- Email: [email protected]
Epinephrine is not a useful addition to intrathecal fentanyl or fentanyl-bupivacaine for labor analgesia
Epinephrine Is Not a Useful Addition to Intrathecal Fentanyl or Fentanyl-Bupivacaine for Labor Analgesia Stephanie R. Goodman, M.D., Susan H. Kim-Lo, M.D., Christopher F. Ciliberto, M.D., Diane M. Ridley, M.D., and Richard M. Smiley, M.D., Ph.D. Background and Objectives: Intrathecal fentanyl provides effective labor analgesia for a limited time with frequent side effects. We evaluated the effects of adding epinephrine to intrathecal fentanyl with and without bupivacaine. Methods: Eighty healthy, term, nulliparous parturients with cervical dilation of 5 cm or less received combined spinal-epidural (CSE) analgesia. Subjects were randomized in a double-blind fashion to 1 of 4 intrathecal solutions containing fentanyl 35 g with either saline (F); bupivacaine 2.5 mg ⫹ saline (FB); bupivacaine 2.5 mg ⫹ epinephrine 100 g (FBE); or epinephrine 100 g ⫹ saline (FE). Patients were evaluated for visual analog pain score, duration of spinal analgesia (time until patient request for additional analgesia), nausea/vomiting, pruritus, sensory and motor block, maternal blood pressure, and fetal heart rate (FHR). Results: Intrathecal bupivacaine significantly prolonged fentanyl analgesia with or without epinephrine (P ⫽ .018), but epinephrine did not significantly prolong the duration of fentanyl alone or with bupivacaine (F, 92 ⫾ 39 minutes; FB, 125 ⫾ 31 minutes; FBE, 134 ⫾ 42 minutes; and FE, 117 ⫾ 48 minutes). Intrathecal epinephrine was associated with a higher incidence of severe nausea (P ⫽ .001), and the FBE group had more lower extremity weakness (P ⫽ .047). There was no difference in the incidence of severe pruritus, FHR deceleration, or delivery outcome between the groups. Conclusions: These results suggest that intrathecal epinephrine does not prolong the duration of fentanyl or fentanyl with bupivacaine for labor analgesia in nulliparous parturients. Additionally, intrathecal epinephrine did not decrease the incidence of side effects and therefore cannot be recommended. Reg Anesth Pain Med 2002;27:374-379. Key Words:
Anesthesia, Combined spinal and epidural, Epinephrine, Labor, Obstetrics, Pain.
T
he combined spinal-epidural (CSE) technique has become popular for providing labor analgesia. Initially, opioids were used in the subarachFrom the Department of Anesthesiology, Columbia University College of Physicians and Surgeons (S.R.G., S.H.K-L., C.F.C., R.M.S.), New York, New York; and Elmhurst Hospital Center (D.M.R.), Queens, New York. Accepted for publication January 21, 2002. Supported in part by a gift from Becton Dickinson (Franklin Lakes, NJ) and a House Staff Research Award from Presbyterian Hospital (New York, NY). Work performed in the Department of Anesthesiology, Columbia University College of Physicians and Surgeons. Presented at the Annual Meeting of the Society for Obstetric Anesthesia and Perinatology, April 29, 1998, Vancouver, BC, Canada and the Annual Meeting of the American Society of Anesthesiology, October 17, 1998, Orlando, FL. Reprint requests: Stephanie R. Goodman, M.D., Columbia University College of Physicians and Surgeons, 630 West 168th St, PH-5, New York, NY 10032. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2704-0005$35.00/0 doi:10.1053/rapm.2002.33283
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noid space to provide rapid onset of analgesia, hemodynamic stability, and no motor block. The use of opioids alone is limited, however, by a relatively short duration of analgesia, limited pain relief during the second stage of labor, and frequent side effects, especially pruritus. Several different drugs have been added to intrathecal opioids to increase the duration or quality of analgesia and/or decrease side effects. The addition of intrathecal bupivacaine to sufentanil and fentanyl significantly prolongs the duration of labor analgesia in early, nulliparous patients.1,2 Intrathecal epinephrine prolonged the duration of bupivacaine with sufentanil for labor analgesia.3 Pruritus may be reduced by the addition of epinephrine to sufentanil and by the addition of bupivacaine to fentanyl.4,5 Few studies have assessed the effect of the addition of local anesthetics and epinephrine to intrathecal fentanyl for labor analgesia. We designed this
Regional Anesthesia and Pain Medicine, Vol 27, No 4 (July–August), 2002: pp 374 –379
Intrathecal Fentanyl-Bupivacaine-Epinephrine
randomized, double-blind, prospective trial to evaluate the effects of epinephrine on intrathecal fentanyl and fentanyl plus bupivacaine in nulliparous patients in early labor.
