Post-thoracotomy pain arises as a result of severe chest wall trauma, including extensive muscle cutting and costo-vertebral joint distortion . Many strategies aiming to control post-thoracotomy pain have been described in order to elicit this important co-factor in the occurrence of serious cardio-pulmonary complications . It has been shown that epidural block is the most efficient option as it cuts off afferent nociceptive input and inhibits efferent sympathetic outflow in response to painful stimuli . Local anaesthetics block the volley of nerve impulses in the unmyelinated C fibres and prevent prolonged widespread increase in reflex excitability in the spinal cord dorsal horn . Epidural analgesia after thoracotomy has also been shown to reduce the very high incidence of chronification in this group of patients . Using a local anaesthetic-opioid mixture has been demonstrated to improve the quality of analgesia and to decrease dose requirements of local anaesthetics as compared to local anaesthetics alone [6,7].
For many years, bupivacaine has been the most widely used local anaesthetic for epidural block in patients undergoing major surgery. However, its use has sometimes resulted in fatal cardiovascular and/or central nervous system toxicity . Levobupivacaine, the pure S(-) enantiomer of racemic bupivacaine and ropivacaine, commercially available as a pure S(-) enantiomer solution have been developed for the purpose of reducing the potential toxicity and improving the relative sensory and motor block profiles [9-12]. The potency ratio between bupivacaine, levobupivacaine and ropivacaine is still debated. Recent studies on parturients seem to indicate that levobupivacaine is slightly more potent than ropivacaine , but other investigations have shown equipotency . There are no clinical studies comparing ropivacaine and levobupivacaine in patients undergoing lung surgery. The aim of this prospective, randomized double-blind study was to evaluate the efficacy and safety of two commercially available solutions of ropivacaine (0.2% w/v) and levobupivacaine (0.125% w/v) combined with sufentanil 1 μg mL−1 in patients after thoracotomy for lung surgery. The total amount/hour of sufentanil, which equals approximately 6 μg mL−1 of fentanyl, was chosen according to the findings of other investigations .
The following specific hypothesis was formulated: visual analogue scale at rest (VASr), VASc and patient-controlled analgesia (PCA) morphine consumption will show difference in the two groups of patients.
After obtaining local Ethics Committee approval and written informed consent, 54 consecutive patients, ASA physical status I-III, undergoing elective lateral thoracotomy for lobectomy or pneumonectomy, were enrolled in the study. Patients were included if they were 18-75 yr old, able to read and understand the Italian language and if they had normal mental health. Exclusion criteria were lack of patient's consent, sepsis, inability to understand visual analogue pain and nausea scores or PCA use, coagulopathy, allergy to amide-type local anaesthetics or opioids. All the patients were informed that giving informed consent to participate in the study did not exclude the possibility to withdraw at any time. At the time of preoperative visit, patients were familiarized with a 10-cm VAS device for pain (0 = no pain at all, 10 = worst imaginable pain) and they were instructed on the PCA use. Patients were premedicated with diazepam 8-10 mg given orally 30 min before induction of anaesthesia.
According to a computer-generated sequence of numbers, patients were randomly assigned to either the ropivacaine (R) or levobupivacaine (L) group.
In the operating room, after infusion of 500 mL Ringer solution via an intravenous (i.v.) cannula, a 20-G epidural catheter was inserted through an 18-G Tuohy needle, using the paramedian approach, into the epidural space at the thoracic level (between T-4 and T-8). The epidural catheter was directed cephalad for a distance of 4 cm and fixed to the back of the patient. After a negative aspiration test and a negative test dose of 3 mL of 7.5 mg mL−1 ropivacaine (Group R) or 5 mg mL−1 levobupivacaine (Group L), a further 6 mL of the same respective solutions were injected through the catheter. After 15 min, the sensory block was assessed by pinprick and a continuous epidural infusion was initiated, through an elastomeric pump, of 2 mg mL−1 ropivacaine (Group R) or 1.25 mg mL−1 levobupivacaine (Group L), either with sufentanil 1 μg mL−1, set at 5 mL h−1 and continued for 48 h. The epidural opioid-anaesthetic mixture was prepared by an investigator who was not involved in data recording. In both groups anaesthesia was induced with propofol 2 mg kg−1 and positioning of an endobronchial double-lumen tube was facilitated by using cis-atracurium 0.15 mg kg−1. Maintenance of anaesthesia was provided by using sevoflurane and sufentanil boluses according to clinical necessity. Total consumption of sufentanil (μg) was recorded at the end of surgery.
