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A Randomized, Double-Blinded Comparison of Thoracic Epidural Ropivacaine, Ropivacaine/Fentanyl, or Bupivacaine/Fentanyl for Postthoracotomy Analgesia

Macias, Antonio, MD*,; Monedero, Pablo, MD, PhD*,; Adame, María, MD, PhD*,; Torre, Wenceslao, MD, PhD†,; Fidalgo, Isabel, MD*,; Hidalgo, Francisco, MD, PhD*

doi: 10.1097/00000539-200211000-00046
TECHNOLOGY, COMPUTING, AND SIMULATION: Research Report
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Epidural ropivacaine has not been compared with bupivacaine for postthoracotomy analgesia. Eighty patients undergoing elective lung surgery were randomized in a double-blinded manner to receive one of three solutions for high thoracic epidural analgesia. A continuous epidural infusion of 0.1 mL · kg−1 · h−1 of either 0.2% ropivacaine, 0.15% ropivacaine/fentanyl 5 μg/mL, or 0.1% bupivacaine/fentanyl 5 μg/mL was started at admission to the intensive care unit. We assessed pain scores (rest and spirometry), IV morphine consumption, spirometry, hand grip strength, Paco2, heart rate, blood pressure, respiratory rate, and side effects (sedation, nausea, vomiting, and pruritus) for 48 h. Thoracic epidural ropivacaine/fentanyl provided adequate pain relief similar to bupivacaine/fentanyl during the first 2 postoperative days after posterolateral thoracotomy. The use of plain 0.2% ropivacaine was associated with worse pain control during spirometry, larger consumption of IV morphine, and increased incidence of postoperative nausea and vomiting. Morphine requirements were larger in the ropivacaine group, with no differences between bupivacaine/fentanyl and ropivacaine/fentanyl groups. Patients in the ropivacaine group experienced more pain and performed worse in spirometry than patients who received epidural fentanyl. There was no significant difference in motor block. We conclude that epidural ropivacaine/fentanyl offers no clinical advantage compared with bupivacaine/fentanyl for postthoracotomy analgesia.

*Department of Anesthesia and Critical Care and †Thoracic Surgery Service, Clinica Universitaria, University of Navarra, Spain

June 17, 2002.

Address correspondence and reprint requests to Pablo Monedero, MD, PhD, Department of Anesthesia and Critical Care, Clinica Universitaria, Pio XII, 36.31008 Pamplona, Spain. Address e-mail to pmonedero@unav.es.

Posterolateral thoracotomies are among the most painful procedures. A variety of analgesic techniques are used for postthoracotomy pain control (1). Continuous thoracic epidural analgesia is widely used and has proved to be superior to IV patient-controlled analgesia (PCA) with a highly potent opioid in respect to overall pain relief and the incidence of sedation and nausea (2). In addition, a meta-analysis (3) confirmed that clinical measures of pulmonary outcome after abdominal surgery are significantly improved by epidural local anesthetic treatment. Ropivacaine is a well tolerated local anesthetic with an efficacy broadly similar to that of bupivacaine (4). It may be a preferred option because of its reduced central nervous system and cardiotoxic potential (5). Furthermore, its decreased propensity for motor block, useful for rapid patient mobilization in the postoperative period (6), could be potentially useful for improvement of respiratory therapy. However, ropivacaine has not been compared with bupivacaine for postthoracotomy analgesia. Therefore, we performed this prospective, randomized, double-blinded study to compare thoracic epidural ropivacaine, with and without fentanyl, versus bupivacaine with fentanyl during the first 48 h after thoracotomy for analgesia, side effects, and some motor function tests.

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Methods

After obtaining institutional human investigation committee approval and informed written consent, we randomized 80 patients undergoing elective lung surgery via a posterolateral midthoracic incision without costectomy to three different solutions (ropivacaine, ropivacaine/fentanyl, or bupivacaine/fentanyl) for postoperative continuous epidural analgesia. Patients were recruited during the period January 1999 to January 2001. Exclusion criteria were ASA physical status more than III, age younger than 18 yr or older than 80 yr, body mass index more than 30 kg/m2, allergy to local anesthetics or opioids, current opioid use, active infectious process, neurological disorders, abnormal coagulation tests, renal or hepatic failure, lack of cooperation, or inability to comprehend or perform verbal and physical assessments.

