Although intrathecal (IT) sufentanil provides effective

Combination of Intrathecal Sufentanil 10 g Plus Bupivacaine 2.5 mg for Labor Analgesia: Is Half the Dose Enough? Alex T. H. Sia, MMed, Jin L. Chong, MMed, and Jen W. Chiu, MMed Department of Anesthesia, KK Women and Children s Hospital, Singapore This controlled, double-blinded, prospective trial of 42 parturients in early labor was conducted to determine whether halving the total amount of intrathecal (IT) sufentanil and bupivacaine reduced the incidence of systemic hypotension while providing adequate analgesia with minimal lower limb motor block. Combined spinal-epidural analgesia (CSE) was instituted; Group A(n 21) received a total of 10 g of sulfentanil plus 2.5 mg of bupivacaine, whereas Group B (n 21) received half that dose. Compared with Group B, Group A had a higher incidence of hypotension (nine parturients in Group A, two in Group B; P 0.05), a greater degree of motor block (P 0.05), and a higher incidence of sedation (nine parturients in Group A were sedated, one in Group B; P 0.01). Group B had higher pain scores for the first 5 min (P 0.05) and a lower level of sensory blockade (median of T7 in Group B compared with T4 in Group A; P 0.01). We conclude that halving the total amount of IT 10 g of sufentanil plus 2.5 mg of bupivacaine is a suitable option for CSE in labor because it reduces the incidence of some side effects, such as hypotension and maternal sedation, without compromising overall high maternal satisfaction. Implications: We showed that adequate labor pain relief could be provided by halving the recommended dose of 10 g of intrathecal sufentanil plus 2.5 mg of bupivacaine. The larger dose, however, produced faster pain relief, which lasted longer than the reduced dose. The mother and baby were not adversely affected with either dose. (Anesth Analg 1999;88:362 6) Although intrathecal (IT) sufentanil provides effective analgesia in labor, it may result in systemic hypotension (1,2). Although adding IT sufentanil to bupivacaine enhances the quality and duration of analgesia (1), this could exacerbate hypotension by potentiating deafferentation and sympathectomy due to the local anesthetic. We performed a pilot study that showed that the combination of 10 g of IT sufentanil plus 2.5 mg of plain bupivacaine, although invariably effective was associated with a higher incidence of hypotension and impairment of muscle power of the lower limbs, albeit mild in some parturients. Based on that pilot study, we performed this study to determine whether halving the total amount of IT sufentanil and bupivacaine would render adequate analgesia with a reduced incidence of hypotension. Accepted for publication November 16, 1998. Address correspondence and reprint requests to Alex T. H. Sia, Department of Anaesthesia, KK Women and Children s Hospital, 100 Bukit Timah Rd., Singapore 229 899. Methods This was a randomized, double-blinded, controlled study (with the approval of our hospital research ethics committee) comprising 42 ASA physical status I parturients in established labor of at least one contraction in 5-min intervals who were scheduled to receive combined spinal-epidural analgesia (CSE). The exclusion criteria were cervical dilation 5 cm, body weight 90 kg, chronological age 45 yr, medical diseases (such as diabetes mellitus, hypertension, and bleeding dyscrasias), obstetric complications (such as preeclampsia, multiple pregnancy, preterm labor, noncephalic presentation, and history of abdominal delivery), and the administration of IM meperidine 4 h before CSE. After providing written consent, the parturients were randomized (by sealed envelopes assignment) into two groups: Group A (control group) and Group B (study group). IV access was achieved in every parturient. Each parturient received an IV preload of 0.5 L of lactated Ringer s solution for hydration. Baseline pain scores (on a 100-point visual analog scale, 0 no pain and 100 worst pain imaginable), systolic blood pressure 1999 by the International Anesthesia Research Society 362 Anesth Analg 1999;88:362 6 0003-2999/99/$5.00