In the recovery room, PCA was provided using an electronic device with morphine 0.6 mg mL−1, programmed to deliver an i.v. bolus of 1 mL with a lockout interval of 7 min and a 10 mg dose limit over 4 h. This amount of rescue morphine per bolus in the PCA device was chosen according to the hospital standards. PCA was connected about 90 min after extubation. If, prior to administering PCA, the patients requested rescue analgesia, they received 1 mg boluses of morphine every 5 min until they were comfortable. Total amount of morphine the patient received, number of PCA requests and time to rescue (h) were recorded.
Arterial blood pressure (BP), heart rate (HR), respiratory rate and oxygen saturation were registered throughout the study period. Sensory block (to pinprick), motor block and pain at rest (VASr) and while coughing (VASc) were assessed every 4 h within 48 h of awakening time. Nausea or vomiting occurrence was also recorded. Ondansetron 8 mg was administered if vomiting occurred more than twice. Motor blockade in the lower limbs was also assessed according to a modified Bromage scale (0 = no motor block, 1 = inability to raise extended legs, 2 = inability to flex knee and 3 = inability to move lower limb). The investigator and the patient were blinded to the type of epidural solution administered.
The postoperative course of all patients was reported including any adverse events (sedation, pruritus, urinary retention, respiratory depression) and duration of postoperative hospital stay. Hypotension was defined as a 20% decrease of systolic BP (SBP) compared with baseline and an SBP less than 90 mmHg. Bradycardia was defined as a rate less than 50 beats per minute, and bradypnoea as a respiratory rate less than 10 breaths per minute. The quality of pain management was judged by the patient on a four-point scale (1 = very dissatisfied, 2 = dissatisfied, 3 = satisfied and 4 = very satisfied).
Data are presented as mean ± SD, median (interquartiles) or as numbers (categorical variables). The number of patients included in the study was based on an a priori power analysis assuming α = 0.05 and β = 0.20. The sample size calculation was performed considering 4 and 2 as means of dependent variable (being the minimum difference of 50%) for the two groups (σ = 2.5). It was estimated that a sample of 52 patients would be required.
Two different pain indicators were used: VAS (at rest and while coughing) and the number of PCA requests. The following null hypothesis was formulated: there are no differences between the two groups as regard to pain indicators. The analyses were conducted on absolute values and on time-related measurements. Patients' characteristic, details of surgery and postoperative morphine consumption data were compared using the t-test, as appropriate. VASr and VASc values were analysed by comparing the area under the curves (AUC) for both groups using the U-test. The χ2-test was used for categorical data. A value of P < 0.05 was considered as significant.
Statistical analyses were performed using Statistica v. 6.1 software (StatSoft, Tulsa, OK, USA).
Two patients were excluded because of protocol deviation (both had accidental removal of the epidural catheter). A total of 52 patients with completed case report forms were included in the study (26 for each group). The two groups were comparable for age, gender, weight, height, duration of surgery, anaesthesia and hospital stay. All the patients' characteristics and details of surgery are shown in Table 1. There were no complications as a result of epidural catheterization and no symptoms suggestive of systemic toxicity for the administered local anaesthetics.
The control of postoperative pain was adequate in both groups as evidenced by the VASr and VASc values (Figs 1 and 2). These values decreased through the postoperative 48 h. No significant differences (U-test) were found between the two groups regarding AUC curves for both VASr and VASc (Table 2). Postoperative morphine consumption data were comparable as seen from Table 2. Extension of sensory block did not differ in the two groups: the upper level ranged between C8 and T1 and the lower levels between T11 and L1 during the study period. All the patients had a Bromage score of 0.
Intraoperatively, two patients, one from each group, suffered from severe hypotension and were treated with ephedrine and i.v. fluids.
