E. Sitsen (*), F. van Poorten (**), G. Jansen (***), R. Kuijpers (**), A. Dahan (*) and

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1 (Acta Anaesth. Belg., 2012, 63, ) A comparison of the efficacy of levobupivacaine 0,125%, ropivacaine 0,125% and ropivacaine 0,2%, all combined with sufentanil 0.5 µg/ml, in patient-controlled epidural analgesia after hysterectomy under combined epidural and general anesthesia E. Sitsen (*), F. van oorten (**), G. Jansen (***), R. Kuijpers (**), A. Dahan (*) and R. Stienstra (****) Abstract : We compared the relative potencies of ropivacaine and levobupivacaine in combination with sufentanil 0,5 µg/ml in postoperative epidural analgesia after abdominal hysterectomy. Methods : In this randomized, prospective, double-blinded study we studied sixty-three patients scheduled for abdominal hysterectomy. They were randomly allocated to receive ropivacaine 0.2% with sufentanil 0.5 µg/ml (group 1), ropivacaine 0.125% with sufentanil 0.5 µg/ml (group 2) or levobupivacaine 0.125% with sufentanil 0.5 µg/ml (group 3) for postoperative pain relief. The primary outcome was the analgesic efficacy of levobupivacaine and ropivacaine in patient-controlled epidural analgesia, as assessed by the number of requests for epidural bolus injections. Secondary outcomes included local anesthetic consumption, numerical rating scale (NRS) scores and neural block characteristics, hemodynamic data and the incidence of side effects, in particular nausea, pruritus, hypotension and sedation. Results : There was no difference between the groups in the number of epidural bolus requests. The hourly consumption of local anesthetic in mg/h in group 2 (8,5 ± 1.5 mg/h) and group 3 (8.1 ± 0.6 mg/h) was similar. However, patients in group 1 (13.1 ± 1.6 mg/h) used significantly more local anesthetic compared to the other groups. Conclusions : In the context of this study there was no clinical difference in potency between epidural ropivacaine and levobupivacaine in a concentration of 0.125% combined with sufentanil 0.5 mg/ml because local anesthetic consumption was primarily driven by sufentanil. Increasing the concentration of ropivacaine to 0.2% did not result in better analgesia or reduction in sufentanil consumption. Key words : CEA ; ropivacaine ; levobupivacaine ; epidural ; randomized double-blind trial ; analgesia. atient-controlled epidural analgesia (CEA) is a popular method for providing post-operative analgesia for painful thoracic, abdominal or orthopedic procedures. Benefits include active involvement of the patient in the analgesic regimen, and avoidance of the time delay associated with physician-administered epidural boluses (1). Bupivacaine, a racemic mixture of the S(-)- and R(-)-enantiomer of bupivacaine, has traditionally been the most widely used local anesthetic for epidural analgesia. However, since the introduction of newer drugs with a better safety profile the popularity of racemic bupivacaine for epidural analgesia is fading. Ropivacaine, structurally closely related to bupivacaine is a pure S(-)-enantiomer with lower cardiac and central nervous system toxicity (2, 3). Moreover, ropivacaine produces less motor blockade (4, 5), which may be a potential advantage during post-operative recovery. The latest advance in local anesthetics, at least in terms of availability to the anesthetic community has been levobupivacaine, the pure S(-) enantiomer of racemic bupivacaine. Like ropivacaine, levobupivacaine has a better safety profile compared to racemic bupivacaine (6, 7). E. Sitsen, M.D. ; F. van oorten, M.D. ; G. Jansen, M.D. ; R. Kuijpers, M.D. ; A. Dahan, M.D., h.d. ; R. Stienstra, M.D., h.d. (*) Department of Anesthesiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (**) Department of Anesthesiology, Reinier de Graaf Gasthuis, ostbus 5011, 2600 GA Delft, The Netherlands. (***) Department of Anesthesiology, Amphia Ziekenhuis, ostbus 90158, 4800 RK Breda, The Netherlands. (****) Department of Anesthesiology, Sint Maartenskliniek, ostbus 9011, 6500 GM Nijmegen, The Netherlands. Correspondence address : Elske Sitsen, Department of Anesthesiology 5-Q, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Tel. : Fax : mesitsen@lumc.nl