Methods Nulliparous parturients at least 18 years of age in active labor, with a single, term (37 to 41 weeks gestation) fetus in vertex presentation, and American Society of Anesthesiologists physical status I or II were eligible for enrollment if they had achieved a cervical dilation of 5 cm or less at the time of their request for labor analgesia. The study was approved by our institutional review board, and written, informed consent was obtained from all subjects. The following demographic and clinical data were recorded for all patients: maternal age, height and weight, cervical dilation, station, use of oxytocin at the time of request for labor analgesia, fetal weight, and mode of delivery (spontaneous vaginal, instrumental vaginal, or cesarean). With the patient in the sitting position, CSE analgesia was performed using a loss of resistance to air technique. The epidural space was entered at L2-3, L3-4, or L4-5 with a 17-gauge Tuohy needle. A 25-gauge Whitacre needle was then placed via the Tuohy needle into the subarachnoid space. When clear, free-flowing, cerebrospinal fluid (CSF) was obtained, the study solution was injected. If CSF could not be obtained or if the epidural needle entered the subarachnoid space, the patient was eliminated from the study protocol. The spinal needle was then removed, and a 19-gauge, single orifice epidural catheter was inserted 3 to 5 cm into the epidural space. No medications were administered through the epidural catheter until the patient requested additional analgesia. Patients were randomized in a double-blind fashion to 1 of 4 intrathecal solutions. Sterile syringes containing the study solution were prepared by the research pharmacy according to a random number table. Each syringe contained 1.1 mL of solution containing saline (F); bupivacaine 2.5 mg ⫹ saline (FB); bupivacaine 2.5 mg ⫹ epinephrine 100 g (FBE); or epinephrine 100 g ⫹ saline (FE). At the time of the CSE procedure, 35 g fentanyl (0.7 mL) was added by the investigator to each syringe for a total volume of 1.8 mL. The primary outcome variable was duration of analgesia, which was defined as the time from intrathecal injection to the subject’s first request for additional analgesia. The request for additional analgesia or delivery of the baby marked the end of the study period. Pain was assessed by a visual analog scale (VAS)
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measuring 100 mm (0 ⫽ no pain, 100 ⫽ worst pain imaginable). Patients were asked to mark their pain on the 100-mm line before initiation of spinal analgesia. Pain was assessed at 5, 10, 15, 30, 45, and 60 minutes after spinal injection and every 30 minutes thereafter until one of the end points of the study was reached. Pruritus and nausea/vomiting were assessed by a 3-point scale (1, none; 2, mild; and 3, severe by patient report) at the same time as the pain assessments. Treatment of severe pruritus or nausea/vomiting was at the discretion of the blinded investigator. Nalbuphine 5 mg, diphenhydramine 25 mg, or both, were used to treat pruritus, while nausea/vomiting was treated with 5 to 10 mg ephedrine if associated with hypotension, 4 mg ondansetron or 10 mg metaclopramide if not. Sensory level, motor block, maternal blood pressure, and both maternal and fetal heart rate (FHR) were recorded at the same time intervals as VAS scores, pruritus, and nausea/vomiting. The upper level of loss of sensation to cold was determined with ice in the midclavicular line bilaterally. The extent of bilateral motor block was measured as 1, full lower extremity strength; 2, weak hip flexion; 3, weak knee extension; 4, weak knee flexion; 5, weak foot dorsiflexion; and 6, weak foot plantar flexion. Maternal hypotension, defined as a decrease of 20% or more below baseline systolic pressure (SBP) or SBP less than 95 mm Hg, was treated with an intravenous fluid bolus (lactated Ringer’s) or ephedrine in 5- to 10-mg increments as needed. FHR decelerations, defined as a decrease to less than 100 beats/min for more than 60 seconds occurring within 45 minutes of spinal placement, were also noted. All continuous variables such as duration of analgesia, VAS scores, and ephedrine dose were evaluated using analysis of variance, with post hoc testing performed by Fisher’s protected least significant difference to correct for multiple comparisons. Categorical data such as pruritus, nausea/vomiting, and weakness were analyzed by Fisher’s exact test. P ⬍ .05 was considered significant.
Results Eighty parturients were enrolled in this study, and technical difficulties occurred in 2 patients. One had a difficult epidural placement and no CSF was obtained, and the other had a dural puncture with the Tuohy needle. Two other patients were inadvertently enrolled without meeting eligibility criteria and were excluded from data analysis. Of the remaining 76 patients, all achieved adequate analgesia after the intrathecal injection and completed the study protocol. There were no differences in
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Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 1. Demographic and Obstetric Data
Age (yr) Height (cm) Weight (kg) Cervical dilation at entry (cm) Fetal station at entry Induced labors (n) Augmented labors (n) Instrumental delivery (n) Cesarean delivery (n) Neonatal weight (g)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
29 ⫾ 5 163 ⫾ 8 81 ⫾ 12 3⫾1 ⫺1 ⫾ 1 12 5 3 4 3,484 ⫾ 656
29 ⫾ 6 164 ⫾ 5 72 ⫾ 11 3⫾1 ⫺1 ⫾ 1 9 3 0 4 3,255 ⫾ 325
29 ⫾ 6 161 ⫾ 8 78 ⫾ 17 3⫾1 ⫺1 ⫾ 1 7 5 3 2 3,430 ⫾ 319
28 ⫾ 5 162 ⫾ 8 76 ⫾ 13 4⫾1 ⫺1 ⫾ 1 6 4 2 4 3,363 ⫾ 490
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. No statistically significant differences between groups.
patient characteristics between the 4 groups (Table 1). The patients in each group did not differ with respect to mode of delivery or weight of the neonate (Table 1). The number of patients in each group who delivered before a request for additional analgesia did not significantly differ. Two (10%) patients in the F group, 4 (22%) in the FB group, 1 (5%) in the FBE group, and 0 (0%) in the FE group did not need injection of their epidural catheters. These patients were excluded from the analysis of intrathecal analgesia duration, but were included in other data analysis. The mean duration of intrathecal analgesia was longer in the patients who received bupivacaine than in those who received fentanyl alone: 125 ⫾ 31 minutes (FB) and 134 ⫾ 42 minutes (FBE) versus 92 ⫾ 39 minutes (F) (P ⫽ .018; Table 2). Although the addition of epinephrine to fentanyl alone and fentanyl-bupivacaine increased the duration of analgesia, this did not reach statistical significance: 117 ⫾ 48 (FE) versus 92 ⫾ 39 minutes (F) and 134 ⫾ 42 (FBE) versus 125 ⫾ 31 minutes (FB). The 4 groups had similar initial VAS scores, but there were significant differences in VAS scores at 5 minutes after the spinal medication was administered. The patients who received bupivacaine had significantly lower VAS scores at 5 minutes than those who did not receive bupivacaine: 3 ⫾ 5 (FB) versus 14 ⫾ 18 (F) and 7 ⫾ 14 (FBE) versus 19 ⫾ 26 (FE) (P ⫽ .027). Also, the patients who received fentanyl alone never reached as low a VAS score
during the study period as the patients in the other groups (Table 2). The incidence of severe pruritus ranged from 20% to 44% of patients, but did not differ significantly between the groups (Table 3). In general, patients complained of pruritus in the area of the upper chest and face. Intrathecal epinephrine was associated with more nausea: 28% of FE patients had severe nausea compared with 0% of F patients and 40% of FBE patients had severe nausea compared with 6% of FB patients (P ⫽ .001; Table 3). Patients in the FBE group received a significantly higher mean ephedrine dose for treatment of hypotension than all other groups (P ⫽ .001; Table 3). After spinal placement, all patient groups had a similar incidence of FHR decelerations compared with baseline. Although it seems that more FHR decelerations were caused by hypotension in the groups that received bupivacaine, this was not found to be statistically significant (Table 3). Decelerations associated with hypotension resolved with ephedrine and intravenous fluids. No cesarean deliveries were performed for this reason, and there were no adverse fetal effects. There were no differences in median sensory levels to ice between any of the groups. More patients in the F and FE groups (40% and 28%, respectively) did not have any detectable sensory level compared with the FB and FBE groups (0 and 10%, respectively) (P ⫽ .006; Table 4). In terms of motor blockade, 95% of the F group, 83% of the FB group, 65% of the FBE group, and 94% of the FE
Table 2. Analgesia Data
Intrathecal analgesia duration (min) VAS score at baseline (mm) VAS score at 5 min (mm) VAS score ⬎2 at 5 min (n) Lowest VAS obtained (mm)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
P Value
92 ⫾ 39 82 ⫾ 19 14 ⫾ 18 6 5 ⫾ 10
117 ⫾ 48 82 ⫾ 17 19 ⫾ 26† 5 1 ⫾ 3*
125 ⫾ 31* 75 ⫾ 16 3 ⫾ 5* 0* 1 ⫾ 2*
134 ⫾ 42* 79 ⫾ 15 7 ⫾ 14‡ 2 1 ⫾ 1*
.018 .563 .027 .027 .038
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. *Different from F, †different from FB, ‡different from FE.
