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Acta Anaesthesiol Scand 2008; 52: 12851290 Printed in Singapore.

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r 2008 The Authors Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/j.1399-6576.2008.01765.x

Comparison of three doses of epidural fentanyl followed by bupivacaine and fentanyl for labor analgesia
S. M. SIDDIK-SAYYID, S. K. TAHA, M. S. AZAR, M. A. HAKKI, R. A. YAMAN, A. S. BARAKA and M. T. AOUAD
Department of Anesthesiology, American University of Beirut-Medical Center, Beirut, Lebanon

Background: Epidural fentanyl 100 mg after lidocaineepinephrine test dose has been shown to provide adequate analgesia in early labor. This investigation determines the effect of three different bolus doses of epidural fentanyl on duration and quality of analgesia during early rst stage of labor. Methods: In this prospective, double-blind study, 103 laboring nulliparous at cervical dilation o5 cm were enrolled. After an epidural test dose of lidocaine (60 mg) with epinephrine (15 mg), parturients received, randomly, bolus of epidural fentanyl 50, 75, or 100 mg, followed by a continuous infusion of epidural bupivacaine 0.0625% and fentanyl 3 mg/ml at a rate of 10 ml/h. Pain scores and maternal sedation, pruritus, nausea, and vomiting were recorded 10, 20, and 30 min after fentanyl, and every 30 min thereafter until rst request for additional analgesia. Results: Adequate analgesia was achieved in 87% (28/32), 94% (35/38), and 94% (31/33) in the fentanyl 50, 75, and 100 mg groups within 20 min. Mean duration of analgesia before re-dosing was signicantly longer in fentanyl 100

and 75 mg groups (185.6 82.9 and 188.5 82.2 min, respectively) as compared with fentanyl 50 mg group (133.6 46.2 min, Po0.016). There was no difference in the incidence of maternal side effects or neonatal Apgar scores among the three groups. Conclusion: After a test dose of lidocaineepinephrine, the three epidural fentanyl doses produced similar effective labor analgesia. However, epidural fentanyl 75 mg followed by epidural infusion of dilute bupivacaine and fentanyl produced longer duration of analgesia than fentanyl 50 mg followed by the same infusion, with no further prolongation when the dose of fentanyl was increased up to 100 mg.
Accepted for publication 7 July 2008 r 2008 The Authors Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation

REVIOUS studies have shown that epidural fentanyl with dilute or even no local anesthetics often provide satisfactory analgesia in early labor with minimal motor block.13 When epidural fentanyl was given as the sole analgesic without local anesthetic, large doses ranging between 125 and 200 mg have been reported to provide satisfactory labor analgesia.2,4 The incidence of side effects of epidural opioid such as pruritus, sedation, nausea, and vomiting is dose dependent.5 Also, decreased neonatal neurobehavior scores at 24 h and more difculty in breastfeeding at 6 weeks post-partum have been reported when cumulative doses of epidural fentanyl higher than 150 mg have been given to the mother throughout the duration of labor.6 Connelly et al.7 have shown that an epidural bolus of 100 mg of fentanyl administered after a test dose of lidocaine and epinephrine, and followed by a continuous infusion of dilute epidural bupiva-

caine and fentanyl provides approximately 3 h of adequate analgesia in early labor without a signicant motor block. However, no previous study has compared in parturients the duration and quality of analgesia as well as maternal and fetal side effects of lower bolus doses of epidural fentanyl using the same technique recommended by Connelly et al. We hypothesized that it may be possible to reduce the initial dose of fentanyl using the same technique recommended by Connelly et al. without jeopardizing the quality and duration of analgesia. This study compared in nulliparous patients during the rst stage of labor the duration and quality of analgesia when one of the three bolus doses of epidural fentanyl (50, 75, or 100 mg) was administered after a test dose of lidocaine and epinephrine, and followed by a continuous infusion of dilute epidural bupivacaine and fentanyl.