2 170 e. sitsen et al. Controversy exists regarding the relative poten cies of racemic bupivacaine, levobupivacaine, and ropivacaine. Obstetric up-down sequential allocation studies showed that ropivacaine was 40% less potent compared to racemic bupivacaine (8, 9), but found levobupivacaine and racemic bupivacaine to be equipotent (10). In a previous study aimed to detect a possible difference in potency between levobupivacaine and ropivacaine, we studied the consumption of epidural ropivacaine 0.2%, ropivacaine 0.125% and levobupivacaine 0.125%, all in combination with sufentanil 1 mg/ml, necessary to obtain adequate pain relief after total knee replacement (11). The conclusion of that study was that the CEA consumption of the epidural mixture was largely determined by sufentanil ; this implicates that the sufentanil concentration in the epidural mixture may have been too high, obscuring a possible difference in potency between levobupivacaine and ropivacaine. The aim of the present study is to compare the efficacy of epidural levobupivacaine and ropivacaine, both in combination with sufentanil, in postoperative patient-controlled epidural analgesia following hysterectomy using a lower sufentanil dose of 0,5 mg/ml. The null hypothesis is the absence of a potency difference between levobupivacaine and ropivacaine, the alternative hypothesis being a potency difference in favor of levobupivacaine. Assuming a possible potency difference of 40%, three mixtures will be compared : levobupivacaine 0.125%/sufentanil 0.5 µg/ml, ropivacaine 0.2%/sufentanil 0.5 µg/ml and ropivacaine 0.125%/ sufentanil 0.5 µg/ml. Methods Ethical approval of this study was provided by the Medical Ethics Committees of the Leiden University Medical Center, Leiden, the Netherlands and the Medical Ethic Committee in the Reinier de Graaf Hospital, Delft, The Netherlands, and written informed consent was obtained from all patients. The study design was multicenter, randomized, prospective and double-blind. Sixty-three patients ASA (American Society of Anesthesiologists) classification I-II, aged > 18 years, scheduled for elective abdominal hysterectomy under combined epidural and general anesthesia were studied. Exclusion criteria were known hypersensitivity to amide-type local anesthetics or opioids, a history of neurological or psychiatric disease, patients on chronic analgesic therapy, inability to understand the principle of patient-controlled epidural analgesia (CEA) and/or to operate the CEA device, and any contraindication for epidural analgesia. Eligible patients were asked to participate in the study during a visit at the preoperative anesthesia screening unit ; the CEA device and the numerical rating scale (NRS ; 0 representing no pain and 10 the worst pain imaginable) were explained and patients were instructed to titrate themselves postoperatively to a NRS score of 3 or less. After the institution of routine monitoring (ECG, non-invasive blood pressure and peripheral oxygen saturation) and intravenous access, the patient was placed in the sitting position. The aim was to access the epidural space through the 9 th thoracic interspace ; identification was made by counting down from the vertebra prominens (C7). After identifying the epidural space with a 16 G epidural needle (ortex, UK) using the loss of resistance to saline technique, an epidural catheter was inserted 5 cm into the epidural space. After removal of the epidural needle, the patient was placed in the supine horizontal position. Using sealed envelopes and a computergenerated randomization list, patients were randomly allocated to one of three groups of 21 patients each. Following negative aspiration, a loading dose of 10 ml local anesthetic was administered through the epidural catheter and the time was designated as T = 0. atients in groups 1 and 2 received ropivacaine 0.75%, patients in group 3 received levobupivacaine 0.75%. Fifteen minutes after the administration of the epidural loading dose, correct placement of the epidural catheter was verified by bilateral absence of temperature discrimination in the tenth thoracic dermatome in the anterior axillary line using a bottle containing frozen water. In case of absence of sensory block, the epidural catheter was removed and the patient was excluded from the study. After establishing the presence of bilateral sensory block, general anesthesia was induced with propofol, remifentanil and rocuronium, and maintained with propofol and remifentanil. At the end of surgery, residual muscle relaxation was reversed intravenously with atropine 0.01 mg/kg and neostigmine 0.02 mg/kg and the patient s trachea extubated. One hour after the epidural loading dose (T = 1), a CEA device (Gemstar, Hospira, Hoofddorp, The Netherlands) with a blinded cassette was connected to the epidural catheter. atients in group 1 received a mixture of ropivacaine 0.2% and sufentanil 0.5 mg/ml ; patients in group 2 received