Values of systolic and diastolic arterial pressure and HR were stable in all patients through the 48-h postoperative period. There was no statistically significant difference between the groups with regard to these three variables. A low percentage of patients in both groups showed minor adverse events (nausea, vomiting, pruritus, urinary retention) with no significant differences (see Table 2). Two patients in Group R and one in Group L received ondansetron 8 mg. No sedation, bradypnoea or respiratory depression in any patients was observed. No serious adverse events were recorded. All patients in the two groups were either satisfied or very satisfied regarding the quality of analgesia. Rescue analgesia before starting PCA, represented by manual boluses of morphine, was similar in the two groups. The mean number of PCA requests was not significantly different.
This study demonstrated that the investigated doses of ropivacaine and levobupivacaine in combination with sufentanil 1 μg mL−1 provide equal quality of analgesia in patients undergoing thoracic surgery. This was proved by AUC analysis that revealed VASr and VASc values resemblance for the two groups. Time to request for rescue analgesia and amount of PCA morphine and patients' satisfaction were also similar.
The potency ratio between ropivacaine and levobupivacaine has been the subject of many debates [16-18]. Few clinical studies have compared these new local anaesthetics when administered in continuous epidural infusion. Launo and colleagues reported no differences in the quality of analgesia and the degree of motor block using 0.2% w/v ropivacaine vs. 0.125% w/v levobupivacaine with added fentanyl 2 μg mL−1 for thoracic epidural analgesia after aortic surgery . Different from the study of Launo and colleagues, this study investigated the efficacy of the same anaesthetic doses in patients undergoing pulmonary surgery. Senard and colleagues compared the efficacy, dose requirements, side-effects and motor block observed during infusion of 0.1% w/v levobupivacaine or 0.1% w/v ropivacaine administered by PCEA in combination with continuous infusion of 0.1 mg h−1 morphine after major abdominal surgery . The study showed no differences in quality of pain relief and hourly consumption of the local anaesthetics. No patients from either group had a motor block when assessed on the Bromage scale after the fourth postoperative hour. However, on the second postoperative day, 19 patients in the ropivacaine group (76%) vs. 12 in the levobupivacaine group (48%) were able to ambulate (P < 0.05) . During the past few years, attention has focused on early mobilization and ambulation as part of an acute rehabilitation programme to accelerate postoperative recovery. It is therefore mandatory that the local anaesthetic used postoperatively produces analgesia without motor block . We did not register motor block probably because the catheter was placed at the thoracic level and the infusion rate was low (5 mL h−1) to cause blockade of the lumbar nerve roots.
Evidence from the literature suggest that wide thoracic sympathetic blockade with a high dose of local anaesthetic can cause hypotension in patients during the postoperative period . We did not observe severe hypotension or bradycardia postoperatively in this study. This was probably due to the use of a low local anaesthetic dose, which may reduce the extension of sympathetic blockade, as confirmed by this clinical study. It has been known that the combination of a local anaesthetic and an opioid via the thoracic epidural catheter has the advantage of leading the anaesthetist to use a small dose of each drug with consequent reduction of side-effects . The additive effect of these two different categories of drugs in producing effective analgesia has been recently documented using an isobolographic design .
The lack of brainstem-mediated side-effects such as sedation and respiratory depression in this study was probably due to the supposed segmental effect of sufentanil, which seems to have limited rostral spread within the intrathecal space .
In addition, the doses of each local anaesthetic required to produce adequate postoperative analgesia resulted in a similar incidence of minor adverse effects. The low morphine rescue total amount used by PCA was probably responsible for the reduced percentage of nausea and vomiting that may cause considerable discomfort for patients.
The final patients' judgment about pain management confirmed the achieved adequate analgesia and the low occurrence of discomforting side-effects in both groups.
In conclusion, thoracic epidural infusion of ropivacaine 0.2% w/v or levobupivacaine 0.125% w/v combined with sufentanil 1 μg mL−1 provide similar pain relief at rest and during coughing after thoracotomy and results in a similar incidence of side-effects.
The authors would like to thank Jacqueline Melvin for having revised the language of the manuscript.
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