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Methods
After institutional review board approval, written informed consent was obtained from 103 ASA physical status I or II nulliparous parturients in labor at more than 36 weeks of gestation and requesting epidural analgesia for pain relief. The study was conducted in the maternity unit between August 2005 and June 2006. A reassuring fetal heart rate pattern was required for inclusion in the study. All fetuses were in vertex presentation. Women with cervical dilation 45 cm, severe medical or obstetric complications, multiple gestation, contraindication to epidural analgesia, local anesthetics or fentanyl allergy, and history of chronic opioid use or recent acute opioid use were excluded from the study. Patients were assigned using a computer-generated table of random numbers to one of three groups: group 50, group 75, or group 100. The results of the randomization were concealed in opaque envelopes and opened sequentially immediately before placement of the epidural. The patients baseline vital signs (blood pressure, heart rate, and respiratory rate) were documented between contractions, and each patient completed during contractions a baseline assessment with a 10-cm visual analog scale (VAS) score for pain with 0 representing no pain and 10 being the worst pain imaginable. Patients were asked about the presence of pruritus or nausea and/or vomiting before epidural placement. All parturients received oxytocin infusion for labor augmentation. Each parturient received 5001000 ml lactated Ringers solution IV before placing the epidural catheter. With the parturients in a sitting position, the epidural space was located by the loss of resistance technique with minimal amount of saline, using a 16-G Tuohy needle at the L23 or L34 interspace. A 20-G multiorice epidural catheter was threaded 34 cm within the epidural space, and was taped securely. Epidural was performed by an anesthesia attending or a fourth-year resident under the attendings supervision. All patients received via the epidural catheter a test dose of 3 ml of 2% lidocaine and epinephrine 15 mg. Three minutes later, patients who did not experience symptoms suggestive of intravenous or intrathecal injection following the test dose, received one of the three bolus doses of fentanyl diluted to a total volume of 10 ml with preservative-free normal saline: fentanyl 50 mg in group 50, 75 mg in group 75, or 100 mg in group 100. Once pain relief was achieved, patients in the three

groups received an infusion of 0.0625% bupivacaine with fentanyl 3 mg/ml at a rate of 10 ml/h. Pain relief was dened as VAS pain score o3 cm. During labor, the patients were maintained supine with left uterine displacement, and, as usual in our institution, were allowed to move in bed but did not ambulate. Data collection was undertaken by the anesthesiologist. Both the patient and the anesthesiologist assessing the patients were unaware of the group assignment. VAS pain scores as well as the incidence and severity of maternal side effects such as pruritus, sedation, nausea, and vomiting were recorded 10, 20, and 30 min after the administration of fentanyl, and every 30 min thereafter until the rst request for additional analgesia. At the time of each assessment, vital signs and Bromage motor scale score8 were evaluated. Motor block was dened as none, partial (just able to move the knees), almost complete (able to move the feet only), or complete (unable to move the lower extremities). Pruritus was rated as 0 5 none, 1 5 minimal (present with minimal symptoms), 2 5 moderate (bothersome but not requiring treatment), or 3 5 severe (requiring therapy). Sedation was categorized as 1 5 none (awake), 2 5 mild (drowsy), 3 5 moderate (sleepy), or 4 5 severe (unarousable). For clinical signicance, patients were considered sedated only in the presence of moderate or severe sedation. Nausea was evaluated as 0 5 absent, 1 5 mild nausea, 2 5 severe nausea and/or vomiting. Respiratory depression was dened as respiratory rate o10/ min. The fetal heart rate pattern was evaluated at each interval, and any changes were documented. The time at which each patient requested additional analgesia was recorded and a cervical examination was performed. The additional analgesia consisted of 10 ml of 0.125% bupivacaine. The duration of analgesia, dened as the time from the initial dose of fentanyl until the rst request for additional analgesia, duration of labor, dened as the time from the initial dose of fentanyl until delivery, and incidence of cesarean delivery were determined. Neonatal Apgar scores were determined by the pediatrician or the obstetrician. Continuous data are reported as means standard deviation (SD) and are analyzed using analysis of variance. LSD test was applied for post hoc analysis. Categorical data are reported as numbers and percentages and are analyzed using w2 or Fishers exact test as appropriate. Nonparametric data are reported as medians and ranges and are analyzed using MannWhitney U-test. A Kaplan

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Meier plot of the patients remaining comfortable over time was generated. Statistical signicance was determined at a P value o0.05. The primary outcome variable was the duration of analgesia. Before this study was initiated, a power analysis was performed. With an SD of 40 min,6 a 40-min difference in the mean duration of analgesia among the groups was considered clinically signicant. A calculation based on a rate of 0.05 and a power of 80% yielded a required sample size of 23 patients per group. Because we expected approximately a 20% dropout rate because of inadequate analgesia within 20 min after the initial study dose of fentanyl, vaginal delivery, or cesarean delivery before the request for additional analgesia, we increased our sample size by 50%.

