Abstract
Objective
Sufficient sensory blockade between L1 and T10 is required to relieve visceral pain during early labor. We examined whether the addition of fentanyl to a loading dose of 0.0625% bupivacaine could provide dose-dependent analgesic effects on early-stage labor pain.
Methods
Sixty parturients who requested epidural analgesia for labor pain were enrolled and randomly allocated to one of three groups. Group A (n = 20) received 10 mL of 0.0625% epidural bupivacaine as a loading dose alone. Group B (n = 20) received the same bupivacaine loading dose in combination with 2 mg/mL fentanyl. Group C (n = 20) received the same loading bupivacaine dose plus 4 mg/mL fentanyl. All patients received diluted bupivacaine plus 2 mg/mL fentanyl at a rate of 10 mL/hr as a maintenance dose. Fifteen minutes later, we recorded the highest cephalic and lowest caudal anesthetized dermatomes, side effects, and the number of patients who asked for supplemental analgesia.
Results
The highest anesthetized cephalic dermatome was at the level of T12 (T9 – L1) in Group A, T9 (T8 – T12) in Group B and T7 (T5 – T9) in Group C (p < 0.05 among the three groups). Eleven patients (55%) requested supplemental bupivacaine for inadequate analgesia in Group A, six in Group B (30%), and none in Group C (0%). Pruritus was reported by seven (35%) patients in Group B and eight (40%) patients in Group C, but none in Group A.
Conclusion
The addition of fentanyl to epidural bupivacaine dose-dependently increased the analgesic effect and higher loading doses of fentanyl increased the dermatomic coverage. We suggest that 0.0625% bupivacaine plus 4 mg/mL fentanyl is the ideal loading dose to provide the greatest segmental analgesia for early labor pain with minimal side effects.
Keywords
analgesia, obstetrical; bupivacaine; fentanyl; labor pain;
1. Introduction
Continuous epidural infusion of local anesthetics and opioids is widely used in clinical practice to relieve labor pain.1,2 The combination of local an-esthetics with fentanyl allows for lower doses of both drugs, while maintaining adequate analgesia.3,4 Chestnut et al reported that continuous epidural infusion of 0.0625% bupivacaine plus 0.0002% fen-tanyl (2 μg/mL) at a rate of 12.5 mL/hr produced analgesia similar to that provided by epidural infu-sion of 0.125% bupivacaine alone with less intense motor block.5 Labor pain has two components, visceral and somatic pain. During early-stage labor, the visceral pain associated with uterine contrac-tion and cervical dilation usually requires analge-sic coverage to contain T10 to L1 dermatomes. Although previous studies reported that the com-bination of a low-concentration local anesthetic with different doses of fentanyl provides good epidural analgesia,6,7 no study has yet evaluated the analgesic effect of different epidural fentanyl doses on the dermatomic level during early labor. The aim of this study was to examine whether in-creasing the loading dose of epidural fentanyl (4 μg/mL) could yield analgesia that covers more dermatomes and provide better analgesia for vis-ceral pain during early labor.
2. Methods
Sixty-two healthy pregnant women at term con-sented to participate in our research program of labor pain relief, which was approved by our insti-tutional review board. Adequate epidural analge-sia for the visceral pain during first-stage labor requires sensory block up to T10. We excluded patients with preeclampsia, insulin-dependent dia-betes, severe medical or obstetric complications, and contraindications for epidural analgesia.
Patients were allocated to one of the three treat-ment groups in a double-blind, randomized fashion by picking a sealed envelope containing a note in-dicating the allocated group. All of the analgesic solutions were prepared by nurse-anesthetists who were not involved in the performance or evaluation of epidural analgesia. The study solution was ad-ministered in a double-blind manner. The anesthe-siologist who performed the procedure was blinded to the concentration of the solution used or group allocation. The assessment was performed by observ-ers who were ignorant of the analgesic technique. Each parturient received 500 mL lactated Ringer’s solution over 10 minutes before inducing the epi-dural block and were kept in the lateral decubitus position for epidural puncture. We used a 16G Portex epidural mini-pack for epidural block and identi-fied the epidural space using the loss of resistance technique. The epidural catheter was placed when cervical dilation was ≥ 2 cm. The epidural space was entered at the L3−4 interspace and 3 cm of the catheter was left cephalad in the epidural space. Aspiration of the in-place catheter for blood or cerebrospinal fluid was done to rule out or confirm correct placement.