Intrathecal Fentanyl-Bupivacaine-Epinephrine
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Table 3. Maternal and Fetal Side Effect Data
Incidence of severe pruritus (%) Incidence of severe nausea (%) Ephedrine dose (mg) Incidence of FHR decel (n) FHR decel from hypotension (n)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
P Value
20 0 2⫾7 3 1
17 28* 2⫾5 3 0
44 6 5 ⫾ 11 5 4
25 40† 13 ⫾ 11‡ 4 3
.279 .001 .001 .825 .161
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. *Different from F, †different from FB, ‡different from all other groups.
group had full lower extremity strength. More patients in the FBE group than the F group had decreased hip flexion (P ⫽ .047; Table 5).
Discussion Vasoconstrictors, usually epinephrine or less commonly phenylephrine, have been added to subarachnoid local anesthetics for many years to prolong the duration of surgical spinal anesthesia.6,7 More recently, epinephrine has been added to sufentanil with or without bupivacaine to prolong the duration of spinal labor analgesia.4 Although the addition of epinephrine did not change the duration of labor analgesia compared with plain sufentanil, it has been shown to significantly prolong the labor analgesia provided by sufentanil with bupivacaine.3,8 Epinephrine could increase or prolong the analgesia from opioids or local anesthetics by at least 2 mechanisms. Vasoconstriction, predominantly via ␣1-adrenergic receptor activation, may decrease systemic absorption of the analgesic agent from the spinal site of action. Alternatively or additionally, ␣2-adrenergic receptor stimulation may result in intrinsic analgesic activity. Our results indicate that the addition of 100 g intrathecal epinephrine to 35 g fentanyl with or without 2.5 mg bupivacaine does not prolong the duration of labor analgesia in early, nulliparous patients. The results of our study are consistent with other studies showing an increase in labor analgesia duration when bupivacaine is added to sufentanil or fentanyl.1,5 We also confirm the faster onset of analgesia provided by the addition of bupivacaine to fentanyl, which has been described previously.2 It is unclear why we were not able to show a difference in analgesia duration with the addition of epinephrine. Our data show a trend in the direction of
increased duration of analgesia with epinephrine, especially when added to fentanyl alone, but this did not achieve statistical significance. The lower dose of epinephrine (100 g) used in our study may not be a large enough dose to have an effect, although Gautier et al.8 were able to show a prolongation of analgesia using only 25 g epinephrine. There could also be a difference in the response of fentanyl to epinephrine compared with sufentanil. Both are lipophilic synthetic opioids, but their pharmacodynamics differ when given intravenously or intrathecally.9 In a study of intrathecal opioids administered to pigs, fentanyl and sufentanil had different pharmacokinetic behavior. Intrathecal fentanyl distributed rapidly into the epidural space and fat, whereas sufentanil had a high spinal cord volume of distribution.10 We may not have had enough power to detect a difference in this study with 4 groups and a relatively small sample size. A post hoc power analysis showed that we had less than 50% power to detect a difference on the order of 20 to 25 minutes in analgesia duration between groups, because the standard deviation within the groups was much greater than in previous studies and, therefore, greater than we anticipated. Thus it is possible that the 25-minute difference in analgesia duration between the fentanyl and fentanyl-epinephrine group could be a real difference. If our standard deviations had been similar to those reported in previous studies (20 to 30 minutes),1,2 we would have had more than 70% power to detect a 30-minute difference. It is unclear why we saw more variability in our subjects, but our results suggest that the clinical significance of any small, even statistically significant change in duration between groups would be limited by the variability in response between sub-
Table 4. Spinal Sensory Levels
Highest dermatomal level Incidence of no level (%)
F (n ⫽ 20)
FB (n ⫽ 18)
FBE (n ⫽ 20)
FE (n ⫽ 18)
P Value
T4 (T3-L4) 40
T3 (C7-T6) 0
T2 (C6-T6) 10
T3 (C7-T8) 28
.006
NOTE. Results expressed as median (range).
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Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 5. Incidence of Motor Block F FE FB FBE P (n ⫽ 20) (n ⫽ 18) (n ⫽ 18) (n ⫽ 20) Value
Weak toe plantar flexion Weak toe dorsiflexion Weak knee flexion Weak knee extension Weak hip flexion Full lower extremity strength
0
0
0
2
0 0
0 0
0 0
2 4
0 1
0 1
0 3
2 7
19
17
15
13*
.047
NOTE. Results expressed as number of patients in each category (n). *Different from F.