Results
One hundred and three patients (32 patients in group 50, 38 patients in group 75, and 33 patients in group 100) were enrolled in the study. There was no difference in demographic variables or cervical dilation at the time of enrollment among the three groups (Table 1). Nine patients were excluded from further analysis because of inadequate pain relief within 20 min of administration of the epidural dose of fentanyl (four patients in group 50, three patients in group 75, and two patients in group 100). These patients became comfortable after the administration of a bolus of epidural local anesthetic. The remaining 94 patients [(28/32) 87%, (35/ 38) 94%, and (31/33) 94% in group 50, group 75, and group 100, respectively] obtained adequate pain relief (VASo3) and were analyzed. Baseline VAS pain scores were similar in the three groups. At 10 min, the median VAS scores were reduced by 82% in group 50, 81% in group 75, and 79% in group 100 (P40.05). At 20 min, VAS scores were decreased by 91% in group 50, 93% in group 75, and 94% in group 100 (P40.05). Also,

there was no signicant difference in pain scores among the three groups at any of the time points (Fig. 1). Figure 2 shows the percent of parturients in each group with continuing analgesia as a function of time. Eighteen patients out of the remaining 94 patients had vaginal delivery or cesarean delivery before the request for additional analgesia. These patients were excluded from analysis of duration of analgesia and cervical dilation at the time of re-dose, but were included in other endpoints analysis. The mean duration of analgesia was signicantly longer in group 100 and group 75 as compared with group 50 (P 5 0.009 between groups 50 and 75; P 5 0.016 between groups 50 and 100; P 5 0.015 among the three groups). No signicant difference was noted between group 100 and group 75 (Table 2). Cervical dilation at the time of re-dose was not signicantly different among the three groups. The total incidence of cesarean delivery (including those who had cesarean delivery before the need for a redose) was 21% with no signicant difference among the three groups. Also, duration of labor was not signicantly different among the three groups (Table 2). Duration of labor in parturients who delivered vaginally before the need for a re-dose ranged between 110 and 300 min. None of the patients had pruritus, or nausea and/or vomiting before epidural placement. There was no signicant difference in the incidence and severity of pruritus, sedation, or nausea and/or vomiting among the three groups. Moderate sedation occurred only in two patients of the 100 mg group during the rst 30 min after the bolus injection of the epidural fentanyl (Table 3). No respiratory rate o10 was recorded in any patient. During the study period, motor block as reected by the Bromage score was absent in all patients. The Apgar scores were similar among the three groups. At 1 min after birth, three neonates in each group had Apgar scores o7, and at 5 min, all neonates scored more than 7.

Table 1
Patient characteristics. Group 50 (n 5 32) Age (year) Height (cm) Weight (kg) Cervical dilation before epidural analgesia (cm) 27.1 3.7 161.6 5.5 72.7 9.3 4 (34) Group 75 (n 5 38) 28.5 5.1 160.6 6.2 75.9 11.4 3 (25) Group 100 (n 5 33) 27 4.7 161.8 4.6 73.9 9.8 3 (25)

Group 50, fentanyl 50 mg; group 75,fentanyl 75 mg; group 100, fentanyl 100 mg. Data are presented as means (SD) and medians (range). No statistical signicance was found among the three groups.

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10 Visual Analog Pain Score 8 6 4 2 0 0 10 20 30 60 90 120 150 180 210

Time (min)

Fig. 1. Visual analog scale pain scores for the three groups at time intervals up to 2.5 h. The boxes represent the 2575th percentiles, and the solid lines represent the medians. The extended bars represent the 1090th percentiles. Pain scores were not obtained after the administration of additional analgesia. There were no signicant differences among the groups at any time period. Group 50, fentanyl 50 mg; group 75, fentanyl 75 mg; group 100, fentanyl 100 mg.