Before injecting the test dose, a baseline visual analog scale (VAS) score was obtained (0 = no pain, 100 = worst possible pain) from all patients. Each parturients received a 2-mL dose of 2% lidocaine with 1:200,000 epinephrine. Five minutes later, if the initial dose was negative for intrathecal injec-tion or intravascular injection, a loading dose was given to start analgesia. Patients in Group A (n = 21) received 10 mL of 0.0625% bupivacaine alone as a loading dose. Group B (n = 20) received 10 mL of 0.0625% bupivacaine plus 2 μg/mL fentanyl. Group C (n = 21) received 10 mL of 0.0625% bupivacaine plus 4 μg/mL fentanyl. All patients then received con-tinuous epidural infusion with 0.0625% bupivacaine plus 2 μg/mL fentanyl given at a rate of 10 mL/hr to maintain analgesia until full dilation of the cervix was achieved. The patients were placed in the recum-bent position with left uterine displacement.
If pain relief was not satisfactory 15 minutes after continuous infusion, patients could request supplemental analgesia with a 5-mL bolus dose of 0.0625% bupivacaine via the epidural catheter. If this step-up dose did not achieve adequate analge-sia after 15 minutes, the epidural catheter was re-moved and another catheter was inserted in the correct epidural space. VAS scores and the severity of side effects, if any, were recorded at 15, 30 and 60 minutes after starting the epidural infusion. All patients were assessed by observers who were blinded to the analgesic technique. At 15 minutes after the administration of the epidural infusion, the cephalic and caudal levels of loss of pain sen-sation by pinprick were recorded. We determined the highest cephalic and lowest caudal anesthe-tized dermatomes and calculated the total number of dermatomes anesthetized. We also compared the number of patients with sensory blockade lev-els up to T10 and higher in all three groups.
At each assessment, VAS scores and complica-tions (such as nausea, vomiting, pruritus and urinary retention), along with maternal vital signs, abnor-mal fetal heart rate, and Bromage motor scale scores were recorded. The motor scale was de-fined as “no block” suggesting full ability to flex the knee and feet, “partial block” suggesting ability to flex the knee and resist gravity with full movement of the feet, “almost complete block” suggesting inability to flex the knee but retaining the ability to flex the feet, and “complete block” suggesting an inability to move the legs or feet.8 Pruritus was rated as none, minimal (minimal symptoms), mod-erate (bothersome but not requiring therapy) or severe (requiring therapy).
2.1. Statistical analysis
A power analysis (using Sample Power® 1.2; SPSS Inc., Chicago, IL, USA) showed that at least 18 pa-tients per group would provide 80% power to de-tect at least a 50% difference in the incidence of patients with sensory block up to T10 or higher from 25% in Group A, 75% in Group B and to 100% in Group C. Normality was checked for each continu-ous variable, and normally distributed values are expressed as mean ± standard deviation (SD), number (%), and others as median (range) where appropri-ate. Continuous variables (patient characteristics: gestational age, maternal age, height, and weight) were compared among the three groups using one-way ANOVA. If there were significant differences among the three groups, Tukey’s post hoc test was used to determine differences between pairs of groups. Categorical data (such as patients request-ing supplemental dose of 5 mL bupivacaine, patients with sensory block up to T10 or higher, the incidence of pruritus, nausea, vomiting, cesarean delivery and assisted birth) were reported as numbers and per-centages and were analyzed using 3 × 2 χ2 tests. If there were significant differences among the three groups, post hoc analyses were performed using 2 × 2 χ2 tests and Fisher’s exact test to determine differences between pairs of groups. Nonparametric data (such as the highest cephalic anesthetized der-matome and the lowest caudal anesthetized der-matome) are reported as medians and ranges and were analyzed using the Kruskal−Wallis test, fol-lowed by post hoc Mann−Whitney U tests to deter-mine differences between pairs of groups. Values of p < 0.05 indicated statistical significance. All statis-tical analyses were performed using SPSS version 10.0 (SPSS Inc.).