jects. If epinephrine does increase the duration of intrathecal fentanyl labor analgesia, it is likely a small effect, and of questionable clinical utility, especially given the high incidence of side effects. That is, a mean increase in 20 or 25 minutes by epinephrine would not be a strong argument in favor of its use because this time is less than the usual variation between patients and would not be useful to make clinical decisions. To our knowledge, no previous studies have reported the effect of epinephrine on intrathecal fentanyl labor analgesia. Intrathecal fentanyl commonly causes significant pruritus, especially in obstetric patients. Palmer et al.11 showed that at doses between 5 and 45 g intrathecal fentanyl for labor analgesia, the incidence of pruritus ranged from 67% to 100%. Several studies have shown that epinephrine decreases the pruritus caused by intrathecal opioids. In a labor analgesia study, 200 g intrathecal epinephrine reduced sufentanil-induced pruritus from 80% to 45%.4 Malinow et al.12 reported a similar reduction in pruritus with the addition of epinephrine to intrathecal fentanyl during anesthesia for postpartum tubal ligation. We did not see a difference in the incidence of pruritus with the addition of 100 g epinephrine to fentanyl or fentanyl-bupivacaine. Our dose may have been too low to have significant effects on the absorption, distribution, or effects of intrathecal fentanyl. However, not all investigators have found epinephrine to be useful for pruritus. Bromage et al.13 found that epinephrine increased the severity of pruritus caused by intrathecal morphine in healthy male volunteers. Similar findings were reported with the addition of epinephrine to epidural bupivacaine and morphine for cesarean deliveries.14 Campbell et al.3 did not detect a difference in the incidence of pruritus in laboring women who received intrathecal sufentanil and bupivacaine with or without 200 g epinephrine. In one study, the addition of intrathecal bupivacaine to
fentanyl was associated with a reduction in the frequency of pruritus from 95% to 36%.5 It may be that the effect, if any, of epinephrine on opioidinduced pruritus is small, making detection of the effect on this subjective phenomenon difficult in small- to moderate-sized studies. The incidence of severe nausea was significantly higher in the groups who received epinephrine than in those that did not. Camann et al.4 reported an increased incidence of nausea from 0% to 35% when intrathecal epinephrine was added to sufentanil. Epinephrine-induced nausea has been noted by some,13 but not all investigators.3 Although it is not known precisely why intrathecal epinephrine causes nausea and vomiting, it is likely through the central effects of ␣-adrenoceptor stimulation. There is evidence in cats that vomiting caused by intracerebroventricular injection of epinephrine can be blocked by phentolamine, which acts as an antagonist at ␣2-adrenoceptors, and not by prazosin, an ␣1-adrenoceptor antagonist.15 Transient FHR decelerations after the onset of labor analgesia occurred in equal frequency between our patient groups, with an incidence ranging from 15% to 28%. These decelerations occurred up until 45 minutes after the time of spinal drug administration. Patients in the fentanyl-bupivacaine-epinephrine group did receive a higher dose of ephedrine for treatment of hypotension. Other investigators have reported a similar incidence of FHR decelerations occurring after intrathecal sufentanil.16,17 Cohen et al.16 found a 15% incidence of FHR decelerations after intrathecal plain sufentanil, and Nielsen et al.17 found a 22% incidence. While there is some controversy regarding the effect of intrathecal opioids on FHR decelerations, several studies have failed to show a difference in incidence caused by intrathecal versus epidural labor analgesia.17,18 A recent large, retrospective study, however, did find that intrathecal sufentanil produced significantly more nonreassuring FHR tracings than intrathecal bupivacaine with and without sufentanil.19 We found no difference between the groups in terms of the highest median sensory dermatomal level achieved. Interestingly, we found that 60% of the patients who received fentanyl alone and 72% of those who received fentanyl with epinephrine had demonstrable sensory levels. This is consistent with reports of sensory levels in association with intrathecal opioids.2,16,20 Motor weakness is usually undesired by the patient and may impact the outcome of labor. Campbell et al.3 found no difference in the ability of parturients to ambulate if they received 200 g intrathecal epinephrine in addition to bupivacaine
Intrathecal Fentanyl-Bupivacaine-Epinephrine
and sufentanil. Although we did not specifically test our patients for the ability to ambulate, more patients in the FBE group had weak hip flexion compared with the F group. In conclusion, we found that the addition of 100 g epinephrine did not prolong the duration of labor analgesia from intrathecal fentanyl or fentanyl with bupivacaine. Epinephrine had no effect on the incidence or severity of pruritus but was associated with increased nausea. Because we are unable to show that intrathecal epinephrine has a beneficial effect and epinephrine itself appears to contribute to side effects, we are unable to recommend its use for intrathecal labor analgesia provided by fentanyl with or without bupivacaine.
References 1. Campbell D, Camann W, Datta S. The addition of bupivacaine to intrathecal sufentanil for labor analgesia. Anesth Analg 1995;81:305-309. 2. Palmer C, Van Maren G, Nogami W, Alves D. Bupivacaine augments intrathecal fentanyl for labor analgesia. Anesthesiology 1999;91:84-89. 3. Campbell D, Banner R, Crone L, Gore-Hickman W, Yip R. Addition of epinephrine to intrathecal bupivacaine and sufentanil for ambulatory labor analgesia. Anesthesiology 1997;86:525-531. 4. Camann W, Minzter B, Denney R, Datta S. Intrathecal sufentanil for labor analgesia: Effects of added epinephrine. Anesthesiology 1993;78:870-874. 5. Asokumar B, Newman M, McCarthy R, Ivankovich A, Tuman K. Intrathecal bupivacaine reduces pruritus and prolongs duration of fentanyl analgesia during labor: A prospective, randomized controlled trial. Anesth Analg 1998;87:1309-1315. 6. Concepcion M, Maddi R, Francis D, Rocco A, Murray E, Covino B. Vasoconstrictors in spinal anesthesia with tetracaine—A comparison of epinephrine and phenylephrine. Anesth Analg 1984;63:134-138. 7. Leicht C, Carlson S. Prolongation of lidocaine spinal anesthesia with epinephrine and phenylephrine. Anesth Analg 1986;65:365-369. 8. Gautier P, Debry F, Fanard L, Van Steenberge A, Hody J. Ambulatory combined spinal-epidural analgesia for labor: Influence of epinephrine on bupivacaine-sufentanil combination. Reg Anesth Pain Med 1997;22:143-149.
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9. Gaiser R, Cheek T, Gutsche B. Comparison of three different doses of intrathecal fentanyl and sufentanil for labor analgesia. J Clin Anesth 1998;10:488-493. 10. Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000; 92:739-753. 11. Palmer C, Cork R, Hays R, Van Maren G, Alves D. The dose-response relation of intrathecal fentanyl for labor analgesia. Anesthesiology 1998;88:355-361. 12. Malinow A, Mokriski B, Nomura M, Kaufman M, Snell J, Sharp G, Howard R. Effect of epinephrine on intrathecal fentanyl analgesia in patients undergoing postpartum tubal ligation. Anesthesiology 1990;73: 381-385. 13. Bromage P, Camporesi E, Durant P, Nielsen C. Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology 1983;58:257-262. 14. Douglas M, Kim J, Ross P, McMorland G. The effect of epinephrine in local anesthetic on epidural morphine-induced pruritus. Can Anaesth Soc J 1986;33: 737-740. 15. Hikasa Y, Akiba T, Iino Y, Matsukura M, Takase K, Ogasawara S. Central ␣-adrenoceptor subtypes involved in the emetic pathway in cats. Eur J Pharmacol 1992;229:241-251. 16. Cohen S, Cherry C, Holbrook R, El-Sayed Y, Gibson R, Jaffe R. Intrathecal sufentanil for labor analgesiasensory changes, side effects, and fetal heart rate changes. Anesth Analg 1993;77:1155-1160. 17. Nielsen P, Erickson J, Abouleish E, Perriatt S, Sheppard C. Fetal heart rate changes after intrathecal sufentanil or epidural bupivacaine for labor analgesia: Incidence and clinical significance. Anesth Analg 1996;83:742-746. 18. Palmer C, Maciulla J, Cork R, Nogami W, Gossler K, Alves D. The incidence of fetal heart rate changes after intrathecal fentanyl labor analgesia. Anesth Analg 1999;88:577-581. 19. Van de Velde M, Vercauteren M, Vandermeersch E. Fetal heart rate abnormalities after regional analgesia for labor pain: The effect of intrathecal opioids. Reg Anesth Pain Med 2001;26:257-262. 20. Riley E, Hamilton C, Cohen S. Intrathecal sufentanil produces sensory changes without hypotension in male volunteers. Anesthesiology 1998;89:73-78.