Percent Not Requiring Additional Analgesic

100

group 50 75 100

80

60

40

20

0 0 100 200 300 400 Analgesic Duration in Minutes 500

Fig. 2. KaplanMeier plot of the percentage of patients in each group who continued to remain comfortable. Group 50, fentanyl 50 mg; group 75, fentanyl 75 mg; group 100, fentanyl 100 mg.

Discussion
Our principal nding is that effective analgesia was achieved in a similar proportion of patients after the three bolus doses of epidural fentanyl. However, the duration of analgesia in these patients after fentanyl 100 and 75 mg and lidocaine followed by the dilute epidural bupivacaine and fentanyl infusion was signicantly longer than that achieved after fentanyl 50 mg followed by the same infusion. Adequate analgesia during labor has been achieved with epidural fentanyl alone without a

test dose.2,4 In a previous study, Capogna et al.4 have shown that the minimum analgesic dose of fentanyl used as the sole analgesic for epidural analgesia during the rst stage of labor was 124.2 mg. However, the present study showed that satisfactory analgesia followed boluses of epidural fentanyl 50, 75, and 100 mg when combined with a lidocaine test dose without any signicant difference in pain reduction at 10 and 20 min among the three groups. The local anesthetic test dose may have contributed to the analgesic effect of fentanyl. Because opioids and local anesthetics interact synergistically,9 lower doses of fentanyl are required to produce analgesia when combined with epidural lidocaine than when administered alone. Although the duration of analgesia after the fentanyl bolus followed by the infusion increased by increasing the dose of fentanyl from 50 to 75 mg, there was no further prolongation when the dose was increased up to 100 mg, suggesting that when the epidural fentanyl is followed by an infusion of dilute bupivacaine and fentanyl, the duration of analgesia reaches a ceiling with a fentanyl dose of 75 mg. Previously, Halonen et al. conducted a study with a similar purpose, and compared two bolus doses of epidural fentanyl given during the induction of anesthesia with 0.5% bupivacaine for cesarean delivery. They found that the addition of 50 mg of fentanyl increases patient comfort and improves the quality of epidural anesthesia for cesarean delivery, and that adding 100 mg does not give further advantage.10 Also, Wong et al. have demonstrated a similar ceiling effect with intrathecal fentanyl when combined spinalepidural (CSE) analgesia was used in parturients with induced labor. They showed that increasing doses of intrathecal fentanyl (515 mg) were associated with increasing duration of analgesia, but further prolongation of duration was not seen with greater doses (2025 mg).11 Many anesthesiologists recommend starting epidural infusion after initiation of epidural or CSE analgesia in an attempt to prolong the duration of action of the initial dose.7,12 In our patients, the epidural infusion of 0.0625% bupivacaine with fentanyl 3 mg/ml was initiated in the three groups once pain relief was achieved following the epidural bolus of fentanyl. The mean analgesic durations following epidural fentanyl 100 and 75 mg (185 and 188 min, respectively) compare similarly with the analgesic duration previously reported by Connelly et al.7using epidural fentanyl 100 mg, followed by an epidural infusion similar to that used in our study (198 min). However, these results may not apply if

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Table 2
Obstetric data. Group 50 (n 5 28) Duration of labor (min) Vaginal delivery before need for re-dose (n) Cesarean delivery before need for re-dose (n) Total incidence of cesarean delivery (n) Instrumental delivery (n) Duration of analgesia (min)*,w Cervical dilation at re-dose (cm)w 280.2 131.8 2 2 5 2 133.6 46.2 8 (310) Group 75 (n 5 35) 301.1 131.7 2 5 9 0 188.5 82.2** 9 (210) Group 100 (n 5 31) 343.1 199 4 3 8 1 185.6 82.9*** 6 (210)

Group 50 5 fentanyl 50 mg, group 75 5 fentanyl 75 mg, group 100 5 fentanyl 100 mg. Data are presented as means (SD), medians (range), or numbers. No statistical signicance was found among the three3 groups unless otherwise specied. *P 5 0.015 among the three3 groups. **P 5 0.009 between group 50 and group 75. ***P 5 0.016 between group 50 and group 100. w Eighteen patients were excluded from analysis of duration of analgesia and cervical dilation at re-dose because of vaginal delivery or cesarean delivery before the need for a re-dose (number of patients analyzed: n 5 24 in group 50, n 5 28 in group 75, and n 5 24 in group 100).