ANESTH ANALG OBSTETRIC ANESTHESIA SIA ET AL. 363 1999;88:362 6 REDUCED-DOSE COMBINED S-EPI IN LABOR (measured noninvasively on the left arm), and fetal heart tracing were obtained. Every parturient received CSE in the left lateral position at the L2-3 or L3-4 level with a 17-gauge Weiss epidural needle. The epidural space was accessed by using the loss of resistance to air technique, followed by dural puncture with a 27-gauge Whitacre spinal needle with the epidural needle serving as the introducer for the spinal needle. Each parturient in Group A received a combination of 10 g of IT sufentanil and 2.5 mg of plain bupivacaine in a total volume of 4 ml, diluted in isotonic sodium chloride solution. Group B received 5 g ofit sufentanil plus 1.25 mg of bupivacaine; i.e., half the total amount of drugs used in Group A, but in the same volume of 4 ml. These solutions were prepared by one of the investigators who was not involved with the assessment of the parturient after CSE had been instituted by another investigator, who was blinded to the drugs used. The anesthetic solutions were injected over 20 s for each case, with the orifices of the respective spinal needles facing the cephalad direction. After the administration of the IT dose, the epidural catheter was inserted 3 cm into the epidural space. After a negative aspiration test for blood, the epidural catheter was flushed with 1 ml of isotonic sodium chloride solution. No test dose was given epidurally. Unsuccessful dural taps after two attempts excluded the patient from the study, and epidural analgesia was instituted accordingly. In the first minute after CSE, all the parturients were turned to the semisupine position with a wedge to effect left uterine displacement. During the first 30 min after CSE, the parturients were assessed on the following variables and categories: 1. Blood pressure every 5 min 2. Pain scores 5, 15, and 30 min after CSE 3. Highest sensory block to cold (ice) 5, 15, and 30 min after CSE 4. Maximal degree of motor block in the lower limbs 5, 15, and 30 min after CSE based on the modified Bromage scale (0 no impairment; 1 unable to raise the extended leg but able to move knees and feet; 2 unable to raise extended leg as well as flex knees, able to move foot; 3 not able to flex ankle, feet, or knees [complete block]). 5. Shivering, pruritus, nausea, vomiting, and sedation. In this study, sedation was defined by a Ramsay score of 4, i.e., patient asleep but had a brisk response to a light glabellar tap or loud auditory stimulus (3). Any reduction of the systolic blood pressure 20% of the baseline value (i.e., the preblock value obtained just before CSE), was promptly treated with 5 mg boluses of ephedrine IV. Respiratory depression (shallow respiration 8 bpm) and severe sedation (Ramsay score 4) would have provided justification to abandon the study and to administer 0.4 mg of IV naloxone. Nausea and vomiting would be treated by 10 mg of metoclopramide IV. If the pain score was still 30 15 min after CSE, the parturient would be excluded from the study, and epidural analgesia would be reinstituted with 8 ml of 0.25% bupivacaine (after a test dose of 5 ml of 1% lidocaine) via the epidural catheter. The duration from CSE to the time when the parturient began to experience the onset of pain again (time as determined by the request for further analgesia) was noted. At this time, 8 12 ml of 0.25% bupivacaine in 4 ml aliquots would be given via the epidural catheter (after a test dose of 50 mg of lidocaine). Once the pain score was 30, the epidural infusion of 0.125% bupivacaine would be started at 10 ml/h. Data on the following were also collected for each group: the mode of delivery, the duration of second stage, the total amount of spinal and epidural bupivacaine used, the neonatal birthweight and Apgar scores (at 1 and 5 min of birth), overall satisfaction with analgesia (immediately postdelivery on a 0 100 scale; 0 very dissatisfied and 100 extremely satisfied), postdural puncture headache before discharge from hospital ( 36 h after CSE), and fetal heart tracing 1 h before and 1 h after CSE. This was reviewed by the obstetrician who was blinded to the drugs received by the parturients. The cardiotocogram was classified as normal (reactive) based on the following criteria: at least two accelerations ( 15 beats for 15 s) in 20 min, baseline heart rate 110 150 bpm, baseline variability of 5 25 bpm, and early decelerations. Any deviation from the above would be classified as abnormal (nonreassuring), and the appropriate obstetric intervention would be effected. All the fetal cardiotocograms were confirmed to be normal (reactive) before labor analgesia. The following tests were used for the comparison of the data between the two groups: Student s t-test for the demographic data and blood pressures; Wilcoxon rank-sum test for cervical dilation before the administration of CSE, pain scores at the start of the study (i.e., the baseline values) and over the next 30 min, the extent of sensory dermatomal block (5, 15, and 30 min after CSE), the time to the first request for top-up analgesia after the initial intrathecal dose, the duration of second stage, the satisfaction scores, and the Apgar scores of the neonates after birth; Fisher s exact test for the incidence of hypotension (defined as a reduction of the systolic pressure by 20%), the parity of the parturients, the Bromage scores, and the incidence of side effects (hypotension, nausea/vomiting, and shivering); and 2 test was used to compare the differences

