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Department of Anesthesiology and Surgical Intensive Care, University of Münster, Münster, Germany
Address correspondence and reprint requests to Hugo Van Aken, MD, PhD, FRCA, FANZCA, Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin der Westfälischen Wilhelms-Universität Münster, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. Address e-mail to hva{at}anit.uni-muenster.de
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Abstract |
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Implications: Sufentanil is added to epidural infusions of ropivacaine 0.2% wt/vol to improve the effectiveness of postoperative pain management. Regarding the risk of side effects, however, it is still unclear what concentration of sufentanil should be added to the local anesthetic. For postoperative thoracic epidural analgesia after major abdominal surgery, the combination of ropivacaine 0.2% wt/vol and 0.75 µg/mL sufentanil resulted in an appropriate cost:benefit ratio between good analgesia and side effects.
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Introduction |
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Plasma accumulation after continuous long-term epidural drug administration during the postoperative period may cause severe side effects, and this has been shown to occur with epidural sufentanil (4,5). After surgery, the blood’s protein-binding capacity of ropivacaine increases, preventing plasma levels of free ropivacaine from accumulating. This effect has been demonstrated for a short period of 24 h of continuous epidural ropivacaine 0.2% wt/vol infusion (8). After major abdominal surgery patients usually need epidural drugs for 96 h. Thus, it is meaningful to administer epidural ropivacaine and observe plasma levels during this period.
Our prospective, double-blinded, randomized study was aimed to determine the optimal dose of epidural sufentanil to be added to ropivacaine 0.2% wt/vol in relation to optimal analgesia, minimal side effects and its pharmacokinetics.
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Methods |
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Before the induction of general anesthesia, a thoracic epidural catheter was inserted at T9-11. After a test dose of 2 mL of bupivacaine 0.5% wt/vol with epinephrine 1:200 000, 15 mL of ropivacaine 0.5% wt/vol (R), or ropivacaine 0.5% wt/vol with an addition of 0.5 µg/mL (R+S0.5), 0.75 µg/ml (R+S0.75), or 1.0 µg/mL sufentanil (R+S1) was administered in three single doses of 5 mL to establish a sensory blockade up to the level of T4. After confirmation of the block, a continuous epidural infusion with ropivacaine 0.2% wt/vol and the respective sufentanil concentration was administered at 5 mL/h. General anesthesia was induced with thiopental (3–7 mg/kg), alfentanil (10–20 µg/kg), droperidol (1.25 mg), and cisatracurium (0.1–0.12 mg/kg). All patients were intubated orotracheally and their lungs were ventilated to maintain normocapnia with continuous positive-pressure ventilation. Anesthesia was maintained with isoflurane (0.5%–0.6% inspiratory concentration) and 65% nitrous oxide in oxygen. The depth of intraoperative anesthesia was assessed by using clinical standards, i.e., symptoms of cardiovascular reactivity or sweating. If anesthesia did not fulfill the requirements, the anesthetist was allowed to apply up to 10 mL of the epidural study medication. If satisfactory anesthesia could not be accomplished, balanced anesthesia was provided with fentanyl as needed. Volume therapy, transfusions, and other procedures followed the usual standards.
During the postoperative course, physicians from the acute pain service adjusted the infusion rate of the study medication twice a day to the individual patient’s requirements. Additional bolus doses of 2 mL up to every 20 min for on-demand self-administration were set in the bedside pump’s program. The aim was to achieve a dynamic pain score (i.e., for coughing, taking deep breaths, etc.) of 40 or less on a visual analog scale (VAS), with zero representing no pain and 100 being the worst pain possible. Drug dosage was only limited by side effects such as sedation, respiratory depression, nausea, or pruritus. If there was any doubt concerning the correct position of the epidural catheter, 5 mL of ropivacaine 0.5% wt/vol was administered. If an adequate analgetic effect (VAS 
40) could not be achieved, the patient was excluded from the trial and was provided with a patient-controlled IV analgesia pump with piritramide and additional antipyretic agents.
On the fourth postoperative day, the continuous infusion dose was reduced by 50%. On the fifth postoperative morning, the infusion was terminated, the epidural catheter was removed, and patients were treated according to the intensity of the pain with IV metamizole, propacetamol, tramadol, or piritramide.
Once a day, an independent investigator recorded all of the study data. The drug dosage was assessed according to the daily cumulative volume of epidural infusion administered. The quality of pain control was judged according to the dynamic VAS score and the demand for additional bolus doses or other analgetic medication. The following side effects of ropivacaine and sufentanil were examined: motor block [Bromage scores (9) 0 = normal motor function; 1 or greater = reduced motor function], respiratory depression (1 = normal respiratory rate, 2 = respiratory rate 8–12 breaths/min, 3 = respiratory rate < 8 breaths/min), sedation (1 = awake patient looks around; 2 = tired, sleepy, patient easy to wake up, when spoken to; 3 = asleep, can easily be woken by a light glabellar tap; 4 = coma, sedated, a sluggish response–too deep) (6), nausea (yes or no), emesis (yes or no), and pruritus (yes or no).