Anesthesia, Combined spinal and epidural, Epinephrine, Labor, Obstetrics, Pain.
T
he combined spinal-epidural (CSE) technique has become popular for providing labor analgesia. Initially, opioids were used in the subarachFrom the Department of Anesthesiology, Columbia University College of Physicians and Surgeons (S.R.G., S.H.K-L., C.F.C., R.M.S.), New York, New York; and Elmhurst Hospital Center (D.M.R.), Queens, New York. Accepted for publication January 21, 2002. Supported in part by a gift from Becton Dickinson (Franklin Lakes, NJ) and a House Staff Research Award from Presbyterian Hospital (New York, NY). Work performed in the Department of Anesthesiology, Columbia University College of Physicians and Surgeons. Presented at the Annual Meeting of the Society for Obstetric Anesthesia and Perinatology, April 29, 1998, Vancouver, BC, Canada and the Annual Meeting of the American Society of Anesthesiology, October 17, 1998, Orlando, FL. Reprint requests: Stephanie R. Goodman, M.D., Columbia University College of Physicians and Surgeons, 630 West 168th St, PH-5, New York, NY 10032. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2704-0005$35.00/0 doi:10.1053/rapm.2002.33283
374
noid space to provide rapid onset of analgesia, hemodynamic stability, and no motor block. The use of opioids alone is limited, however, by a relatively short duration of analgesia, limited pain relief during the second stage of labor, and frequent side effects, especially pruritus. Several different drugs have been added to intrathecal opioids to increase the duration or quality of analgesia and/or decrease side effects. The addition of intrathecal bupivacaine to sufentanil and fentanyl significantly prolongs the duration of labor analgesia in early, nulliparous patients.1,2 Intrathecal epinephrine prolonged the duration of bupivacaine with sufentanil for labor analgesia.3 Pruritus may be reduced by the addition of epinephrine to sufentanil and by the addition of bupivacaine to fentanyl.4,5 Few studies have assessed the effect of the addition of local anesthetics and epinephrine to intrathecal fentanyl for labor analgesia. We designed this
Regional Anesthesia and Pain Medicine, Vol 27, No 4 (July–August), 2002: pp 374 –379
Intrathecal Fentanyl-Bupivacaine-Epinephrine
randomized, double-blind, prospective trial to evaluate the effects of epinephrine on intrathecal fentanyl and fentanyl plus bupivacaine in nulliparous patients in early labor.
Methods Nulliparous parturients at least 18 years of age in active labor, with a single, term (37 to 41 weeks gestation) fetus in vertex presentation, and American Society of Anesthesiologists physical status I or II were eligible for enrollment if they had achieved a cervical dilation of 5 cm or less at the time of their request for labor analgesia. The study was approved by our institutional review board, and written, informed consent was obtained from all subjects. The following demographic and clinical data were recorded for all patients: maternal age, height and weight, cervical dilation, station, use of oxytocin at the time of request for labor analgesia, fetal weight, and mode of delivery (spontaneous vaginal, instrumental vaginal, or cesarean). With the patient in the sitting position, CSE analgesia was performed using a loss of resistance to air technique. The epidural space was entered at L2-3, L3-4, or L4-5 with a 17-gauge Tuohy needle. A 25-gauge Whitacre needle was then placed via the Tuohy needle into the subarachnoid space. When clear, free-flowing, cerebrospinal fluid (CSF) was obtained, the study solution was injected. If CSF could not be obtained or if the epidural needle entered the subarachnoid space, the patient was eliminated from the study protocol. The spinal needle was then removed, and a 19-gauge, single orifice epidural catheter was inserted 3 to 5 cm into the epidural space. No medications were administered through the epidural catheter until the patient requested additional analgesia. Patients were randomized in a double-blind fashion to 1 of 4 intrathecal solutions. Sterile syringes containing the study solution were prepared by the research pharmacy according to a random number table. Each syringe contained 1.1 mL of solution containing saline (F); bupivacaine 2.5 mg ⫹ saline (FB); bupivacaine 2.5 mg ⫹ epinephrine 100 g (FBE); or epinephrine 100 g ⫹ saline (FE). At the time of the CSE procedure, 35 g fentanyl (0.7 mL) was added by the investigator to each syringe for a total volume of 1.8 mL. The primary outcome variable was duration of analgesia, which was defined as the time from intrathecal injection to the subject’s first request for additional analgesia. The request for additional analgesia or delivery of the baby marked the end of the study period. Pain was assessed by a visual analog scale (VAS)
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measuring 100 mm (0 ⫽ no pain, 100 ⫽ worst pain imaginable). Patients were asked to mark their pain on the 100-mm line before initiation of spinal analgesia. Pain was assessed at 5, 10, 15, 30, 45, and 60 minutes after spinal injection and every 30 minutes thereafter until one of the end points of the study was reached. Pruritus and nausea/vomiting were assessed by a 3-point scale (1, none; 2, mild; and 3, severe by patient report) at the same time as the pain assessments. Treatment of severe pruritus or nausea/vomiting was at the discretion of the blinded investigator. Nalbuphine 5 mg, diphenhydramine 25 mg, or both, were used to treat pruritus, while nausea/vomiting was treated with 5 to 10 mg ephedrine if associated with hypotension, 4 mg ondansetron or 10 mg metaclopramide if not. Sensory level, motor block, maternal blood pressure, and both maternal and fetal heart rate (FHR) were recorded at the same time intervals as VAS scores, pruritus, and nausea/vomiting. The upper level of loss of sensation to cold was determined with ice in the midclavicular line bilaterally. The extent of bilateral motor block was measured as 1, full lower extremity strength; 2, weak hip flexion; 3, weak knee extension; 4, weak knee flexion; 5, weak foot dorsiflexion; and 6, weak foot plantar flexion. Maternal hypotension, defined as a decrease of 20% or more below baseline systolic pressure (SBP) or SBP less than 95 mm Hg, was treated with an intravenous fluid bolus (lactated Ringer’s) or ephedrine in 5- to 10-mg increments as needed. FHR decelerations, defined as a decrease to less than 100 beats/min for more than 60 seconds occurring within 45 minutes of spinal placement, were also noted. All continuous variables such as duration of analgesia, VAS scores, and ephedrine dose were evaluated using analysis of variance, with post hoc testing performed by Fisher’s protected least significant difference to correct for multiple comparisons. Categorical data such as pruritus, nausea/vomiting, and weakness were analyzed by Fisher’s exact test. P ⬍ .05 was considered significant.