On the day before surgery, patients received instructions on how to use a PCA device, perform a simple spirometry with a portable monitor device (Ohmeda 5410 Volume Monitor™, Datex-Ohmeda, Helsinki, Finland) through a mouth-piece, squeeze a hand grip strength dynamometer, and measure pain with a visual analog scale (VAS) that consisted of an unmarked 100-mm line, with 0 mm representing no pain and 100 mm representing the worst pain imaginable. Basal spirometry, including forced vital capacity, peak expiratory flow rate (PEFR), and forced expiratory volume in 1 s, and grip strength were recorded. Grip strength was tested with a standard JAMAR hydraulic hand dynamometer, according to Mathiowetz recommendations (7). The best score of three successive trials was recorded for each hand. The same test instrument was used for pre- and posttesting. Patients were premedicated the night before surgery with bromazepam 100 μg/kg (maximal dose, 6 mg) and, when they arrived to the holding area, with IV midazolam (2 mg) and atropine (10 μg/kg) during a rapid IV infusion of 500 mL of 4% modified gelatin solution (Gelafundin, B. Braun, Melsungen, Germany). All patients underwent a standardized combined epidural-general anesthetic. An epidural catheter was placed 5 cm into the epidural space at the T3-4 vertebral interspace in the sitting position. An epidural test dose of 3 mL of lidocaine 2% with 1:200,000 epinephrine was injected through the catheter. After a negative response to the test dose was confirmed, general anesthesia was induced with 0.25 mg/kg of etomidate, 0.5 mg/kg of atracurium, and 2 μg/kg of fentanyl. General anesthesia was maintained with isoflurane, nitrous oxide, and oxygen (up to a minimum alveolar anesthetic concentration of 1.2). A left-sided double-lumen tube for one-lung ventilation, a subclavian catheter for central venous pressure monitoring, a radial artery catheter for invasive blood pressure monitoring and blood gas analysis, and an indwelling bladder catheter to avoid urinary retention were inserted. The correct position of the endobronchial tube was confirmed by fiberoptic bronchoscopy after the patient was in the lateral decubitus position. An epidural bolus dose of 0.1 mL/kg of 0.175% bupivacaine/fentanyl 15 μg/mL was administered during surgical preparation and drape, followed by a continuous infusion of 0.1 mL · kg−1 · h−1 of 0.125% bupivacaine/fentanyl 10 μg/mL until admission to the intensive care unit (ICU). Hypotension (blood pressure <20% from baseline measurement) was treated with incremental doses of IV ephedrine (5 mg). Further muscle relaxation with atracurium was administered at the discretion of the anesthesia team. Whenever the blood pressure or heart rate increased by more than 20%, depth of anesthesia was judged inadequate, and hemodynamic control was ensured with incremental doses of IV fentanyl (100 μg). The same surgeon performed all the operations. Isoflurane administration was stopped at the beginning of parietal closure. Patients were awakened and their tracheas were extubated at the conclusion of surgery if they met standard extubation criteria. The patients were transferred to the ICU for close monitoring over the next 48 h.

At skin closure, patients were assigned (by a computer generated randomization) in a double-blinded manner to receive 1 of 3 solutions for postoperative epidural analgesia prepared by our pharmacy: 0.2% ropivacaine (Group R), 0.15% ropivacaine/fentanyl 5 μg/mL (Group RF), or 0.1% bupivacaine/fentanyl 5 μg/mL (Group BF). A continuous epidural infusion of 0.1 mL · kg−1 · h−1 was started at admission in the ICU. All patients received pro-paracetamol 2 g IV every 6 h and ondansetron 4 mg IV every 4 h if nausea or vomiting were present. Patients were asked to score pain at admission to the ICU, and titration with IV morphine administered by a nurse was performed when the VAS was more than 40 mm at rest. IV PCA was then started with a PCA device programmed to deliver morphine in bolus doses of 2 mg, with a lockout duration of 8 min and an unrestricted total dose.

Data were collected by a blinded observer 2, 6, 12, 24, 36, and 48 h after patients arrived in the ICU. Data collection included the total amount of morphine (nurse and PCA consumption), VAS scores for pain at rest and during PEFR measurement with the patient semireclined, spirometry (forced vital capacity, PEFR, and forced expiratory volume in 1 s), heart rate, blood pressure, respiratory rate, and side effects, such as postoperative nausea and vomiting (PONV), pruritus, and sedation scores judged by the observer (1 = wide awake, 2 = drowsy or dozing intermittently, 3 = mostly sleeping but easily awakened, 4 = asleep and difficulty responding to verbal commands, and 5 = awakened only by shaking). The presence of bilateral sensory loss to cold (ice) was confirmed in all patients in the early postoperative period, although no formal assessment of this was made. Motor strength in both hands was assessed by hand dynamometry 24 h after ICU admission. Arterial blood samples were taken for Paco2 measurement at 2 and 12 h after ICU admission. In the fourth postoperative day, anxious and/or depressive personality was assessed by a well known scoring scale (Hamilton rating scale for anxiety and Hamilton rating scale for depression).