364 OBSTETRIC ANESTHESIA SIA ET AL. ANESTH ANALG REDUCED-DOSE COMBINED S-EPI IN LABOR 1999;88:362 6 Table 1. Parturients Demographic Profile Group A Group B Age (yr) 27.0 4.83 28.3 4.72 Weight (kg) 64.0 8.90 64.9 8.67 Height (cm) 154.2 5.62 155.7 3.97 Systolic blood pressure (mm Hg) 118.9 9.71 116.9 11.99 Pain scores (0 100 visual analog scale) 83 (65 100) 85 (56 100) Cervical dilation (cm) 3 (2 5) 3 (2 5) Proportion of primiparas 17/21 (81) 16/21 (76) Use of oxytocin 9/21 (43) 10/21 (48) Values are mean sd, median (range), or proportion (%). in the use of oxytocin before CSE, the incidence of side effects (pruritus and sedation), the fetal heart changes, and the various modes of delivery. The number of subjects in each group was determined to detect (with a power of 0.8 and P value of 0.05) a difference of 50% reduction in the incidence of hypotension between the two groups (compared with the baseline values). Results Both Groups A and B were similar in terms of weight, height, and age (Table 1). Similarly, no significant difference was detected in their baseline values of systolic blood pressure, pain scores, cervical dilation, parity, or use of oxytocin before CSE. Six parturients in Group A and five in Group B received CSE at the L2-3 level, with the remaining parturients at the L3-4 level. The systolic blood pressure in Group A 10 min after CSE (mean sd 102 11 mm Hg) was significantly lower than that in Group B at the same time interval (111 9mmHg;P 0.01). For the rest of the assigned 5-min intervals, no difference in the absolute values of blood pressure was detected. The mean systolic blood of the parturients measured during the rest of the 5-min intervals was 102 109 mm Hg in Group A and 111 120 mm Hg in Group B. We also found a significant increase in the incidence of hypotension in Group A (43% vs 9%; P 0.05). Parturients in Group B registered higher pain scores 5 min after CSE (P 0.05), with a median score of 8 (highest score 45, lowest score 0), compared with Group A, which had a median score of 0 (highest 12, lowest 0). This was probably a reflection of a slower onset of analgesia with the reduced dose. There was no difference in the treatment effect between the two groups 15 and 30 min after CSE, with pain scores of 0 11 and 0 10 in Group A and Group B, respectively. There was no significant difference in the total amount of bupivacaine used, the duration of second stage of labor, the mode of delivery, the changes in the fetal heart rate, the Apgar scores, the neonatal birthweight, and the overall satisfaction scores (Table 2). However, the level of sensory dermatomal block to cold was significantly higher in Group A throughout the duration of the assessment (P 0.01). The duration of analgesia as reflected by the time to the first request for analgesia was also significantly longer in Group A (P 0.01). In terms of side effects, Group A had a higher incidence motor blockade of lower limbs 15 min after CSE (P 0.05). Apart from the incidence of sedation being lower in Group B (P 0.05), the incidence of the other side effects was similar in the two groups (Table 3). None of the parturients had respiratory depression. One parturient had a postdural puncture headache (in Group A, 18 h after CSE), which lasted for 24 h with conservative analgesic treatment. We were unable to obtain cerebral spinal fluid for one parturient, and she was excluded from the study. All the parturients had pain scores 30 after the IT dose. Three parturients in Group A and two in Group B delivered vaginally before the epidural top-ups. Discussion We used 5 g of sufentanil and 1.25 mg of bupivacaine with the chief aim of reducing the incidence of hypotension. Our results showed that the incidence of hypotension was increased in the group of parturients that had received the larger dose (i.e., 10 g of sufentanil plus 2.5 mg of bupivacaine). However, the