Patients operated on for esophagectomy experience severe pain due to the thoracic and abdominal surgical wounds. Their ability to cough and take deep breaths is impaired, which may contribute to the high incidence of postoperative pulmonary complications after esophagectomy with a thoracotomy . Interpleural (IP) analgesia has several advantages and offers an alternative to other analgesic methods, such as parenteral narcotics and epidural and intercostal nerve blocks . IP analgesia after esophagectomy has been reported once and found to be efficient . However, there is controversy about its efficacy for pain relief after lung surgery with thoracotomy [4-6], mainly because of loss of bupivacaine by pleural drainage [7,8]. No clinical toxicity of intermittent pleural instillations of bupivacaine has been reported, despite high plasma concentrations considered as potentially toxic levels [9,10]. Potential toxicity may be less with lidocaine than with bupivacaine, but IP analgesia with lidocaine has been evaluated only after rib fractures  and lung surgery through a sternotomy .
The purpose of the present controlled, double-blind study was to investigate the efficacy of IP analgesia with bupivacaine or lidocaine in the management of postoperative pain after esophageal surgery with a right thoracotomy, and to measure the plasma concentrations of bupivacaine and lidocaine after intermittent IP administrations.
After institutional approval and informed consent, 36 patients (aged 59 +/- 10 yr) scheduled for esophagectomy were included in the study. Patients with a history of recent pneumonia or pleuritis, cardiac rhythm disturbances, convulsions, or allergies to local anesthetics were excluded from participation. The patient-controlled analgesia (PCA) system (Abbott Lifecare Registered Trademark 4200; Abbott Laboratories, N. Chicago, IL) and the linear visual analog scales (VAS) were explained to the patients prior to the study. All patients were anesthetized using a standardized technique: premedication with flunitrazepam, induction with thiopental, myorelaxation with a continuous infusion of atracurium, maintenance with 50% nitrous oxide in oxygen, phenoperidine, and isoflurane supplementation as required. After intubation, ventilation was controlled with a ventilator Drager SA set to deliver a tidal volume of 10 mL/kg at a frequency of 15/min. During thoracotomy single-lung ventilation was not used. The esophagectomy was performed using T-5 right thoracotomy and a midline upper abdominal incision. Thoracic drainage was achieved with two chest tubes, one at the apex and the other along the mediastinal pleura. At the end of the surgical procedure before chest closure, the surgeon inserted percutaneously in the seventh intercostal space two IP catheters (Pleurocath Registered Trademark, 8 Fr; Laboratoire pharmaceutique Plastimed, St. Leu-la-Foret, Cedex, France). The two catheters were directed posteriorly under direct vision, toward the third and the ninth intercostal space on the paravertebral line, respectively. The correct position of the catheters was verified by chest radio-graph. The study began in the surgical intensive care unit when the patients were fully awake and warm. Patients were randomly assigned into three groups. Patients in the bupivacaine group (Gr B) received 1 mg/kg of 0.5% bupivacaine with epinephrine 1:200000, saline 0.9% was added until a total volume of 20 mL, patients in the lidocaine group (Gr L) received 3 mg/kg of 2% lidocaine with epinephrine 1:200000 in 20 mL of saline 0.9%, and patients in the placebo group (Gr P) received 20 mL of saline 0.9%. The contents of the syringe, prepared by the pharmacist for the double-blind study, were divided equally to be injected through a bacterial filter in the two IP catheters, every 4 h for 2 days. Patients were kept in a supine position and the chest tubes were clamped for 10 min after each administration. Weaning of ventilation was attempted the morning of the day after the operation and the patient was extubated if the respiratory rate was >or=to 13/min. Duration of operation, mechanical ventilation, intubation, and time of resumption of normal transit (defined as passage of flatus preceded at least 12 h by bowel sounds) and the total dose of phenoperidine used during the peroperative period were recorded.
The degree of postoperative pain was assessed using a VAS scale (0-10 cm; 0 = complete pain relief and 10 = unbearable pain), every 4 h just before the next IP injection. Pain was assessed at rest (VASR), after a deep breath or cough (VASC), at the thoracotomy (VAST), and at the laparotomy (VASL) after a slight compression of the wound. Moreover, patients were allowed to self-administer bolus doses of 1 mg of morphine using the PCA system with a lockout interval of 10 min.
Radial arterial blood samples were taken at 5, 10, 15, 20, 30, 60, 120, and 240 min after the first IP injection and on the second day, just before the seventh injection, 15, 60, and 120 min after the seventh injection. Samples were obtained for all the patients when the blinded study was finished. Six patients in Gr B and six in Gr L were randomly chosen for plasma concentration analysis. After centrifugation, the plasma was separated and kept deep frozen (-30 degrees C) until analysis by gas chromatography according to a method derived from Coyle and Denson . The sensitivity of the method was 10 ng/mL for bupivacaine and less than 5 ng/mL for lidocaine with a coefficient of variation of 12% at 30 ng/mL and 5% at 200 ng/mL.