Demographic variables, medical history, preoperative physical status, intraoperative medication, duration of general anesthesia, blood loss, volume replacement, fluid balance, and transfusions were recorded in a standardized protocol for further analysis.
Plasma concentrations of sufentanil, ropivacaine, and 
1-acid glycoprotein were measured in a randomized subsample of 40 patients (10 from each group) to assess pharmacokinetic data of the epidural drugs. This subsample was randomized by using a set of random numbers for each treatment group. Blood (2–5 mL) was sampled (stored in heparinized tubes) from a central venous catheter at 1, 30, 120, and 240 min after the initial epidural dose, during postoperative days 1–4 (i.e., after 24, 48, 72, and 96 h), and 30, 120, and 240 min after termination of the epidural infusion. The blood was centrifuged at 4000–5000 rpm, and plasma samples were stored at -20°C until analyzed. Total and free ropivacaine and 1-acid glycoprotein plasma levels were determined by using high-pressure liquid chromatography with ultraviolet detection at the Pulmonary Function Laboratory, University Department of Surgery, Giessen, Germany. Radioimmunoassay to analyze plasma concentrations of free sufentanil was performed by Jansen-CILAG, Beerse, Belgium.
Regarding the pharmacokinetics of epidural drugs, a sample size of 10 patients in each group would allow us to detect a significant effect size of F = 0.6 with a statistical power of 1-ß = 0.8 and a significance level of = 0.05. Because of the variety of psychological, social, cultural, and somatic influences of pain, we expect that differences will not be as distinct as with pharmacokinetic data. Therefore, an effect size of F = 0.35 with a sample size of n = 22 patients each group (1-ß = 0.8 and = 0.05) was defined as appropriate (10).
Statistical testing was performed by using the Statistical Package for the Social Sciences (SPSS 6.1.) system (SPSS Inc., Chicago, IL). Nominal scale variables were described by using relative and absolute frequencies, and the 
2 test was used to assess differences between groups. Fisher’s exact test was used if matched cells were rare (expected frequencies less than five). Variables with interval or rational scales were described as means and standard deviation. One-way analysis of variance with post hoc Scheffé tests, or repeated-measures analysis of variance was used to compare groups. Within-subjects factors were analyzed by comparing each category of the factor against the average of the previous categories (reverse Helmert contrasts); simple contrasts were used to analyze between subjects factors. Pearson or Spearman correlation coefficients were calculated to determine the covariation of variables.
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Results |
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There were no significant differences between the groups with regard to demographic data, intraoperative characteristics, and preoperative diagnoses (Table 1). Seven patients (one in Group R, two in Group R+S0.5, and four in Group R+S1) had impending renal failure with elevated urea levels, however, they still had normal urine output.
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1-acid glycoprotein decreased during this period (P = 0.00), and there was a significant effect for interaction, showing that from different plasma levels after 1 min, the concentrations decreased to comparable values after 240 min (P = 0.03; Tables 4 and 5; Figure 3). Postoperatively, total ropivacaine plasma levels increased in all groups, reached a maximum after 48 and 72 h, and decreased after 96 h (P = 0.00). Concentrations of free ropivacaine were similar in all groups, and there was a decrease during the observation period, because of a very high mean score in Group R+S1 (P = 0.01). There was no difference among the groups with regard to 1-acid glycoprotein levels, but there was a significant increase over the total observation period of 96 h (P = 0.00; Tables 4 and 5, Figure 3). After termination of the epidural infusion, plasma concentrations of total and free ropivacaine decreased, but were still demonstrable after a period of 240 min (total ropivacaine: P = 0.00; free ropivacaine: P = 0.00). Concentrations of 1-acid glycoprotein were comparable among the groups, and remained unchanged after termination of the epidural drug infusions (Tables 4 and 5, Figures 2 and 3).
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Discussion |
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Our study confirms previous investigations, that adding opioids to epidural local anesthetics improves postoperative pain management (6). Epidural local anesthetics reduce pain very effectively (12). Unfortunately, optimal analgesia can often only be achieved at concentrations that produce motor blockade of the lower extremities, causing delay of early postoperative mobilization (13). Ropivacaine is very effective in reducing postoperative pain during rest at concentrations of 0.1% wt/vol or 0.2% wt/vol. At a concentration of 0.3% wt/vol, however, with an analgesic strength that is sufficient to control dynamic pain, motor blockade of the lower extremities is often observed (14,15). Even under the experimental conditions of this study, in which drug dosage was titrated to achieve a dynamic VAS score of 40 or less, reducing the variance in the VAS scores, the drug combination was superior to local anesthetic monotherapy. Adding 0.75 µg/mL or 1.00 µg/mL improved analgesia similarly, whereas the addition of 0.5 µg/mL sufentanil had no effect. Despite the observed enhancement of analgesia, the addition of 0.75 µg/mL or more sufentanil did not result in reduced administration of the infused solutions. This effect is presumably a result of the titration strategy, in which only an upper, but no lower, limit of pain was defined. Drug dosage was not aimed to keep a specific range of VAS scores and, thus, was not reduced in patients with dynamic VAS scores of less than 40.
