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OBSTETRIC ANESTHESIA

Intrathecal Fentanyl, Sufentanil, or Placebo Combined with Hyperbaric Mepivacaine 2% for Parturients Undergoing Elective Cesarean Delivery

Dirk Meininger, MD^*, Christian Byhahn, MD^*, Paul Kessler, MD^*, Jonas Nordmeyer, MD^*, Yasmin Alparslan^*, Brian A. Hall, MD, and Dorothee H. Bremerich, MD^*

*Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany, and Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota

Address correspondence and reprint requests to Dorothee H. Bremerich, MD, Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Johann Wolfgang Goethe-University Clinic, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. Address e-mail to bremerich{at}em.uni-frankfurt.de

	Abstract

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Worldwide, long-acting bupivacaine is the most popular local anesthetic for spinal anesthesia in parturients undergoing elective cesarean delivery. With advances in surgical techniques, e.g., the Misgav Ladach method, and shorter duration of surgery, the local anesthetic mepivacaine, with an intermediate duration of action, may be a reasonable alternative. Our aim in the present study was to evaluate the effects of 2% hyperbaric mepivacaine alone, or combined with either intrathecal fentanyl (5 and 10 µg), or sufentanil (2.5 and 5 µg), on sensory, motor, and analgesic block characteristics, hemodynamic variables, and neonatal outcome in a randomized, prospective, and double-blinded study (n = 100, 20 parturients per group, singleton pregnancy, >37 wk of gestation). No parturient experienced intraoperative pain. The average duration of motor block Bromage 3 in all groups was 68 min, and resolution time to Bromage 0 was 118 min. Maximal cephalad sensory block level was T3-6 and could be established within 6 min. Complete analgesia was significantly prolonged in all groups receiving intrathecal opioids, yet, with sufentanil 5 µg, even the duration of effective analgesia was significantly extended. Neonatal outcome was not affected by intrathecal opioid administration. In conclusion, 2% hyperbaric mepivacaine is a feasible local anesthetic for spinal anesthesia in parturients undergoing elective cesarean delivery, particularly with short duration of surgery.

IMPLICATIONS: Sensory, motor, and analgesic block characteristics of the local anesthetic mepivacaine alone or combined with intrathecal opioids were studied in parturients undergoing elective cesarean delivery in a randomized, double-blinded clinical trial. Mepivacaine was found to be an acceptable local anesthetic for spinal anesthesia in parturients undergoing cesarean delivery. In combination with sufentanil 5 µg, complete and effective analgesia were significantly prolonged.

	Introduction

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Worldwide, bupivacaine is the most popular local anesthetic for spinal anesthesia in parturients undergoing elective cesarean delivery (1,2). With advances in surgical technique, e.g., the Misgav Ladach method, and shorter duration of surgery (3), the local anesthetic, mepivacaine, with a shorter duration of action, may be a reasonable alternative. However, despite reports of successful use of mepivacaine for spinal anesthesia in the 1960s (4), its intrathecal use for parturients undergoing cesarean delivery has not yet been described.

Intrathecal opioids combined with various local anesthetics markedly improve quality and duration of postoperative analgesia after cesarean delivery, provide better parturient comfort, and do not affect neonatal outcome significantly (5–7). Supplementary intrathecal fentanyl and sufentanil are often used for cesarean delivery (6,7). There is, however, controversy regarding the specific benefits, the various side effects, and the appropriate dosage of these opioids (5).

Our aim in the present study was to evaluate whether 2% hyperbaric mepivacaine alone is an alternative local anesthetic for spinal anesthesia in parturients undergoing elective cesarean delivery. Furthermore, we investigated the sensory, motor, and analgesic block characteristics of intrathecal fentanyl 5 and 10 µg, compared with sufentanil 2.5 and 5 µg, and placebo when added to 2% hyperbaric mepivacaine. Neonatal outcome as well as adverse effects over 72 h were also assessed.

	Methods

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After Institutional Ethics Committee approval and written, informed consent, 100 ASA physical status I parturients at full-term gestation presenting for elective cesarean delivery were included in this prospective, randomized, double-blinded study.