The primary end point of this study was the total amount of morphine received by the patient (nurse plus PCA consumption). A power analysis with a pilot study indicated that a sample size of 25 patients per group would allow us to detect a 20% difference in morphine consumption (P = 0.05; power = 0.8). All continuous data are presented as mean and sd. The assumption of normality was checked using the Kolmogorov-Smirnov test before applying repeated-measures analysis of variance to analyze morphine consumption, VAS scores for pain, heart rate, blood pressure, respiratory variables, and motor strength differences between groups. Categorical data were examined by Fisher’s exact test. All reported P values are two-tailed, and P < 0.05 was considered significant. Statistical analysis was performed by using SPSS 7.0 for Windows software package (SPSS Inc, Chicago, IL).

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Results

Ninety-two patients were initially enrolled, and eight patients were excluded because of protocol violations (lost data and nurse changes in protocol) and one because of re-operation for postoperative bleeding. An epidural catheter could not be placed in three patients for technical reasons, therefore they were converted to intrathecal morphine (8) and excluded from the study. Thus, eighty patients were studied. Patient characteristics and operative data were comparable among the groups, including personality assessment (Table 1). Surgery was uneventful in all cases, even though half of them (40 of 80) required intraoperative ephedrine for hypotension after an epidural bolus of the anesthetic. The trachea could not be extubated in four patients (Group BF, 2; Group R, 1; and Group RF, 1) at the end of the procedure but was extubated 30 to 60 min after arrival in the ICU. These patients were retained in the study. Forty-eight patients (Group BF, 14; Group R, 19; and Group RF, 15) required initial titration with IV morphine for pain on arrival in the ICU.

Table 1

Table 1

Morphine requirements were larger in Group R (Fig. 1), with no differences between Groups BF and RF. VAS pain scores at rest (Fig. 2) were equivalent among the groups, but patients in Group R experienced more pain during PEFR measurement at 2 and 12 h after ICU admission (Fig. 3). Respiratory variables showed no differences in respiratory rate among groups but slightly worse performance in spirometry in Group R (Table 2).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Table 2

Table 2

Hemodynamic variables were equivalent among the groups. Only three patients (Group BF, 2 and Group R, 1) required ephedrine in the postoperative period for hypotension. There was no significant difference in motor block, assessed by grip strength, 24 h after ICU admission (Table 3).

Table 3

Table 3

With regard to side effects, the incidence of pruritus was equivalent among the groups, but PONV was more frequent in Group R (Table 3). The degree of sedation in the three groups was similar over the 48-h study period. There were no severely sedated patients in any group (no patient was mostly sleeping), and no case of respiratory depression was observed (Table 3).

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Discussion

We present the first comparative study of epidural ropivacaine versus bupivacaine for postoperative analgesia after thoracotomy. Our study showed that a continuous epidural infusion of ropivacaine/fentanyl provided similar analgesia to bupivacaine/fentanyl during the first two postoperative days after posterolateral thoracotomy. Total IV morphine requirements were similar with adequate pain relief at rest and on deep breathing. The use of epidural plain ropivacaine, despite IV PCA with morphine to obtain similar VAS pain score at rest, was associated with worse pain control on movement (during PEFR measurement), larger consumption of IV morphine, and increased incidence of PONV. Ropivacaine was compared with bupivacaine/fentanyl, our usual practice solution that has been widely used for postthoracotomy pain control (1). Our expectations of less motor block with improvement in pulmonary mechanics with the use of ropivacaine were not fulfilled; therefore, the only reason to replace bupivacaine would be the better toxicity profile of ropivacaine (less cardiac and central nervous system toxicity) (4,5). A cost/benefit study is warranted because ropivacaine is more expensive than bupivacaine, and the potential improvement in toxicity with ropivacaine may not be clinically significant, even with an inadvertent intravascular migration of the epidural catheter, considering the small doses of opioid/local anesthetic being used for analgesia.

Comparison between epidural ropivacaine and bupivacaine has been performed for pain control in labor (9–11) and after abdominal (6,12,13) or orthopedic surgery (14), but this is the first study after thoracotomy and with a high thoracic epidural catheter. Results of comparative studies of postoperative epidural analgesia infusions of ropivacaine versus bupivacaine had been conflicting so that the relative potencies and potential advantages of ropivacaine are still unclear. Some studies reported equipotency (6,12), others equal analgesic potency but decreased motor-block with ropivacaine (14), and in the first stage of labor, ropivacaine was less potent than bupivacaine (10,11). In our usual practice, and in accordance with previous experience, we use epidural 0.1% bupivacaine with fentanyl 5 μg/mL, and we wanted to compare it with ropivacaine. The ropivacaine dose was selected according to potency ratio (11) and the recommendations in the literature; 0.2% ropivacaine was the usual dose for postoperative analgesia, and we reduced it further with the addition of fentanyl trying to achieve a theoretical equal analgesic potency. We observed that the addition of fentanyl had a stronger effect than the change of local anesthetic concentration. The benefit and sparing effect of local anesthetic by the use of fentanyl is well known (15). Opioids improve the quality of postoperative epidural analgesia with ropivacaine (4), as we found in our study. To compare the analgesic potency of the solutions, we used a fixed epidural infusion with additional rescue opioid analgesia with IV morphine PCA. Different morphine consumption would indicate different potency.