Results Eighty parturients were enrolled in this study, and technical difficulties occurred in 2 patients. One had a difficult epidural placement and no CSF was obtained, and the other had a dural puncture with the Tuohy needle. Two other patients were inadvertently enrolled without meeting eligibility criteria and were excluded from data analysis. Of the remaining 76 patients, all achieved adequate analgesia after the intrathecal injection and completed the study protocol. There were no differences in
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Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 1. Demographic and Obstetric Data
Age (yr) Height (cm) Weight (kg) Cervical dilation at entry (cm) Fetal station at entry Induced labors (n) Augmented labors (n) Instrumental delivery (n) Cesarean delivery (n) Neonatal weight (g)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
29 ⫾ 5 163 ⫾ 8 81 ⫾ 12 3⫾1 ⫺1 ⫾ 1 12 5 3 4 3,484 ⫾ 656
29 ⫾ 6 164 ⫾ 5 72 ⫾ 11 3⫾1 ⫺1 ⫾ 1 9 3 0 4 3,255 ⫾ 325
29 ⫾ 6 161 ⫾ 8 78 ⫾ 17 3⫾1 ⫺1 ⫾ 1 7 5 3 2 3,430 ⫾ 319
28 ⫾ 5 162 ⫾ 8 76 ⫾ 13 4⫾1 ⫺1 ⫾ 1 6 4 2 4 3,363 ⫾ 490
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. No statistically significant differences between groups.
patient characteristics between the 4 groups (Table 1). The patients in each group did not differ with respect to mode of delivery or weight of the neonate (Table 1). The number of patients in each group who delivered before a request for additional analgesia did not significantly differ. Two (10%) patients in the F group, 4 (22%) in the FB group, 1 (5%) in the FBE group, and 0 (0%) in the FE group did not need injection of their epidural catheters. These patients were excluded from the analysis of intrathecal analgesia duration, but were included in other data analysis. The mean duration of intrathecal analgesia was longer in the patients who received bupivacaine than in those who received fentanyl alone: 125 ⫾ 31 minutes (FB) and 134 ⫾ 42 minutes (FBE) versus 92 ⫾ 39 minutes (F) (P ⫽ .018; Table 2). Although the addition of epinephrine to fentanyl alone and fentanyl-bupivacaine increased the duration of analgesia, this did not reach statistical significance: 117 ⫾ 48 (FE) versus 92 ⫾ 39 minutes (F) and 134 ⫾ 42 (FBE) versus 125 ⫾ 31 minutes (FB). The 4 groups had similar initial VAS scores, but there were significant differences in VAS scores at 5 minutes after the spinal medication was administered. The patients who received bupivacaine had significantly lower VAS scores at 5 minutes than those who did not receive bupivacaine: 3 ⫾ 5 (FB) versus 14 ⫾ 18 (F) and 7 ⫾ 14 (FBE) versus 19 ⫾ 26 (FE) (P ⫽ .027). Also, the patients who received fentanyl alone never reached as low a VAS score
during the study period as the patients in the other groups (Table 2). The incidence of severe pruritus ranged from 20% to 44% of patients, but did not differ significantly between the groups (Table 3). In general, patients complained of pruritus in the area of the upper chest and face. Intrathecal epinephrine was associated with more nausea: 28% of FE patients had severe nausea compared with 0% of F patients and 40% of FBE patients had severe nausea compared with 6% of FB patients (P ⫽ .001; Table 3). Patients in the FBE group received a significantly higher mean ephedrine dose for treatment of hypotension than all other groups (P ⫽ .001; Table 3). After spinal placement, all patient groups had a similar incidence of FHR decelerations compared with baseline. Although it seems that more FHR decelerations were caused by hypotension in the groups that received bupivacaine, this was not found to be statistically significant (Table 3). Decelerations associated with hypotension resolved with ephedrine and intravenous fluids. No cesarean deliveries were performed for this reason, and there were no adverse fetal effects. There were no differences in median sensory levels to ice between any of the groups. More patients in the F and FE groups (40% and 28%, respectively) did not have any detectable sensory level compared with the FB and FBE groups (0 and 10%, respectively) (P ⫽ .006; Table 4). In terms of motor blockade, 95% of the F group, 83% of the FB group, 65% of the FBE group, and 94% of the FE
Table 2. Analgesia Data
Intrathecal analgesia duration (min) VAS score at baseline (mm) VAS score at 5 min (mm) VAS score ⬎2 at 5 min (n) Lowest VAS obtained (mm)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
P Value
92 ⫾ 39 82 ⫾ 19 14 ⫾ 18 6 5 ⫾ 10
117 ⫾ 48 82 ⫾ 17 19 ⫾ 26† 5 1 ⫾ 3*
125 ⫾ 31* 75 ⫾ 16 3 ⫾ 5* 0* 1 ⫾ 2*
134 ⫾ 42* 79 ⫾ 15 7 ⫾ 14‡ 2 1 ⫾ 1*
.018 .563 .027 .027 .038
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. *Different from F, †different from FB, ‡different from FE.