3. Results
Sixty-two women agreed to participate in this study. Successful epidural block was achieved in 20 pa-tients in Group A, 20 in Group B, and 20 in Group C. Two patients (one in Group A, and one in Group C) were excluded from data analysis because of epi-dural block failure (false-positive epidural catheter insertion). The three groups of patients were com-pared with regard to maternal age, weight at term, height, gestational age, VAS scores and stage of cervical dilation at baseline (Table 1). Demographic variables and obstetric characteristics were similar among the three groups. Baseline VAS pain scores and cervical dilation were also similar among the three groups. No patients in any group had baseline VAS pain scores < 30. Therefore, all of the patients recruited in this study suffered from significant early labor pain (at least more than mild pain sensation).
The highest cephalic anesthetized dermatome at 15 minutes after the administration of the epidural infusion was T12 (T9−L1) in Group A, T9 (T8−T12) in Group B and T7 (T5−T9) in Group C (Table 2). The lowest caudal anesthetized dermatome at 15 min-utes after the administration of the epidural infu-sion was L1 (T12−L4) in Group A, L3 (L2−L5) in Group B and L4 (L3−L5) in Group C (Table 2). The highest cephalic anesthetized dermatome and the lowest caudal anesthetized dermatomes were sig-nificantly different among the three groups based on Kruskal−Wallis test (p < 0.05) (Table 2). After post hoc comparisons using Mann−Whitney’s U test, there were significant differences between pairs of groups for both anesthetized dermatome (p < 0.05) (Table 2). Since the epidural analgesia for the vis-ceral pain of first-stage labor needs to provide a sensory block spanning from T10 to L1, our results showed that the number of patients with sensory block to T10 or higher was greatest in Group C (100% vs. 75% in Group B and 25% in Group A) with signifi-cant differences between groups (p < 0.05) (Table 2). The number of patients who needed supplemental bupivacaine was 11 in Group A, six in Group B, and none in Group C (Table 2). The proportion of patients requiring a supplemental dose was significantly lower in Group C than in Groups A and B (0% vs. 55% and 30%, respectively, p < 0.05). Meanwhile, this was sig-nificantly lower in Group B than in Group A (30% vs. 55%, p < 0.05).
None of the patients in any group showed “motor block” at 15 minutes after bolus injection. The incidence of pruritus was significantly higher in Groups B (35%) and C (40%) than in Group A (0%), but the difference was not significant between Groups B and C (Table 2). However, none of the patients in any group required specific treatment for pruritus during labor, and none of the patients had motor block that needed treatment after the loading dose was given or during labor. No signifi-cant difference was noted among the three groups in terms of the incidence of nausea and vomiting. The incidence of nausea was 15% in Group A, 10% in Group B and 20% in Group C, and the incidence of vomiting was 5% in all three groups (Table 2). The incidence of cesarean delivery was 25% in Group A, 30% in Group B and 25% in Group C and the incidence of assisted birth was 20% in Group A, 15% in Group B and 15% in Group C, without significant differences among the three groups (Table 2).
4. Discussion
Epidural analgesia with a loading dose of 2 μg/mL fentanyl and 0.0625% bupivacaine is widely used to relieve early labor pain. However, this dose does not always provide T10−L1 sensory block and sup-plemental doses may be needed. We found that epidural analgesia with 4 μg/mL fentanyl and 0.0625% bupivacaine for labor pain could provide wider seg-mental analgesia than bupivacaine alone or 2 μg/mL fentanyl with bupivacaine, and improved analgesia for early labor pain. Furthermore, this regimen did not cause significant side effects, except for pruritus.