clinical relevance of this finding was questionable, as the difference was only at the 10th minute observation, and no resultant adverse maternal or fetal effects were evident. Although the IT administration of 10 g of sufentanil alone rendered excellent analgesia in early labor, it sometimes caused hypotension via an undetermined mechanism, although an earlier article (4) had suggested that this was not directly due to a pharmacologic sympathectomy. However, because of the near immediate pain relief, the resultant decreased circulating catecholamines could contribute to hypotension (2). Moreover, although any local anesthetic effect produced by 10 g of sufentanil on its own was of no significance [although decreased isolated neural

ANESTH ANALG OBSTETRIC ANESTHESIA SIA ET AL. 365 1999;88:362 6 REDUCED-DOSE COMBINED S-EPI IN LABOR Table 2. Parturient and Neonate Data Group A Group B Highest sensory block T4 (C7 T10) T7 (T2 T12)* Time to first analgesia request after CSE (min) 164 31 120 33* Total bupivacaine CSE used (mg) 97 43 90 37 Duration of second stage of labor (min) 101.3 37 69.6 53 Intrapartum fetal heart tracing Normal 16/21 17/21 Nonreassuring 5/21 4/21 Apgar scores 7 1 min 19/21 20/21 5 min 21/21 21/21 Mode of delivery Normal 8 11 Instrumental (forceps/vacuum) 5 4 Abdominal 8 6 Neonatal birthweights (g) 3261 (412) 3487 (338) Analgesia satisfaction score (0 100 VAS) 85 (70 100) 87 (75 100) Values are median (range) or mean sd. VAS visual analog scale, CSE combined spiral-epidural. * P 0.01 between groups. Table 3. Incidence of Side Effects Group A Group B SBP reduced by 20% within 30 min 9/21 2/21* of CSE Motor block (Bromage score 0) 5 min after CSE 2/21 0/21 15 min after CSE 5/21 0/21* 30 min after CSE 4/21 0/21 Sedation 9 1* Pruritus 9 8 Nausea and vomiting 1 1 Respiratory depression 0 0 Shivering 1 0 Postdural puncture headache 1 0 * Significant difference between the two groups (P 0.05). CSE combined spinal-epidural anesthesia, SBP systolic blood pressure. conduction has been demonstrated at higher concentrations (5)], its effect when used in combination with bupivacaine, as well as the degree of positive interaction, remained unknown. Also, one could argue whether the addition of 2.5 mg of bupivacaine to 10 g of sufentanil was superfluous, considering the 95% effective dose of 8.9 g for IT sufentanil in early labor analgesia, as recently reported (6). The observation of a greater incidence of sedation in the group that received the larger combination dose initially caused some concern. This was because, apart from bradypnea and oxygen desaturation on pulse oximetry, a depressed level of consciousness (possibly caused by hypercarbia) could be an early sign of respiratory depression after the administration of opioids in the central neuraxis (7). Respiratory depression could very rarely be associated with IT sufentanil (8,9). However, none of the parturients had respiratory rates 8 breaths/min and/or shallow breathing; therefore, in our study, the increased incidence of sedation did not seem to be related to any neonatal adverse effect or respiratory depression, although our study had insufficient power to detect the latter per se. In all cases, the effect of sedation resolved within a half hour. Not surprisingly, the dermatomal level of sensory block was also higher in the group that received the larger combination dose, although this did not result in any complication, such as respiratory compromise. The extra value of the larger dose combination of sufentanil plus bupivacaine is arguable. The prolongation of analgesia offered the practical advantage of fewer parturients requiring epidural top-ups before delivery, especially when given late in labor (10). This advantage was not realized in our study because CSE was instituted early, and 80% of the parturients required a subsequent top-up. Moreover, despite the prolongation of analgesic duration, the overall satisfaction score was not improved in Group A, possibly because the subsequent top-ups of epidural analgesia were effected without delay in both groups. The delayed onset of analgesia associated with the smaller IT dose would seem to fall short of one of the greatest advantages of CSE in labor, i.e., the near immediate and almost complete pain relief conferred by the larger IT dose. However, our results showed that despite the shorter duration and a slower onset of analgesia, the overall maternal satisfaction was high, making 5 g of IT sufentanil plus 1.25 mg of bupivacaine a viable option for labor analgesia. The larger combination dose prolonged the duration of analgesia, but it also produced motor impairment of the lower limbs in some of the parturients. This was significantly evident 15 min after CSE, and, even at 30 min, residual block albeit mild was still