To facilitate blinding, test solutions were prepared by a pharmacist who was not otherwise involved in the study. The preservative-free study drug was diluted to a total volume of 3 mL, containing 60 mg of mepivacaine, the opioid, and 8.6% glucose (95 mg of glucose monohydrate/mL) to assure hyperbaricity. Neither the anesthesiologist nor the parturient herself was aware of the drugs or dose administered (sealed envelope randomization). The parturients had fasted a minimum of 6 h preoperatively. Large-bore IV access was secured in the right forearm and lactated Ringer’s solution 500 mL and hydroxyethyl starch 6% 500 mL were administered IV for prophylactic volume preload 30–45 min before the induction of anesthesia (8). All parturients received 50 mg of IV ranitidine, and 20 mL of 0.3 M sodium citrate orally upon arrival to the operating room to reduce the risk of acid aspiration syndrome. A pulse oximeter, blood pressure cuff, and electrocardiograph were placed for baseline measurements. Heart rate and arterial oxygen saturation were monitored continuously; noninvasive arterial blood pressure was recorded at 1-min intervals from the time of intrathecal injection until delivery, and thereafter at 5-min intervals until the end of surgery. With the parturient in the sitting position, a 25-gauge pencil-point needle was inserted into the subarachnoid space, preferably into the L2-3 interspace in a midline approach. The parturients were randomly allocated into groups of 20 each to receive 60 mg of 2% mepivacaine plus either saline, fentanyl 5 µg, fentanyl 10 µg, sufentanil 2.5 µg, or sufentanil 5 µg intrathecally with the aperture of the needle oriented in a cephalad direction. Immediately after drug injection, the parturient was positioned supine on the operating table with a 15° leftward tilt. Oxygen 2–4 L/min was delivered routinely via nasal cannula until delivery. If maternal hypotension, defined as a systolic blood pressure <100 mm Hg occurred, it was promptly treated with 40 mg of IV cafedrine and 2 mg of IV theodrenaline (0.4 mL of Akrinor®; Arzneimittelwerk Dresden GmbH, Radebeul, Germany) (9) and repeated as needed. Bradycardia was defined as a heart rate <60 bpm and was treated with 0.5 mg of IV atropine. Immediately after delivery, all parturients received an IV bolus of oxytocin 10 IU, followed by a slow infusion (±15 min) of 30 IU of oxytocin in 100 mL of 0.9% saline solution. Furthermore, all parturients received 1.5 g of cefuroxim after delivery.

Sensory block was assessed bilaterally by loss of cold sensation, and the degree of motor block was determined according to the Bromage scale (10) (0 = free movements of legs and feet; 1 = just able to flex knees, free movements of feet; 2 = unable to flex knees, free movement of feet; and 3 = unable to move legs or feet). After intrathecal injection, sensory and motor block assessments were performed every minute until delivery, and subsequently at 5-min intervals until the end of surgery. Thereafter, spinal block characteristics were assessed at 15-min intervals until complete recovery of motor function and sensation at the L1 dermatome were determined. In accordance with Dahlgren et al. (7), a 100-mm Visual Analog Scale (VAS) (0 = no pain, 100 = worst imaginable pain) was used postoperatively to measure duration of complete (VAS score = 0) and effective (VAS score 40 of 100) analgesia at 15-min intervals. These variables were arbitrarily defined; at a pain score of 41 of 100, the parturient received an IV opioid by a nurse in the postanesthesia care unit. The presence or absence of adverse effects, including nausea, vomiting, pruritus, shivering, backache, and postdural puncture headache during the first 72 h after spinal anesthesia as well as any treatment requirements were noted by questioning the parturients at regular time intervals (every 24 h).

The surgical procedure, a modified Misgav Ladach technique, was uniform in all parturients (3), and was performed each time by the same obstetrician with the assistance of a second–third year resident.

At delivery, arterial and venous blood samples were drawn from a double-clamped segment of the umbilical cord and immediately analyzed for neonatal acid-base status. Apgar scores were determined by a neonatologist not otherwise involved in the study at 1, 5, and 10 min after delivery.

Data were presented as mean ± SD, median, and range, or number of parturients where appropriate. Calculation and data analysis were performed by using a statistical package (GraphPad InStat^TM 3.0; GraphPad Software, San Diego, CA). After verifying Gaussian distribution, statistical significance was determined by using one-way analysis of variance with Student-Newman-Keuls adjustment for multiple comparisons. Fisher’s exact test was performed to compare contingencies, and the P values calculated with the latter test were -adjusted according to Bonferroni when multiple comparisons were made. Differences were considered to be statistically significant if P was <0.05.

	Results

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Demographics and Incidence of Repeat Cesarean Deliveries
All 100 parturients completed the study. They received 60 mg of mepivacaine 2% plus either saline (n = 20), fentanyl 5 (n = 20) or 10 µg (n = 20), or sufentanil 2.5 (n = 20) or 5 µg (n = 20). The site of subarachnoid injection was L2-3 in 77% of the parturients, L3-4 in 17%, and L4-5 in 6%. Except for slight differences in body weight, there were no statistically significant differences in terms of demographic data, the insertion site, or the incidence of repeat cesarean delivery (Table 1).

View larger version (24K): [in this window] [in a new window]   Figure 1. Analgesic block characteristics of intrathecal mepivacaine alone or in combination with fentanyl (5 or 10 µg) or sufentanil (2.5 or 5 µg). Data are mean ± SD, n = 20 in each group. *P < 0.05 mepivacaine versus any other group; P < 0.05 sufentanil 2.5 µg versus mepivacaine; #P < 0.05 sufentanil 5 µg versus any other group.

Regardless of the drugs used for spinal anesthesia, slight-to-moderate backache was observed in 2–4 parturients per group (Table 4).

	Discussion

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Sensory and Motor Block Characteristics
Worldwide, bupivacaine alone or combined with opioids is the most commonly used local anesthetic for spinal anesthesia in parturients undergoing cesarean delivery (1,2), producing a profound, long-lasting motor block (7). If combined with intrathecal opioids, local anesthetic requirements can be decreased, resulting in a shorter duration of motor block as well as a significantly extended postoperative maternal analgesia (11,12). With the introduction of a new technique for cesarean delivery (the Misgav Ladach method), the duration of this surgery has been markedly decreased (3), making local anesthetics characterized by a shorter motor block, e.g., mepivacaine, more optimal. Spinal mepivacaine either alone or in combination with opioids has not been evaluated in parturients undergoing cesarean delivery.