All results in the tables are expressed as mean +/- SD. Graphic representation of VAS in the figures are median and 95% confidence intervals  based on nonparametric tests . Cumulated morphine consumption in Figure 5 is represented as mean and SEM. Because morphine requirements and VAS pain scores were not normally distributed, differences among the three groups were studied using Kruskall-Wallis H tests for each time. When a critical H value was obtained, comparisons among the three groups were performed using parametric one-way analysis of variance for ranked data followed by a Bonferroni t-test . Age and weight were compared using an unpaired t-test. Fisher's exact test was used for comparison of proportions. A P value less than 0.05 was considered significant.
Six patients were excluded from the study: thre for misunderstanding of the PCA system, one for hemothorax, one for an abnormal quantity of blood at aspiration on the catheters, and one for loss of local anesthetic around the catheter after injection. The three groups were not different with respect to age, sex ratio, weight, duration of the operation, total dose of phenoperidine used during the perioperative period, duration of mechanical ventilation, duration of tracheal intubation, return of intestinal gas, or hospital stay in the intensive care unit Table 1.
There was no significant difference in mean VASR, VASC, and VASL scores among the three groups Figure 1, Figure 2, and Figure 3. Inversely, pain at thoracotomy (VAST) was significantly lower in Gr B at 12, 16, 28, and 32 h when compared with Gr P and Gr L (P < 0.05) Figure 4. There was no statistical difference in mean VAST between Gr L and Gr P.
Daily consumptions of morphine Table 2 were lower in Gr B than in Gr P, but it reached the significant level for Day 2 (P < 0.02) and for Day 1 + 2 (P < 0.02). Daily morphine consumption was higher in Gr L than in Gr B, for Day 1 (P < 0.01), Day 2 (P < 0.05), and Day 1 + 2 (P < 0.01), but was similar in Gr L and Gr P. Cumulated morphine consumption Figure 5 was significantly lower in Gr B than in Gr P from the 32nd (P < 0.05) until the 48th postoperative hour (P < 0.02). From the 20th to the 48th postoperative hour, cumulated morphine consumption was higher in Gr L than in Gr B (P < 0.01). A significant difference (P < 0.05) was found only at the 20th postoperative hour between Gr L and Gr P.
Individual plasma concentration profiles after the first and the seventh IP injection of bupivacaine or lidocaine are presented for six patients in each group in Figure 6 and Figure 7. Mean peak concentrations of lidocaine and bupivacaine after the first IP injection were 0.87 +/- 0.71 micro gram/mL (range, 0.29-2.07) and 0.37 +/- 0.39 micro gram/mL (range, 0.06-1.09), respectively. After the seventh IP injection plasma concentration profiles of the two drugs showed wide individual variation; peak plasma concentration ranged from 1.75 to 5.48 micro gram/mL and 1.49 to 3.91 micro gram/mL for lidocaine and bupivacaine, respectively. No patient had symptoms of local anesthetic toxicity.
The present study indicated that IP analgesia with bupivacaine after esophagectomy reduced morphine requirements in comparison to a placebo. The reduction in morphine consumption was probably due to a decrease in the thoracic pain, but not to a reduction in the abdominal pain. Conversely, IP analgesia with lidocaine was ineffective: morphine requirements and mean VAS scores were similar to those observed in the placebo group. Furthermore, it was confirmed that the inclusion of different assessments of pain may have allowed the discrimination between different postoperative analgesic regimens as has been recently demonstrated by Dahl et al. . Finally, if analgesic techniques that produce VAS values in the range of 0-3 cm represent adequate analgesia , the present results could not be considered as satisfying. It must be emphasized that morphine administration by PCA was not sufficient, even in association with bupivacaine IP analgesia.
In the only study performed after esophagectomy, similar results were reported: IP analgesia decreases pain at the level of the thoracotomy and reduces the additional need for parenteral paracetamol . As in the present study, the abdominal pain was unaltered by IP analgesia. However, this evaluation may be criticized for the methodology. The authors did not use a PCA device for supplemental analgesia and VAS was only recorded 2 h after the interpleural injection, once a day. Surprisingly, analgesia was obtained despite a very low dose of bupivacaine, 10 mL of 0.25% bupivacaine with epinephrine every 8 h.