Another possible approach would be a patient-controlled epidural analgesia (PCEA), where a different volume of local anesthetic-opioid would indicate different potency. The main advantage of PCEA would be the reduction of IV morphine with its side effects. PCEA decreases epidural bupivacaine/fentanyl requirements and improves analgesia and patient satisfaction (16). Furthermore, when a PCEA technique is used for epidural analgesia after lower abdominal surgery, the ropivacaine concentration can be reduced to the range of 0.05% to 0.1% combined with fentanyl (17,18). The use of these more dilute solutions, even 0.05% instead of 0.1%, seems to result in decreased local anesthetic use without compromising analgesia (6). We do not know if the same results can be obtained in high thoracic epidural analgesia after thoracotomy. The limitations of PCEA, compared with IV PCA, are the need for several adjustments in background infusion rates, the risk of hypotension, and the need for rescue treatment because of inadequate analgesia (catheter displacement, unilateral block, and tachyphylaxis) in approximately 10% of patients (18).

Another possible limitation of our study is the use of fixed small-volume/large-concentration opioid/local anesthetic solutions. Our epidural analgesic regimen could be optimized by the use of a large-volume/small-concentration of local anesthetic that has been shown to reduce drug consumption, suggesting that the therapeutic ratio of ropivacaine can be widened with large-volume solutions (18). Administration of large-volume/small-concentration solutions could produce more extensive sensory block and increased spread of a dilute opioid to allow interaction with a larger surface area of opioid receptors (17). Despite large morphine consumption, we observed high average pain scores that may be explained by the lack of nonsteroidal antiinflammatory drugs in our study together with shoulder pain. Ipsilateral shoulder pain after thoracotomy is common and may be severe, even in the presence of a functioning thoracic epidural. Ketorolac (19) or infiltration of the phrenic nerve with local anesthetic (20) can reduce this shoulder pain, potentially allowing the ideal goal of a pain-free thoracotomy.

With regard to motor block, we could not find any significant improvement in spirometry or grip strength with ropivacaine compared with bupivacaine. Ropivacaine may have a theoretical advantage compared with bupivacaine because of its lesser motor block with improved intercostal muscle strength and increased effort-related exhalation (PEFR). Nevertheless, in previous studies, thoracic epidural anesthesia with a single dose of 0.25% bupivacaine did not change inspiratory muscle force and did not adversely affect ventilatory mechanics (21). Weakness in the intercostal muscles is induced by epidural local anesthetic (although overall lung volumes are minimally affected) (22), but the deterioration of pulmonary mechanics in the early postoperative period is thought to be caused mainly by the respiratory effects of severe postoperative pain. So the slightly worse performance in spirometry in Group R may be explained by worse pain control. Better pain control with epidural fentanyl may have contributed to the lack of differences in pulmonary mechanics between Groups BF and RF. Furthermore, nausea and vomiting related to the use of morphine may have had a negative effect on spirometric performance because forceful recruitment of the abdominal musculature may have been voluntarily inhibited. Lack of difference in grip strength can probably be explained by our small-volume epidural solution that was not enough to block the median nerve roots (C6-T1), although we did not measure the spread of sensory block. The presence of bilateral sensory loss to cold (ice) and the very small IV fentanyl requirements during surgery are both indirect confirmation of the correct placement of the epidural catheter.

The increased incidence of PONV in the ropivacaine group could be explained by larger consumption of IV morphine. Our incidence of side effects, mainly PONV, was frequent in all groups, thus prophylactic antiemetics are required. Despite an increased consumption of morphine in the ropivacaine group, we could not observe any difference in the sedation scale among patients.

In summary, a continuous thoracic epidural infusion of 0.1 mL · kg−1 · h−1 of 0.15% ropivacaine/fentanyl 5 μg/mL provides an adequate pain relief and similar analgesia to 0.1% bupivacaine/fentanyl 5 μg/mL during the first two postoperative days after posterolateral thoracotomy. The use of plain 0.2% ropivacaine is associated with worse pain control with movement (during PEFR measurement), larger consumption of IV morphine, and increased incidence of PONV. We conclude that epidural ropivacaine/fentanyl offers no clinical advantage compared with bupivacaine/fentanyl for postthoracotomy analgesia.

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