Table 3
Maternal side effects. Group 50 (n 5 28) Incidence of pruritus Mild Moderate Severe Incidence of sedation Moderate Severe Incidence of nausea and/or vomiting Mild nausea Severe nausea and/or vomiting 11 (39.3) 9 2 0 0 (0) 0 0 3 (10.7) 3 0 Group 75 (n 5 35) 15 (42.9) 11 3 0 0 (0) 0 0 4 (11.4) 2 2 Group 100 (n 5 31) 18 (58) 12 3 3 2 (6.5) 2 0 2 (6.5) 2 0

Group 50, fentanyl 50 mg; group 75, fentanyl 75 mg; group 100, fentanyl 100 mg. Values are numbers (percentages). No statistical signicance was found among the three groups.

no epidural infusion was initiated immediately after epidural fentanyl injection. Connelly and colleagues7,13,14 have shown that epidural fentanyl 100 mg without an epidural infusion provides 124 145 min of labor analgesia, similar to the duration we observed with epidural fentanyl 50 mg (133 min). Epidural administration of an opioid is effective in the treatment of early labor pain, but the dose needed to maintain analgesia is accompanied by signicant side effects (e.g. pruritus, nausea, perhaps neonatal depression). In addition, epidural administration of an opioid alone provides inadequate analgesia during the advanced phase of the rst stage of labor as well as during the second stage.15 By combining an opioid with a low concentrated solution of local anesthetic, adequate analgesia can be provided throughout labor with minimal motor block, nausea, and pruritus, and with no neonatal depression.16 In our study, eight parturients delivered vaginally without any request for additional analgesia, suggesting that fentanyl

followed by dilute concentration of bupivacaine and fentanyl would be satisfactory in parturients with more advanced labor.1 Pruritus is the most common side effect of the epidural opioids5; the symptoms are usually mild and well tolerated by the patient, and treatment is rarely required.13 We specically asked about the presence of pruritus, which may explain the high incidence in our report. Whenever sedation occurs following intrathecal or epidural opioids, respiratory depression must be suspected. Only moderate sedation was noted in two out of 31 patients in the 100 mg fentanyl group, with no effect on the respiratory rate of the parturients. No difference in the neonatal Apgar scores was detected at 1 and 5 min after birth among the three groups. In our study, we did not attempt to have the parturients walk as per our hospital protocol. The degree of motor block was only assessed by the Bromage score, which did not show motor impair-

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ment. However, the validity of the Bromage score as a test for ambulation was questioned, because it might not correlate with the ability to perform other motor tests such as standing up, bending the knees, and walking. In a previous report, Roelants et al.17showed that the parturients ability to ambulate was reduced in spite of the absence of motor block as assessed by Bromage score. One limitation of our study is that 26% of the patients were excluded from analysis of duration of analgesia because of dropout before the studys primary endpoint was observed. Using this methodology, the measurement of the duration of analgesia achieved by the three different doses of epidural fentanyl used was possible. The validity of the primary outcome, which is the duration of analgesia, was ascertained, because our a priori power analysis (n 5 23 patients in each group) was met. The higher number of dropout due to vaginal and cesarean delivery before the request for additional analgesia in the present report as compared with the Connelly report may be partly explained by the fact that all our parturients received oxytocin infusion, as opposed to only 14 out of 25 parturients in the Connelly study.7 In conclusion, this study showed in nulliparous parturients during the rst stage of labor that the three doses of epidural fentanyl after a test dose of lidocaine and epinephrine provide comparable effective analgesia. However, epidural fentanyl 75 mg followed by an infusion of epidural bupivacaine 0.0625% and fentanyl 3 mg/ml produced longer duration of analgesia than fentanyl 50 mg followed by the same infusion. Increasing the dose to 100 mg does not give any further advantage.