Intrathecal Fentanyl-Bupivacaine-Epinephrine
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Table 3. Maternal and Fetal Side Effect Data
Incidence of severe pruritus (%) Incidence of severe nausea (%) Ephedrine dose (mg) Incidence of FHR decel (n) FHR decel from hypotension (n)
F (n ⫽ 20)
FE (n ⫽ 18)
FB (n ⫽ 18)
FBE (n ⫽ 20)
P Value
20 0 2⫾7 3 1
17 28* 2⫾5 3 0
44 6 5 ⫾ 11 5 4
25 40† 13 ⫾ 11‡ 4 3
.279 .001 .001 .825 .161
NOTE. Results expressed as mean ⫾ SD unless otherwise stated. *Different from F, †different from FB, ‡different from all other groups.
group had full lower extremity strength. More patients in the FBE group than the F group had decreased hip flexion (P ⫽ .047; Table 5).
Discussion Vasoconstrictors, usually epinephrine or less commonly phenylephrine, have been added to subarachnoid local anesthetics for many years to prolong the duration of surgical spinal anesthesia.6,7 More recently, epinephrine has been added to sufentanil with or without bupivacaine to prolong the duration of spinal labor analgesia.4 Although the addition of epinephrine did not change the duration of labor analgesia compared with plain sufentanil, it has been shown to significantly prolong the labor analgesia provided by sufentanil with bupivacaine.3,8 Epinephrine could increase or prolong the analgesia from opioids or local anesthetics by at least 2 mechanisms. Vasoconstriction, predominantly via ␣1-adrenergic receptor activation, may decrease systemic absorption of the analgesic agent from the spinal site of action. Alternatively or additionally, ␣2-adrenergic receptor stimulation may result in intrinsic analgesic activity. Our results indicate that the addition of 100 g intrathecal epinephrine to 35 g fentanyl with or without 2.5 mg bupivacaine does not prolong the duration of labor analgesia in early, nulliparous patients. The results of our study are consistent with other studies showing an increase in labor analgesia duration when bupivacaine is added to sufentanil or fentanyl.1,5 We also confirm the faster onset of analgesia provided by the addition of bupivacaine to fentanyl, which has been described previously.2 It is unclear why we were not able to show a difference in analgesia duration with the addition of epinephrine. Our data show a trend in the direction of
increased duration of analgesia with epinephrine, especially when added to fentanyl alone, but this did not achieve statistical significance. The lower dose of epinephrine (100 g) used in our study may not be a large enough dose to have an effect, although Gautier et al.8 were able to show a prolongation of analgesia using only 25 g epinephrine. There could also be a difference in the response of fentanyl to epinephrine compared with sufentanil. Both are lipophilic synthetic opioids, but their pharmacodynamics differ when given intravenously or intrathecally.9 In a study of intrathecal opioids administered to pigs, fentanyl and sufentanil had different pharmacokinetic behavior. Intrathecal fentanyl distributed rapidly into the epidural space and fat, whereas sufentanil had a high spinal cord volume of distribution.10 We may not have had enough power to detect a difference in this study with 4 groups and a relatively small sample size. A post hoc power analysis showed that we had less than 50% power to detect a difference on the order of 20 to 25 minutes in analgesia duration between groups, because the standard deviation within the groups was much greater than in previous studies and, therefore, greater than we anticipated. Thus it is possible that the 25-minute difference in analgesia duration between the fentanyl and fentanyl-epinephrine group could be a real difference. If our standard deviations had been similar to those reported in previous studies (20 to 30 minutes),1,2 we would have had more than 70% power to detect a 30-minute difference. It is unclear why we saw more variability in our subjects, but our results suggest that the clinical significance of any small, even statistically significant change in duration between groups would be limited by the variability in response between sub-
Table 4. Spinal Sensory Levels
Highest dermatomal level Incidence of no level (%)
F (n ⫽ 20)
FB (n ⫽ 18)
FBE (n ⫽ 20)
FE (n ⫽ 18)
P Value
T4 (T3-L4) 40
T3 (C7-T6) 0
T2 (C6-T6) 10
T3 (C7-T8) 28
.006
NOTE. Results expressed as median (range).
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Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 5. Incidence of Motor Block F FE FB FBE P (n ⫽ 20) (n ⫽ 18) (n ⫽ 18) (n ⫽ 20) Value
Weak toe plantar flexion Weak toe dorsiflexion Weak knee flexion Weak knee extension Weak hip flexion Full lower extremity strength
0
0
0
2
0 0
0 0
0 0
2 4
0 1
0 1
0 3
2 7
19
17
15
13*
.047
NOTE. Results expressed as number of patients in each category (n). *Different from F.
jects. If epinephrine does increase the duration of intrathecal fentanyl labor analgesia, it is likely a small effect, and of questionable clinical utility, especially given the high incidence of side effects. That is, a mean increase in 20 or 25 minutes by epinephrine would not be a strong argument in favor of its use because this time is less than the usual variation between patients and would not be useful to make clinical decisions. To our knowledge, no previous studies have reported the effect of epinephrine on intrathecal fentanyl labor analgesia. Intrathecal fentanyl commonly causes significant pruritus, especially in obstetric patients. Palmer et al.11 showed that at doses between 5 and 45 g intrathecal fentanyl for labor analgesia, the incidence of pruritus ranged from 67% to 100%. Several studies have shown that epinephrine decreases the pruritus caused by intrathecal opioids. In a labor analgesia study, 200 g intrathecal epinephrine reduced sufentanil-induced pruritus from 80% to 45%.4 Malinow et al.12 reported a similar reduction in pruritus with the addition of epinephrine to intrathecal fentanyl during anesthesia for postpartum tubal ligation. We did not see a difference in the incidence of pruritus with the addition of 100 g epinephrine to fentanyl or fentanyl-bupivacaine. Our dose may have been too low to have significant effects on the absorption, distribution, or effects of intrathecal fentanyl. However, not all investigators have found epinephrine to be useful for pruritus. Bromage et al.13 found that epinephrine increased the severity of pruritus caused by intrathecal morphine in healthy male volunteers. Similar findings were reported with the addition of epinephrine to epidural bupivacaine and morphine for cesarean deliveries.14 Campbell et al.3 did not detect a difference in the incidence of pruritus in laboring women who received intrathecal sufentanil and bupivacaine with or without 200 g epinephrine. In one study, the addition of intrathecal bupivacaine to