3 combined epidural and general anesthesia 171 a mixture of ropivacaine 0.125% and sufentanil 0.5 mg/ml ; patients in group 3 received a mixture of levobupivacaine 0.125% and sufentanil 0.5 mg/ml. The same anesthesiologist that had placed the epidural catheter and administered the epidural loading dose prepared the cassettes ; this anesthesiologist was not involved in the collection of postoperative data. The device was set with a background infusion of 6 ml/h, a bolus dose of 2 ml, a lock-out period of 10 minutes and a maximum of three boluses per hour. CEA was continued for 48 hours postoperatively. In case of insufficient analgesia, an extra epidural top-up of 10 ml local anesthetic 0.75% (ropivacaine in groups 1 and 2, levobupivacaine in group 3) was administered with a maximum of 3 top-ups per 24 h. In case of insufficient analgesia despite an extra epidural bolus, the CEA was discontinued and replaced by i.v. morphine CA. At T = 6 h, 18 h, 24 h and 48 h data were collected by observers who were unaware of the patient s randomization. atients were asked to express their level of pain over the previous time interval with an average NRS pain score, as well as their satisfaction with the method of pain relief with respect to analgesia and comfort with an average NRS satisfaction score (NRS ranging from 0 = very dissatisfied to 10 = highly satisfied). At the same time intervals, patients were assessed for signs of motor blockade of the lower limbs on a twelve point scale, where each joint of the lower limbs (hip, knee, ankle) was scored from 0-2 (0 : no motor block ; 1 : partial motor block ; 2 : complete motor block. artial motor block was defined as the possibility to move the joint, but not sustainable against manual counter pressure). The primary outcome was the analgesic efficacy in patient-controlled epidural analgesia, as assessed by the number of requests for epidural bolus injections. Secondary outcomes were local anesthetic consumption, numerical rating scale (NRS) scores for pain and satisfaction and neural block characteristics (level of sensory blockade and degrees of motor block), time to first demand of a bolus of the epidural solution, hemodynamic data and the incidence of side effects, in particular nausea, pruritus, hypotension and sedation. Average hourly local anesthetic consumption was calculated using data from the CEA device (total infusion time and infused volume), as well as additional top-ups administered during the study period. The epidural loading dose of 75 mg administered at T = 0 was excluded from the calculations to avoid overestimation of the average hourly dose. On the given time intervals patients were interviewed for side effects : nausea and/or vomiting, and pruritus. In the absence of relevant data, the sample size was estimated assuming 40% variability (coefficient of variation) in the number of patient controlled requests for medication. With this assumption the sample size required to have an 80% power of detecting a clinically relevant (40%) difference between group means (level of significance 0.05) was 21 per group. atient age, height and weight, TFD, bolus/ demand ratio and local anesthetic and sufentanil consumption are expressed as mean ± SD. ASA classification is reported as a proportion, NRS for pain and NRS for satisfaction are reported as median (range). Data were analyzed using the Graphad InStat v.3.06 package (Graphad Software Inc, San Diego, CA). The χ 2 -test was used for comparison of proportions. Continuous data were analysed using one-way analysis of variance (ANOVA) or the Kruskal Wallis test, as appropriate. The level of significance was set at Results Sixty-three patients were studied, 21 patients in each group. Shortly after the study had started, the surgical technique for hysterectomy at the Leiden University Medical Center changed from laparotomy to laparoscopy. As a consequence, only 4 patients ; 2 in group 1 (ropivacaine 0.2%), 1 in group 2 (ropivacaine 0.125%) and 1 in group 3 (levobupivacaine 0.125%) were studied at the Leiden University Medical Center and 57 patients in the Reinier de Graaf Gasthuis. In one patient in group 3 (levobupivacaine 0.125%), the epidural catheter was accidentally removed when the patient was transferred from the OR trolley to the bed upon arrival in the recovery. In another patient, also in group 3, the CEA device gave an occlusion alarm when connected to the epidural catheter ; we were unable to resolve this and the epidural catheter was removed. Both patients were withdrawn from the study ; a new epidural catheter was placed in the recovery and both patients received epidural pain relief according to hospital protocol. There were no differences between the groups in demographic data (Table 1).

