 28 patients (14 in each group randomly sampled from the entire group) using a radioimmunoassay  method on blood sampled after the loading dose, 6 h after the start, at the end of the continuous infusion, and 12 h later. The sensitivity of this assay was 0.02 ng/mL. Plasma clonidine concentrations were determined in 28 patients (14 in each group randomly sampled from the entire group) using a radioimmunoassay method on blood sampled after the loading dose, 6 h after the start, at the end of the continuous infusion, and 12 h later. The sensitivity of this assay was 0.1 ng/mL with a coefficient of variation of less than 15%.
9. Perioperative complications were recorded (e.g., heart block, intraoperative hypotension defined as a 30% decrease in systolic arterial blood pressure, orthostatic hypotension, rebound hypertension, nausea and vomiting). Episodes of awareness were detected by using a portable cassette player with headphones playing either classical, jazz, or rock music. Music was introduced at the end of the induction and discontinued at the end of surgery just before the discontinuation of the propofol infusion.
Statistical analysis of variables over time was evaluated by one-way univariate analysis of variance with repeated measures (CSS statistica; Statsoft, Tulsa, OK). When applicable, intergroup differences were analyzed by Tukey's least significant differences test. Comparisons of independent variables were based on t-test. Nonparametric categorial variables were analyzed by Kruskal-Wallis analysis of variance by ranked-sum test. A P value of less than 0.05 was considered statistically significant.
The demographic data of the patients who participated in the study are summarized in Table 1. There was no significant difference between the two groups with respect to age, gender, weight, height, ASA physical status, and duration of surgery. The placement of the epidural catheter was easy and successful at the first attempt in all patients.
The dose of propofol required to induce anesthesia was the same in both groups (169 +/- 37 mg in Group 1 vs 187 +/- 25 mg in Group 2). According to the hemodynamic changes, more propofol reinjections were required in patients of Group 2 (6.5 +/- 4.0 in Group 2 vs 1.6 +/- 1.6 in Group 1; P < 0.001). Additional IV sufentanil boluses were administered 0.6 +/- 0.8 times in Group 1 vs 3.8 +/- 3.7 in Group 2 (P < 0.001). The total number of reinjection doses of sufentanil administered IV was 1.4 micro gram +/- 1.9 in Group 1 vs 9.5 micro gram +/- 9.2 in Group 2 (P < 0.001) Table 2.
Only 6 patients in Group 1 required propofol supplementation at skin incision vs 14 in Group 2 (P < 0.01). Propofol was insufficient to restore baseline hemodynamic values and additional IV sufentanil boluses were required in 2 patients of Group 1 vs 7 patients of Group 2 (difference is not statistically significant [NS]). At peritoneal incision, 4 patients in Group 1 vs 13 patients in Group 2 (P < 0.01) required propofol supplementation. Additional IV sufentanil boluses were given in 1 patient of Group 1 and in 7 patients of Group 2 (P > 0.5). After placement of the surgical retractor, 12 patients in Group 1 vs 16 in Group 2 (NS) required propofol supplementation. Sufentanil was given in 7 patients of Group 1 and in 12 patients of Group 2 (NS). During the rest of the surgical procedure, 5 patients in Group 1 vs 17 in Group 2 required propofol supplementation (P < 0.001). IV sufentanil boluses were administered in one patient of Group 1 vs 16 in Group 2 (P < 0.001).
There was no difference in time to recover between the two groups (12.3 +/- 5.8 min in Group 1 vs 17.2 +/- 9.7 in Group 2). Patients in Group 1 breathed spontaneously sooner than patients in Group 2 (4.8 +/- 4 min vs 11.8 +/- 4.8 min; P <or=to 0.01). The values of arterial pH and arterial or venous PCO2 were in the normal range, and no significant differences were noted between the two groups at any time interval considered.
Study drugs were provided for only 12 h beginning at the induction of anesthesia. Considering the mean surgery time (+/- 5 h), patients thus received approximately 7 h of epidural analgesic therapy.
At the time of tracheal extubation, no patient complained of abdominal pain. The first analgesic demand occurred 321 +/- 332 min after tracheal extubation in the epidural clonidine group and 311 +/- 287 min in the epidural sufentanil group (P = 0.92). During the first 6 postoperative hours, the analgesic demands (both met and unmet) and the total amount of supplemental IV sufentanil delivered were quite low in both groups Figure 1 and Figure 2.
When considering the entire observation period, the IV PCA sufentanil requirements (met analgesic demands) were slightly but significantly reduced in the epidural clonidine (Group 1) (P < 0.04; Figure 1 and Figure 2). This difference reached statistical significance only after the first 24 postoperative hours. The number of unmet analgesic demands was not statistically different at any time interval considered in the two groups Figure 2.
Before the 6th postoperative hour and during epidural infusion, similar levels of pain were recorded in both groups (P > 0.05; Figure 3). After this period, lower levels of pain at rest and particularly after mobilization were demonstrated by the VAS in the clonidine group. This difference was significant until the 36th postoperative hour Figure 3.