References
1. Breen TW, Shapiro T, Glass B, Foster-Payne D, Oriol NE. Epidural anesthesia for labor in an ambulatory patient. Anesth Analg 1993; 77: 91924. 2. Carrie LES, OSullivan GM, Seegobin R. Epidural fentanyl in labour. Anaesthesia 1981; 36: 9659. 3. Justins DM, Francis D, Houlton PG, Reynolds F. A controlled trial of extradural fentanyl in labour. Br J Anaesth 1982; 54: 40914. 4. Capogna G, Camorcia M, Columb MO. Minimum analgesic doses of fentanyl and sufentanil for epidural analgesia in the rst stage of labor. Anesth Analg 2003; 96: 117882. 5. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995; 42: 891903.

6. Beilin Y, Bodian CA, Weiser J, Hossain S, Arnold I, Feierman DE, Martin G, Holzman I. Effect of labor epidural analgesia with and without fentanyl on infant breastfeeding. Anesthesiology 2005; 103: 12117. 7. Connelly NR, Parker RK, Lucas T, El-Mansouri M, Komanduri V, Nayak P, Gutta S, Gibson C, Dunn SM. The inuence of a bupivacaine and fentanyl epidural infusion after epidural fentanyl in patients allowed to ambulate in early labor. Anesth Analg 2001; 93: 10015. 8. Bromage PR. A comparison of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol Scand 1965; 9 (Suppl. XVI): 5569. 9. Vercauteren M, Meert TF. Isobolographic analysis of the interaction between epidural sufentanil and bupivacaine in rats. Pharmacol Biochem Behav 1997; 58: 23742. 10. Halonen PM, Paatero H, Hovorka J, Haasio J, Korttila K. Comparison of two fentanyl doses to improve epidural anaesthesia with 0.5% bupivacaine for Caesarean section. Acta Anaesthesiol Scand 1993; 37: 7749. 11. Wong CA, Scavone BM, Slavenas JP, Vidovich MI, Peaceman AM, Ganchiff JN, Strauss-Hoder T, McCarthy RJ. Efcacy and side effect prole of varying doses of intrathecal fentanyl added to bupivacaine for labor analgesia. Int J Obstet Anesth 2004; 13: 1924. 12. Gaiser RR, Lewin SB, Cheek TG, Gutsche BB. Effects of immediately initiating an epidural infusion in the combined spinal and epidural technique in nulliparous parturients. Reg Anesth Pain Med 2000; 25: 2237. 13. Connelly NR, Parker RK, Pedersen T, Manikantan T, Lucas T, Serban S, El-Mansouri M, DuBois S, Delos Santos E, Rizvi A, Gibson C. Diluent volume for epidural fentanyl and its effect on analgesia in early labor. Anesth Analg 2003; 96: 1799804. 14. Connelly NR, Parker RK, Vallurupalli V, Bhopatkar S, Dunn S. Comparison of epidural fentanyl versus epidural sufentanil for analgesia in ambulatory patients in early labor. Anesth Analg 2000; 91: 3748. 15. Hughes SC, Rosen MA, Shnider SM, Abboud TK, Stefani SJ, Norton M. Maternal and neonatal effects of epidural morphine for labor and delivery. Anesth Analg 1984; 63: 31924. 16. Vertommen JD, Vandermeulen E, Van Aken H, Vaes L, Soetens M, Van Steenberge A, Mourisse P, Willaert J, Noorduin H, Devlieger H, Van Assche AF. The effects of the addition of sufentanil to 0.125% bupivacaine on the quality of analgesia during labor and on the incidence of instrumental deliveries. Anesthesiology 1991; 74: 80914. 17. Roelants F, Mercier-Fuzier V, Lavand homme PM. The effect of a lidocaine test dose on analgesia and mobility after an epidural combination of neostigmine and sufentanil in early labor. Anesth Analg 2006; 103: 153439.

Address: Associate Professor Marie T Aouad Department of Anesthesiology American University of Beirut P.O.Box 11-0236 Beirut, Lebanon e-mail: mm01@aub.edu.lb

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