As has been shown in previous studies, there was a reduction in the quality of analgesia on the first and second postoperative days, which was seen in all groups (5). Because of adjustment of drug dosage to individual needs by the postoperative pain service, however, mean dynamic VAS scores remained within the predefined limits of sufficient analgesia (16).
With regard to supplementary drugs, there was a trend toward a reduced need for supplementary NSAIDs on the first postoperative day in patients receiving the addition of 1 µg/mL sufentanil. According to this analysis, analgesia may be optimal at the highest concentration of sufentanil we used. However, if NSAIDs are coadministered in addition to the epidural drug, the analgesia achieved by 0.75 µg/mL sufentanil and ropivacaine 0.2% wt/vol was not improved by the addition of 1 µg/mL sufentanil. Furthermore, there was a correlation between sufentanil dosage and the incidence of postoperative pruritus.
Referring to the plasma concentrations of continuous epidural ropivacaine, we confirmed the results of other studies by showing an increase in the total concentration, but not the unbound concentration, of the local anesthetic during the postoperative period (17).
The main explanation for the differences between total and free ropivacaine refers to the association with 1-acid glycoprotein. This acute-phase protein increases after surgery, and thus with increasing plasma levels of ropivacaine, there is an elevation in the protein-binding capacity of the blood. As demonstrated in this and other studies (8,17), this effect is not inhibited by epidural analgesia. During the first 240 minutes after the onset of drug plasma concentrations during which surgery was performed, there was a reduction in 1-acid glycoprotein. In accordance with the data reported by Erichsen et al. (8), the plasma concentration then increased continuously during the first 72 postoperative hours. During the following 24 hours, however, the slope of the concentration curve decreased, and plasma levels remained stable until 96 hours after surgery. After termination of the continuous epidural infusion, there was a marked time-dependent decrease in total ropivacaine, whereas the free fraction decreased very slightly. This observation has also been reported by Erichsen et al. (8), and is a result of the metabolism of ropivacaine.
Free ropivacaine remained low and stable during the whole observation period of 96 hours after surgery, without any difference between the patients receiving local anesthetic monotherapy or various concentrations of additional sufentanil. Thus, we conclude that continuous 0.2% wt/vol epidural ropivacaine is safe even for long-term infusion and for the whole period during which patients will require adequate analgesia after major abdominal surgery. Coadministration of sufentanil does not diminish this safety.
The plasma level of free sufentanil increased postoperatively, with concentrations within the range of the minimal effective concentrations of 0.01–0.56 ng/mL (median 0.024 ng/mL) (18). After termination of the epidural infusion, plasma levels decreased very slowly, which is in accordance with reports by Hansdottir et al. (19). These authors agree that IV analgesia may contribute to pain relief after epidural infusion. They emphasize, however, that the efficacy of epidural sufentanil is more likely to be related to its interaction with spinal opioid receptors. Near the site of the epidural administration, a significant proportion of the sufentanil can be demonstrated within the cerebrospinal fluid. The concentration is on average about 4 times that in plasma (19). Via the epidural route, less sufentanil or less supplementary morphine is necessary to achieve the same quality of analgesia as with an IV infusion. Side effects, such as sedation or respiratory depression, were more often observed with IV administration (20,21). Overall, pain relief achieved by sufentanil may be a combined action of spinal and supraspinal opioid receptors.
Plasma levels of sufentanil reached a steady state at concentrations of 0.06–0.12 ng/mL after 48–72 hours. Postoperative ventilation is often necessary when the plasma level reaches 0.64 ng/mL, a concentration which was not observed in the patients in our study at any dose administered. Correspondingly, none of the patients had clinical signs of respiratory depression. There was, however, a correlation between pruritus and sufentanil dosage. Patients should, therefore, receive the minimal dose required for good analgesia.
In view of these results regarding pain relief, we advocate that patients should receive a combination of ropivacaine 0.2% wt/vol and sufentanil 0.75 µg/mL. This combination appears to provide the best analgesia with the fewest side effects of the four combinations tested. Nevertheless, it is necessary to monitor vital functions over a period corresponding to the slope of the plasma sufentanil concentration until a steady state is reached and during the delayed elimination period after the infusion is terminated.
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Acknowledgments |
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