There was no difference in the sedation scales between the two groups at any time interval considered. Particularly, no patients received a score of 3.
Hemodynamic values at rest the day before surgery and preinduction were comparable in the two groups Figure 4 and Figure 5. Epidural sufentanil and clonidine given during the induction of anesthesia significantly reduced the preinduction value of heart rate and mean arterial blood pressure to the same extent (P < 0.01, 10-14 min after the start of the infusion). Minimum heart rate and mean arterial blood pressure occurred approximately 10 min after the end of the loading dose in both groups. During the surgical procedure, however, mean arterial blood pressure increased significantly in the epidural sufentanil group (P < 0.01). In none of the patients considered was bradycardia (heart rate < 40 bpm) or hypotension sufficient to require a specific intervention during the observation period.
One patient in Group 2 presented with an immediate postoperative respiratory depression that required prolonged ventilatory support and was therefore excluded from the postoperative study protocol. The plasma sufentanil concentrations of this patient, measured at the end of surgery, were 0.342 ng/mL. Another patient of this group presented with moderate bradypnea that only required closer postoperative monitoring. Vomiting and mild pruritus were experienced in two other patients. Two patients in Group 1 specifically remembered the kind of music emitted intraoperatively by the portable cassette player, but this perception was not accompanied by any unpleasant memories. Particularly, they were unable to remember any pain, manipulation, or paralysis sensation. None of the patients in the clonidine group developed rebound hypertension during the first postoperative week. The postoperative course was uneventful for all the patients.
The plasma levels of sufentanil were significantly different in both groups only after 20 min and 6 h Figure 6. Plasma levels of clonidine of 1.6 +/- 0.5 ng/mL after the loading dose, 4.6 +/- 1.8 ng/mL at 6 h, 5.75 + 1.9 ng/mL at 12 h, and 2.37 + 0.9 ng/mL at 24 h were measured in Group 1.
The present investigation demonstrates that epidural clonidine at a dose of 4 micro gram/kg followed by a 2-micro gram centered dot kg-1 centered dot h-1 infusion is more efficient than epidural sufentanil at a dose of 0.5 micro gram/kg followed by a 0.25-micro gram centered dot kg-1 centered dot h-1 infusion to provide intraoperative hemodynamic stability as reflected by the reduced requirements in anesthetic (propofol bolus) and analgesic (sufentanil IV bolus) supplementations. In the early postoperative period, both epidural infusions provided adequate postoperative analgesia as disclosed by the very few requirements of supplemental analgesics and the low pain score reported in the two groups. Later, when the epidural infusion was discontinued, a persistent positive effect on postoperative analgesia was observed in patients who received epidural clonidine as demonstrated by the better pain scores and the reduced analgesic requirements observed in this group.
Titration of anesthesia according to the hemodynamic variations elicited by surgical stimulation is a common way to conduct anesthesia. In order to evaluate the efficacy of the hemodynamic stability provided by the tested epidural drugs, we used standardized criteria for the hemodynamic variations requiring supplemental anesthetic injections and standardized anesthetic reinjections. Moreover, a low basal infusion rate of propofol (2 mg centered dot kg-1 centered dot h-1) was specifically used to allow a more sensitive detection of these hemodynamic variations. Using this approach, we demonstrated that a greater anesthetic-sparing effect was provided by epidural clonidine than by epidural sufentanil, at least at the dose used in this study. Several explanations may be proposed for this observation: First, clonidine is an agonist at the alpha2-adrenergic and at the imidazolin preferring receptors. These two systems are highly involved in the control of blood pressure [11,12]. Accordingly, better control of the cardiovascular variations elicited by noxious surgical stimulation may be expected after the use of such products. This is certainly not the only explanation for the observed effect. Experimental work conducted on volunteers by Muzi et al.  indicates that clonidine, despite pronounced interferences with the sympathoadrenal system, only discretely interferes with the sympathetic responses to noxious stimuli. Moreover, the anesthetic-sparing properties of clonidine have been extensively demonstrated . Although sufentanil also possesses anesthetic-sparing effects , it could be hypothesized that more profound anesthesia was provided to the patients in our study by the combination of propofol and epidural clonidine than by the combination of propofol and epidural sufentanil. This assertion is not necessarily in conflict with the two episodes of specific musical memory encountered in this group. The patients who were able to remember the type of music played during the intervention did not have any other memory. These episodes may be compared to the results sometimes obtained with positive suggestion during general anesthesia rather than classic awareness .
Another possibility is that epidural clonidine, despite a lower level of general anesthesia (two episodes of awareness), provides more intense spinal antinociception than that afforded by epidural sufentanil. As nociception is an important determinant of the general anesthetic requirements , it could easily explain the reduced anesthetic requirements in the epidural clonidine group. This is not, however, supported by animal experiments that demonstrated much more potent action on spinally mediated nociceptive reflex when using sufentanil than with clonidine .