4 172 e. sitsen et al. Table 1 atient demographics Age (years) 48.1 ± ± ± 13.3 NS ASA Classification (I/II/III) 10/10/1 12/8/1 8/10/1 NS Weight (kg) 78.2 ± ± ± 13.5 NS Height (cm) ± ± ± 7.5 NS Data are mean ± SD or number of patients. NS = no statistically significant difference. Table 2 ain, satisfaction, and Bolus/Demand Ratio NRS ain T = 0 0 (0-5) 0 (0-4) 0 (0-7) NS T = 6 0 (0-4) 0 (0-4) 0 (0-6) NS T = 18 0 (0-4) 1,5 (0-8) 1 (0-5,5) NS T = 24 0 (0-3) 1(0-8) 0 (0-5) NS T = 48 0 (0-3) 0 (0-4) 0 (0-4) NS NRS Satisfaction T = 0 9 (5-10) 10 (7-10) 9 (6-10) NS T = 6 10 (7-10) 10 (8-10) 9 (7-10) NS T = (7-10) 10 (2-10) 9 (7-10) NS T = (7-10) 10 (7-10) 9 (7-10) NS T = ( 7-10) 9,5 (5-10) 9 (7-10) NS Boluses received 12,9 ± 15, ± ± 11,4 NS Bolus/Demand 0.94 ± ± ± 0.1 NS Ratio NRS ain = Numerical rating scale score for pain (ranging from 0 = no pain to 10 = very painful). NRS Satisfaction = Numerical rating scale score for patient satisfaction (ranging from 0 = highly dissatisfied to 10 = highly satisfied). Bolus/Demand Ratio : The number of granted CEA bolus doses/bolus requests during the 48 h study period. NRS ain and NRS Satisfaction are expressed as median (range) Boluses and Bolus/Demand ratio are expressed as mean ± SD. T = 6, 18, 24 or 48 : 6, 18, 24 or 48 h after administration of the epidural loading dose. NS= no statistically significant difference. Three patients received an additional epidural top-up because of insufficient analgesia, one patient in group 1 and two in group 2. Another patient in group 2 received two epidural top-ups. None of the patients in group 3 required an additional topup. The number of boluses requested and received, NRS values for pain and patient satisfaction were similar for the three groups (Table 2). Local anesthetic consumption in mg/h was significantly higher in group 1 (ropivacaine 0.2%) compared to group 2 (ropivacaine 0.125%) and group 3 (levobupivacaine 0.125%) ; 13.1 ± 1.6 mg in group 1 ; 8.5 ± 1.5 mg in group 2 ; 8.1 ± 0.6 mg in group 3, p < Epidural solution consumption in ml/h was similar and there were no differences in the average hourly sufentanil consumption between the groups. Differences in time to first demand were statistically not significant (Table 3). With the exception of one patient in group 1 who had a motor block score of 6/12 at 6 h and 18 h, all other patients had no motor block, thus a score of 0/12 at 6, 18, 24 and 48 h.

5 combined epidural and general anesthesia 173 Table 3 Average local anesthetic and sufentanil consumption during 48 h Sufentanil µg/h 3.2 ± ± ± 0.2 NS Local anesthetic mg/h 13.1 ± 1.6 * 8.5 ± ± 0.6 < Local anesthetic ml/h 6.5 ± ± ± 0.5 NS TFD (h) 7.8 ± ± ± 6.8 NS Data are mean ± SD. TFD : Time to first demand of the CA morphine device. * significant versus groups 2 and 3. NS : no statistically significant difference. Table 4 ONV and pruritus ONV 6 (29%) 9 (43%) 9 (47%) NS ONV treatment 3 (14%) 5 (24%) 5 (26%) NS ruritus 16 (76%) 14 (67%) 11 (58%) NS ruritus treatment 4 (19%) 3 (14%) 6 (32%) NS Data are expressed as number of patients and proportions. NS : No statistically significant difference. There were no statistically significant differences in the number of patients suffering from nausea or pruritus, neither in the number of patients requiring treatment, treatment consisted of clemastine 1 to 2 mg and if necessary ondansetron 4 to 8 mg intravenously (Table 4). Discussion We found no difference in local anesthetic consumption between patients receiving ropivacaine 0.125% or levobupivacaine 0.125%, and similar sufentanil consumption in the three groups. The three mixtures were equally effective in providing adequate analgesia and patient satisfaction ; motor block of the lower limbs was absent and there were no statistically significant differences in side effects between the three groups. The controversy regarding differences in potency between ropivacaine, levobupivacaine and racemic bupivacaine is largely fuelled by MLAC (minimum local analgesic concentration) (ED-50) studies, much less by clinical comparisons at the upper end of the dose-response curve. Obstetric MLAC studies found a 40% potency difference between ropivacaine and racemic bupivacaine (8, 9), but no difference between levobupivacaine and racemic bupivacaine (10). These findings suggest a similar 40% potency difference between ropivacaine and levobupivacaine, but another MLAC study found ropivacaine and levobupivacaine to be equipotent (12). With these contradictory results, the question