366 OBSTETRIC ANESTHESIA SIA ET AL. ANESTH ANALG REDUCED-DOSE COMBINED S-EPI IN LABOR 1999;88:362 6 present. This experience was not unique to us, as Collis et al. (11) previously reported 11 women who had motor block after the administration of 2.5 mg of bupivacaine (in combination with 25 g of fentanyl instead of 10 g of sufentanil) in their series of 300 parturients. Although our parturients did not ambulate in this particular study, we suspect that the early mobility of the parturients could have been undermined. Our finding is in this regard is in contrast to that of an earlier study that used the identical dose of 10 g of IT sufentanil plus 2.5 mg of bupivacaine but found no motor block (1). We suspected that the difference could be attributed to inherent dissimilarity in the demographic profile of study populations. In addition, because the modified Bromage scale was a categorical assessment by an observer and, hence, not a strictly objective measure of motor block, it would be prone to subjectivity and interobserver variation. In our study, none of the parturients in Group B had any motor blockade of the lower limbs by using the Bromage scale, although we did not use the more sensitive isometric testing by mechano-transducers (12). Based on this finding and pending further investigation, the 5 g of IT sufentanil-1.25 mg of bupivacaine combination may be one of the feasible dose options for walking epidurals. (13) Although suspicious fetal heart tracings developed in some 20% of the parturients (with no preponderance in either group) within 1 h of CSE, none had required operative interventions, and the neonatal outcome was generally favorable. However, the incidence of self-limiting pruritus remained high, independent of the dose of sufentanil used. In conclusion, our study showed that, compared with the reduced dose, the combination of 10 g ofit sufentanil and 2.5 mg of bupivacaine provided a comparable degree of analgesia in early labor. However, the larger dose was superior in producing a quicker onset of action and a longer duration of analgesia. Although side effects seemed to be more common with the larger dose, they were essentially of no clinical significance. Halving the dose of 10 g of sufentanil plus 2.5 mg of bupivacaine did not provide any advantage with regard to regional analgesia in labor. References 1. Campbell DC, Camann WR, Datta S. The addition of bupivacaine to intrathecal sufentanil for labor analgesia. Anesth Analg 1995;81:305 9. 2. Riley ET, Ratner EF, Cohen SE. Intrathecal sufentanil for labor analgesia: do sensory changes predict better analgesia and greater hypotension? Anesth Analg 1997;84:346 51. 3. Ramsay MAE, Savege TM, Simpson BRJ, Goodwin R. Controlled sedation with alphaxalone-alphadalone. BMJ 1974;2: 656 9. 4. Riley ET, Walker D, Hamilton CL, Cohen SE. Intrathecal sufentanil for labor analgesia does not cause a sympathectomy. Anesthesiology 1997;87:874 8. 5. Gissen AJ, Gugino LD, Datta S, et al. Effects of fentanyl and sufentanil on peripheral mammalian nerves. Anesth Analg 1987;66:1272 6. 6. Herman NL, Calicott R, Van Decar TK, et al. Determination of the dose-response relationship for intrathecal sufentanil in laboring patients. Anesth Analg 1997;84:1256 61. 7. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995;42:891 903. 8. Hays RL, Palmer CM. Respiratory depression after intrathecal Sufentanil during labor. Anesthesiology 1994;81:511 2. 9. Jaffee JB, Drease GE, Kelly T, Newman LM. Severe respiratory depression in the obstetric patient after intrathecal meperidine or sufentanil. Int J Obst Anesth 1997;6:182 4. 10. Viscomi CM, Rathmell JP, Mason SB, et al. Analgesia efficacy and side effects of subarachnoid sufentanil-bupivacaine administered to women in advanced labor. Reg Anesth 1996;21:424 9. 11. Collis RE, Baxandall ML, Srikantharajah ID, et al. Combined spinal epidural (CSE) analgesia: technique, management and outcome of 300 mothers. Int J Obst Anesth 1994;3:75 81. 12. Eddleston JM, Holland JJ, Griffin RP, et al. A double-blind comparison of 0.25% ropivacaine and 0.25% bupivacaine for extradural analgesia in labor. Br J Anaesth 1996;76:66 71. 13. Morgan BM. Walking epidurals in labor. Anaesthesia 1995; 50:839 40.