Interestingly, the hemodynamic stabilizing properties of the dose of epidural sufentanil used seemed to resolve approximately 1 h after the beginning of the infusion. Accordingly, more IV reinjections were required in this group during the later phase of surgery. This is not necessarily related to the use of too small a dose of epidural sufentanil. A ceiling effect on the hemodynamic-stabilizing properties of the opioids during general anesthesia could also account for this observation, as it has already been reported in humans and animals [17,18].
In the early postoperative period, the epidural infusion of either clonidine or sufentanil appears to provide adequate postoperative analgesia, as demonstrated by the very low rate of rescue analgesia demands and the good VAS scores in both groups. This is an expected result in the epidural sufentanil group, because the doses used are slightly higher than those reported in the literature to alleviate postoperative pain after abdominal surgery [4,19]. The plasma levels of sufentanil measured in this study were also superior, but they do not simply account for the systemic resorption of epidural sufentanil because low doses of IV sufentanil were also administered.
The good results obtained in the clonidine group do not show beyond question that the treatment schedule of epidural clonidine used is equianalgesic to that of epidural sufentanil. Furthermore, the present investigation cannot discriminate between an intrinsic analgesic effect and a potentiation of opiate analgesia, because all the patients in the epidural clonidine group received IV sufentanil. Potentiation of opiate analgesia by the alpha2-adrenoceptor agonists has been regularly demonstrated in animal and human studies [20,21]. Recently, we demonstrated, using a rodent animal model, that epidural clonidine reduces the ED50 s of sufentanil for a tail withdrawal latency >or=to 10 s by a factor of 3 .
The analysis of the analgesic requirements and the pain VAS after the epidural infusions were discontinued highlighted the residual positive effects of epidural clonidine on postoperative pain. Because significant plasma concentrations of clonidine are still found at 24 postoperative hours, a potentiation of the IV sufentanil bolus delivered by the PCA device probably explains this beneficial effect. Such a positive effect was already described using IV clonidine during anesthesia . Considering the plasma levels of sufentanil at 12 and 24 h, it is surprising that these levels were not significantly different in the two groups, although at these moments the PCA analgesic requests were significantly reduced in the clonidine group. This is not, however, an irrefutable proof of a pure pharmacokinetic interaction between clonidine and sufentanil. Results of sampling during epidural clonidine infusion do not argue for this explanation. Moreover, the time interval between the last satisfied demand and blood sampling was not recorded, so it is possible that a bolus dose of sufentanil was sometimes delivered at a time close to blood sampling for sufentanil determination.
Probably, clonidine-induced excessive postoperative sedation cannot account for this difference in analgesic requirements, because the analysis of the sedation scores does not disclose any difference between the two groups.
The higher VAS scores reported by the patients in the epidural sufentanil group cannot be related to inadequate rescue analgesia because these patients did not ask for additional pain relief, which still could be obtained since no lockout limit was reached. Moreover, the number of unsatisfied analgesic demands was not significantly increased when compared with the number in the clonidine group. Factors other than pain may explain this difference. The anxiolytic effects of clonidine may be strongly involved in this improved postoperative pain management .
No hypotension was recorded in the clonidine group during the observation period. The effect of clonidine on blood pressure is the result of different and conflicting action at central and peripheral sites . According to the plasma levels of clonidine, it is probable that its peripheral vasoconstrictive effects have counterbalanced the central alpha2- or imidazolin-induced hypotensive action. Epidural sufentanil, at the dose used in the present study, led to a serious respiratory depression in one patient. Sufentanil is a highly lipid soluble opiate that migrates less in cerebrospinal fluid, and therefore it will probably cause fewer cases of delayed respiratory depression than morphine after epidural use . Meanwhile, early respiratory depression of various intensity has been regularly noted [4,26]. In the present study, the one patient who presented with major respiratory depression at the end of surgery already had, immediately after the epidural bolus infusion, high plasma sufentanil levels, arguing for an important systemic resorption or a direct intravascular injection.
The present study, considering only one dose of each agonist, does not intend to suggest equianalgesic doses, if any, of clonidine and sufentanil. It is, however, able to indicate some interesting complementary effects between the two drugs. Because epidural clonidine in combination with general anesthesia as used in the present study provided a strong intraoperative hemodynamic stability and allows a significant reduction of the dose of sufentanil required to alleviate postoperative pain, the combination of low doses of both agonists seems the most appropriate way to use these drugs in the perioperative period. This combination will result in a greater efficacy and a reduced risk of possible side effects.
The authors thanks Dr. E. Neyens from Boehringer-Ingelheim and Mr. M. Kuppens from Janssen Pharmaceutica Belgium for providing the sampling of clonidine and sufentanil. The authors also acknowledge Drs. F. Veyckemans and T. F. Meert for critical review of the manuscript.
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© 1995 International Anesthesia Research Society
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