Pain relief with IP analgesia after cholecystectomy with subcostal incision is highly effective [18,19]. But results after thoracotomy are controversial [4,5,9,10]. Some reasons for these conflicting results include: 1) loss of local anesthetic (LA) through the chest drain; 2) dilution of LA in pleural effusion; 3) binding to blood proteins in case of hematic effusion; and 4) uneven distribution of LA in the pleural cavity. As it has been shown by Ferrante et al.  loss of LA through the chest drain can reach 30% of the injected dose. To prevent this loss, chest drains were clamped for 10 min as recommended [5,10]. But one should be aware of the increased risk of atelectasis in thoracotomy patients when the pleural drainage tubing is clamped, even for a short time . Moreover, several authors have reported phrenic nerve paralysis after interpleural injection that could enhance the risk of atelectasis [20,21]. However, no respiratory complications occurred in our patients during this period. To prevent uneven distribution of LA, the double-catheter technique described by Ferrante et al.  was used. They observed a reduction in total morphine consumption in the double-catheter group when compared with the single-catheter group. Thus, the bottom catheter was directed toward the ninth intercostal space to enhance the quantity of LA near the last thoracic nerves for pain relief at the midline upper abdominal incision. Pain relief was not observed either with bupivacaine or lidocaine in comparison to the placebo. This is in accordance with the study of Tartiere et al. . Despite the right subcostal incision they did not observe any pain relief at the laparotomy. Two main reasons can explain this absence of efficacy: first, in the present study the surgeon used a midline upper abdominal incision; second, the bottom part of the thorax cavity is the place where the pleural effusion is the most important, and this could lead to important dilution of LA and decrease the quantity of LA in contact with the last thoracic nerves. In fact, this could account for the wide variation in the plasma concentration of bupivacaine or lidocaine observed after the seventh interpleural injection.
To improve pain relief, higher doses of bupivacaine can be used, but plasma concentration of bupivacaine can reach central nervous system toxic threshold levels with clinical signs of toxicity . In the present study, standard doses of LA were injected every 4 h without clinical suspicion of toxicity. Lee et al.  have demonstrated that repeated IP injection of bupivacaine (600 mg/day) after 24 h lead to high plasma concentrations in some patients as observed in our patients with approximately 400 to 500 mg/day. However, no study has attempted to measure free-fraction of bupivacaine after IP analgesia. In fact, postoperative alpha 1-acid-glycoprotein increases, leading to an increase in protein binding of local anesthetics and to a reduction of free-fraction, thus diminishing the risk of potential central nervous system toxicity . Moreover, Scott  suggests that the absolute toxic plasma concentration may be more dependent on the rate of increase of the concentration than on any exact concentration of bupivacaine.
The present study showed that IP analgesia with lidocaine is inefficient. There is no published evaluation of IP analgesia with lidocaine after thoracotomy or cholecystectomy. Recently, bilateral IP analgesia has been reported in four patients for pain relief after bilateral lung surgery using a sternotomy, with a constant efficacy during 3 h . In our study, IP injections were made every 4 h and the expected duration of pain relief after lidocaine is approximately 3 h as reported by Kawamata et al. . In fact, this could explain the absence of difference for the VAS with Gr P. Moreover, the presence of two surgical incisions and the wide variation of pleural effusion could account for the total absence of efficacy in pain relief. The last reason might explain the lower peak plasma concentration of lidocaine measured in comparison to the level obtained by Carli et al.  in patients with rib fractures despite a three times lower dose of lidocaine in their study.
Insofar as the "zone of analgesic success," defined earlier , was not obtained, it can be stated that IP analgesia with bupivacaine in association with morphine by PCA was inefficient. This zone of analgesic success is easier to obtain by epidural administration of bupivacaine than by a continuous interpleural infusion of bupivacaine after cholecystectomy . Furthermore, in two comparative studies, pain relief after thoracotomy was significantly better with epidural analgesia provided by bupivacaine  or morphine  than with bupivacaine IP analgesia despite supplemental parenteral morphine. In the latter studies parenteral morphine was equivalent to IP analgesia, and in our study administration of morphine with PCA was also inefficient. The failure of intravenous PCA remains to be confirmed because there is no other evaluation of intravenous PCA for analgesia after esophagectomy.
In conclusion, the present study indicated that IP analgesia with bupivacaine after esophagectomy reduced morphine requirements probably due to a decrease in the thoracic pain, but not to a reduction in the abdominal pain. Bolus regimen IP analgesia with lidocaine was ineffective. Thus, when epidural analgesia is unavailable, IP analgesia with bupivacaine may represent a way to decrease morphine consumption. However, morphine administration by PCA was not sufficient, even in association with bupivacaine IP analgesia. This failure of morphine by PCA in comparison to epidural analgesia needs to be confirmed, since it seems a more appropriate technique of analgesia after esophagectomy with thoracotomy.
The authors wish to thank Dr. K. Boulay, Dr. M. Bourveau, and Dr. P. Michel for their help in the protocol, and Dr. D. Antoniolli, Dr. T. Lechevalier (statisticians), and I. Furic (pharmacist) for their scientific and technical help.
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