fentanyl was associated with a reduction in the frequency of pruritus from 95% to 36%.5 It may be that the effect, if any, of epinephrine on opioidinduced pruritus is small, making detection of the effect on this subjective phenomenon difficult in small- to moderate-sized studies. The incidence of severe nausea was significantly higher in the groups who received epinephrine than in those that did not. Camann et al.4 reported an increased incidence of nausea from 0% to 35% when intrathecal epinephrine was added to sufentanil. Epinephrine-induced nausea has been noted by some,13 but not all investigators.3 Although it is not known precisely why intrathecal epinephrine causes nausea and vomiting, it is likely through the central effects of ␣-adrenoceptor stimulation. There is evidence in cats that vomiting caused by intracerebroventricular injection of epinephrine can be blocked by phentolamine, which acts as an antagonist at ␣2-adrenoceptors, and not by prazosin, an ␣1-adrenoceptor antagonist.15 Transient FHR decelerations after the onset of labor analgesia occurred in equal frequency between our patient groups, with an incidence ranging from 15% to 28%. These decelerations occurred up until 45 minutes after the time of spinal drug administration. Patients in the fentanyl-bupivacaine-epinephrine group did receive a higher dose of ephedrine for treatment of hypotension. Other investigators have reported a similar incidence of FHR decelerations occurring after intrathecal sufentanil.16,17 Cohen et al.16 found a 15% incidence of FHR decelerations after intrathecal plain sufentanil, and Nielsen et al.17 found a 22% incidence. While there is some controversy regarding the effect of intrathecal opioids on FHR decelerations, several studies have failed to show a difference in incidence caused by intrathecal versus epidural labor analgesia.17,18 A recent large, retrospective study, however, did find that intrathecal sufentanil produced significantly more nonreassuring FHR tracings than intrathecal bupivacaine with and without sufentanil.19 We found no difference between the groups in terms of the highest median sensory dermatomal level achieved. Interestingly, we found that 60% of the patients who received fentanyl alone and 72% of those who received fentanyl with epinephrine had demonstrable sensory levels. This is consistent with reports of sensory levels in association with intrathecal opioids.2,16,20 Motor weakness is usually undesired by the patient and may impact the outcome of labor. Campbell et al.3 found no difference in the ability of parturients to ambulate if they received 200 g intrathecal epinephrine in addition to bupivacaine
Intrathecal Fentanyl-Bupivacaine-Epinephrine
and sufentanil. Although we did not specifically test our patients for the ability to ambulate, more patients in the FBE group had weak hip flexion compared with the F group. In conclusion, we found that the addition of 100 g epinephrine did not prolong the duration of labor analgesia from intrathecal fentanyl or fentanyl with bupivacaine. Epinephrine had no effect on the incidence or severity of pruritus but was associated with increased nausea. Because we are unable to show that intrathecal epinephrine has a beneficial effect and epinephrine itself appears to contribute to side effects, we are unable to recommend its use for intrathecal labor analgesia provided by fentanyl with or without bupivacaine.
References 1. Campbell D, Camann W, Datta S. The addition of bupivacaine to intrathecal sufentanil for labor analgesia. Anesth Analg 1995;81:305-309. 2. Palmer C, Van Maren G, Nogami W, Alves D. Bupivacaine augments intrathecal fentanyl for labor analgesia. Anesthesiology 1999;91:84-89. 3. Campbell D, Banner R, Crone L, Gore-Hickman W, Yip R. Addition of epinephrine to intrathecal bupivacaine and sufentanil for ambulatory labor analgesia. Anesthesiology 1997;86:525-531. 4. Camann W, Minzter B, Denney R, Datta S. Intrathecal sufentanil for labor analgesia: Effects of added epinephrine. Anesthesiology 1993;78:870-874. 5. Asokumar B, Newman M, McCarthy R, Ivankovich A, Tuman K. Intrathecal bupivacaine reduces pruritus and prolongs duration of fentanyl analgesia during labor: A prospective, randomized controlled trial. Anesth Analg 1998;87:1309-1315. 6. Concepcion M, Maddi R, Francis D, Rocco A, Murray E, Covino B. Vasoconstrictors in spinal anesthesia with tetracaine—A comparison of epinephrine and phenylephrine. Anesth Analg 1984;63:134-138. 7. Leicht C, Carlson S. Prolongation of lidocaine spinal anesthesia with epinephrine and phenylephrine. Anesth Analg 1986;65:365-369. 8. Gautier P, Debry F, Fanard L, Van Steenberge A, Hody J. Ambulatory combined spinal-epidural analgesia for labor: Influence of epinephrine on bupivacaine-sufentanil combination. Reg Anesth Pain Med 1997;22:143-149.
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9. Gaiser R, Cheek T, Gutsche B. Comparison of three different doses of intrathecal fentanyl and sufentanil for labor analgesia. J Clin Anesth 1998;10:488-493. 10. Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000; 92:739-753. 11. Palmer C, Cork R, Hays R, Van Maren G, Alves D. The dose-response relation of intrathecal fentanyl for labor analgesia. Anesthesiology 1998;88:355-361. 12. Malinow A, Mokriski B, Nomura M, Kaufman M, Snell J, Sharp G, Howard R. Effect of epinephrine on intrathecal fentanyl analgesia in patients undergoing postpartum tubal ligation. Anesthesiology 1990;73: 381-385. 13. Bromage P, Camporesi E, Durant P, Nielsen C. Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology 1983;58:257-262. 14. Douglas M, Kim J, Ross P, McMorland G. The effect of epinephrine in local anesthetic on epidural morphine-induced pruritus. Can Anaesth Soc J 1986;33: 737-740. 15. Hikasa Y, Akiba T, Iino Y, Matsukura M, Takase K, Ogasawara S. Central ␣-adrenoceptor subtypes involved in the emetic pathway in cats. Eur J Pharmacol 1992;229:241-251. 16. Cohen S, Cherry C, Holbrook R, El-Sayed Y, Gibson R, Jaffe R. Intrathecal sufentanil for labor analgesiasensory changes, side effects, and fetal heart rate changes. Anesth Analg 1993;77:1155-1160. 17. Nielsen P, Erickson J, Abouleish E, Perriatt S, Sheppard C. Fetal heart rate changes after intrathecal sufentanil or epidural bupivacaine for labor analgesia: Incidence and clinical significance. Anesth Analg 1996;83:742-746. 18. Palmer C, Maciulla J, Cork R, Nogami W, Gossler K, Alves D. The incidence of fetal heart rate changes after intrathecal fentanyl labor analgesia. Anesth Analg 1999;88:577-581. 19. Van de Velde M, Vercauteren M, Vandermeersch E. Fetal heart rate abnormalities after regional analgesia for labor pain: The effect of intrathecal opioids. Reg Anesth Pain Med 2001;26:257-262. 20. Riley E, Hamilton C, Cohen S. Intrathecal sufentanil produces sensory changes without hypotension in male volunteers. Anesthesiology 1998;89:73-78.