Epidural infusion of diluted local anesthetic so-lutions mixed with opioids is a popular technique for pain relief during labor because both drugs inter-act synergistically to provide effective and satis-factory analgesia.9 Elliott reported that continuous epidural infusion of 0.125% bupivacaine with 4 μg/mL fentanyl could provide more effective analge-sia than continuous epidural infusion with 0.125% or 0.25% bupivacaine alone.7 However, few studies have compared the effects of different doses of fentanyl on the dermatomic level of sensory block. Our study revealed that adding 2 or 4 μg/mL fentanyl to 0.0625% bupivacaine for early labor induced sig-nificantly more extensive segmental sensory block. In addition, fewer patients requested supplemental bupivacaine intervention in the bupivacaine-fentanyl groups. We believe that, when a sufficient level of sensory block is initially achieved (sensory blockade T10 or higher), further supplemental doses of bupi-vacaine will be unnecessary.
Fentanyl is clearly an effective adjuvant to aug-ment analgesia provided by epidural bupivacaine.5 It has been demonstrated that epidural fentanyl could decrease epidural bupivacaine requirement during labor in a dose-dependent manner.10 Epidural infusion of diluted bupivacaine and fentanyl can prolong the duration of analgesia without adversely affecting the ability to ambulate. Here, we used the same concentration and the same volume of bupi-vacaine for the loading dose (0.0625% and 10 mL solu-tion). We used a fixed dose of bupivacaine (0.0625%) for comparison because we contemplated that fen-tanyl would extend the sensory block above T10. We showed that the addition of fentanyl to bupi-vacaine could reduce the need of supplemental bupi-vacaine and concurrently provide a sensory block covering more segments during the first stage of labor. This allows for the administration of a smaller cumulative dose of bupivacaine, which should de-crease the incidence of motor block and systemic local anesthetic toxicity.
The mechanism involved in the interaction be-tween epidural fentanyl and epidural bupivacaine is not clear. Many clinical and experimental human pain studies have suggested that epidural fentanyl acts at spinal or supraspinal sites, but a definitive conclusion has not been reached. According to pre-vious reports and by general conception, epidural opioids act primarily through systemic analgesic effects, but still exert some analgesic effects at the spinal level.11 Some studies12 have revealed a spi-nal mechanism of action by demonstrating a seg-mental analgesic effect, whereas other studies13,14 indicated a supraspinal mechanism of action by dem-onstrating a non-segmental analgesic effect after epidural administration of fentanyl. Based on pre-vious studies, epidural fentanyl seems to elicit anal-gesia through a spinal mechanism when administered as a bolus, while other investigators suggest that epidural fentanyl elicits analgesia through a suprasp-inal mechanism after administration by continuous infusion. Ginosar et al15 used a thermal and electri-cal experimental pain model to elucidate the site of action of epidural fentanyl in humans and reported that fentanyl might cause segmental analgesia when administered as a bolus and non-segmental systemic analgesia when administered by continuous infusion. Eichenberger et al16 revealed that fentanyl exerts a direct drug effect on the spinal nerve roots and binds to opioid receptors in the dorsal-root ganglia. This provides a possible mechanism that explains the finding that fentanyl dose-dependently enhanced the dermatomal spread of epidural bupivacaine by eliciting segmental analgesia through a partial spinal mechanism during early labor in our study.
An earlier study suggested that epidural infu-sion of 0.0625% bupivacaine in combination with 0.0002% fentanyl until delivery took place did not significantly increase the incidence of instrumen-tal delivery or prolong the duration of the second stage of labor.17 Further studies are needed to con-firm whether epidural infusion of a bupivacaine/opioid mixture can induce more extensive segmen-tal sensory block than bupivacaine alone. The ad-vantages of a diluted solution of local anesthetic in combination with a lipid-soluble opioid for epidural analgesia include a decreased intensity of motor block, a decreased total dose of local anesthetic, and fewer side effects (e.g., pruritus, nausea, and vomiting).18 Chaney19 reported a dose-dependent re-lationship between lipid-soluble opioids and pruri-tus when opioids were given intrathecally. In our study, the incidence of pruritus in Groups B and C did not differ much and the difference did not reach statistical significance (35% vs. 40%). Meanwhile, nausea and vomiting did not occur in patients in all three groups after the initial loading dose was given.
We conclude that 4 μg/mL fentanyl in combina-tion with bupivacaine as a loading dose for epidural analgesia could provide better relief of visceral pain during early labor without significant side effects, except for pruritus. Furthermore, a supplemental dose of bupivacaine was unnecessary.