arises if MLAC studies are a proper instrument to compare potencies. Another question is whether differences at the ED-50 level equally apply at the high end of the dose-response curve. Mixing opioids with local anesthetics for epidural pain relief has advantages. The addition of an opioid allows for a reduction in local anesthetic concentration, thereby reducing local anestheticrelated side effects such as systemic hypotension and lower limb motor block, without compromising the efficacy of pain relief. The trade-off is itching caused by the opioid, and urinary retention. The efficacy of adding 1 mg/ml sufentanil to either ropivacaine or bupivacaine in providing superior analgesia compared to the local anesthetic alone has been amply demonstrated (13, 14, 15, 16, 17, 18). It is unclear to what extent each component of a local anesthetic/opioid mixture contributes to analgesia. In a previous study designed to detect a 40% potency difference between ropivacaine and

6 174 e. sitsen et al. levobupivacaine, both in combination with sufentanil, we failed to find this potency difference (11). This may be explained on the basis that ropivacaine and levobupivacaine are equipotent at a concentration of 0.125%, but there is also the possibility that the relatively high concentration of sufentanil (1 mg/ml) used in that study disproportionately contributed to analgesia, thereby rendering the contribution of the local anesthetic to a minor part, thus masking a possible difference in potency. Our present study was designed to investigate the same hypothesis as in our previous study, but with a reduction in the sufentanil dose of 50% in an attempt to shift the balance between local anesthetic and opioid with respect to their contribution to postoperative pain relief in the direction of the local anesthetic. We found sufentanil consumption in the three groups to be similar, but consumption of ropivacaine significantly higher in group 1 (ropivacaine 0.2%). Increasing the concentration of ropivacaine did not result in better analgesia, or a reduction in sufentanil consumption. This indicates that postoperative analgesia was primarily driven by sufentanil in the context of this study. In a study looking at different sufentanil concentrations added to ropivacaine 0.2%, Brodner et al. concluded that 0.75 mg/ml was the optimal concentration (19). Increasing the concentration from 0.75% to 1% did not result in better analgesia or a sparing effect on the consumption of ropivacaine ; adding sufentanil in a concentration of 0.5 mg/ml did not differ significantly from ropivacaine 0.2% without sufentanil in terms of analgesia or local anesthetic consumption. Boulier et al. determined the MLAC of ropivacaine and levobupivacaine in combination with sufentanil 0.5 mg/ml in parturients, and found that the addition of sufentanil did not significantly alter the analgesic potency of both ropivacaine and levobupivacaine (20). lacing the results of our study in the perspective of these two studies, it seems reasonable to conclude that at a concentration of 0.125%, the potency difference between ropivacaine and levobupivacaine is either minimal, or non-existent. Epidural opioids can cause itching and may contribute to ONV. Itching caused by epidural sufentanil is reported to vary from 15% to 50% (21, 19, 22). In our present study, the incidence of itching was much higher, varying from 58% to 76% ; this is a remarkable finding, as the average hourly sufentanil consumption in the present study was less than 50% compared to our previous study where we found an incidence of 9% to 11% (11). Similarly, the incidence of ONV in our study varied from 29% to 47%, which is much higher than the 10-20% reported by others (19, 23, 22). Apart from differences in methodology, the higher incidence of ONV may be explained by the type of surgery and the entirely female study population (24). We have no explanation for the high incidence of pruritus as well as for the observation that a relative large portion of the patients required treatment. In conclusion, there was no potency difference between ropivacaine and levobupivacaine in a concentration of 0.125% mixed with sufentanil 0.5 mg/ml. Both solutions provided adequate pain relief with similar side effects. Increasing the concentration of ropivacaine to 0.2% did not result in better analgesia or a reduction in sufentanil consumption. References 1. Liu S. S., Allen H. W., Olsson G. 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