The duration of motor block Bromage 3 and resolution time to Bromage 0 after intrathecal mepivacaine administration is markedly shorter when compared with 15 mg of hyperbaric and plain ropivacaine 0.3% (13) and 12.5 mg of hyperbaric bupivacaine 0.5% (7). In addition, the onset of motor block, defined as time from intrathecal injection to Bromage 1 block was approximately 3 minutes. In our parturients, the maximal cephalad sensory block level was between T3 and T6, comparable to the results with hyperbaric bupivacaine (7), and could be established within 6 minutes after intrathecal injection.

Intra- and Postoperative Analgesia
Numerous studies have clearly demonstrated prolongation of postoperative analgesia when opioids are combined with local anesthetics for spinal anesthesia in parturients undergoing cesarean delivery (5,7,11,12). Because fentanyl and sufentanil added to 2% hyperbaric mepivacaine has not yet been studied in the obstetric setting, we investigated a dose-response relationship of two different concentrations. Statistically significant differences were observed among groups with respect to onset of motor block and regression time of sensory block to T10; however, in our opinion, these findings were not clinically relevant because there was no change in patient care or duration of postanesthesia care unit stay.

Regardless of the opioid and dose administered, complete analgesia was significantly enhanced and prolonged when fentanyl or sufentanil was added to mepivacaine. However, of the opioids and doses studied, sufentanil 5 µg provided the longest duration of complete analgesia. Furthermore, sufentanil was the most potent adjunct to mepivacaine with respect to duration of effective analgesia. In contrast to fentanyl, which did not prolong effective analgesia significantly when compared with mepivacaine alone, sufentanil 2.5 µg almost doubled the duration of effective analgesia. Using sufentanil 5 µg, effective analgesia reached 367 minutes, compared with 85 minutes with mepivacaine alone and 162 minutes with sufentanil 2.5 µg. These results are in accordance with the findings of Dahlgren et al. (7). In their study, with sufentanil 5 µg combined with 12.5 mg of hyperbaric bupivacaine 0.5%, both complete and effective postoperative analgesia were significantly longer compared with fentanyl 10 µg or bupivacaine alone (7). Based on our results, we conclude that sufentanil 5 µg is the optimal choice of opioid and dose when combined with 2% hyperbaric mepivacaine. Nonetheless, it remains speculative whether fentanyl doses larger than 10 µg might have increased duration of complete and effective postoperative analgesia. Belzarena (14), who added fentanyl 0.25, 0.5, or 0.75 µg/kg to hyperbaric bupivacaine, demonstrated a dose-dependent increase in effective analgesia, with fentanyl 0.75 µg/kg producing a 13-hour period of effective analgesia. However, with increasing doses of fentanyl, an increasing incidence of adverse effects, e.g., pruritus and respiratory depression has been described (15).

In contrast, Hunt et al. (16) demonstrated no further increase in duration of postoperative analgesia or any decrease in 24-hour supplementary opioid requirement when the dose of intrathecal fentanyl was increased to >6.25 µg.

Hemodynamics and Adverse Effects
Side effects of intrathecally administered opioids include maternal respiratory depression, nausea, vomiting, and pruritus (17,18). Shivering, nausea, vomiting, and the requirement for antiemetic drugs was observed in all treatment groups sporadically and independent of the specific intrathecal drug or dose administered. Pruritus occurred almost exclusively, and independent of dose, with additional fentanyl or sufentanil. No parturient of any group, however, required antipruritic treatment. Short-term maternal hypotension before delivery was observed with the same frequency in all groups. Assisted ventilation was not required in any of the neonates, nor did respiratory depression occur in any parturient.

A 22% incidence of transient neurologic symptoms has been reported after the intrathecal administration of isobaric lidocaine (19). Rarely, similar symptoms were observed with bupivacaine (20,21) and 4% hyperbaric mepivacaine (22,23). Because of its pharmacologic and structural resemblance to lidocaine, mepivacaine might seem likely to cause transient neurologic symptoms similar to lidocaine. None of our parturients, however, had complaints about transient neurologic symptoms, although slight-to-moderate backache was reported in several parturients. The lack of transient neurologic symptoms in our study may be attributable to the supine position or to factors associated with pregnancy (24).

Neonatal Outcome
Because of its long half-life, detectability in the neonatal plasma up to 24 hours after delivery, and ion trapping characteristics in acidotic neonates, the use of epidural mepivacaine has been discouraged in obstetric anesthesia (25). After the intermittent epidural administration of large-dose mepivacaine (total dose range administered: 360–750 mg, equivalent to 6.6 mg/kg) for labor analgesia, mepivacaine plasma concentrations were reported to be sufficiently large enough to cause neonatal depression as well as maternal toxic side effects (26). These finding were confirmed by Clark et al. (27) and Scanlon et al. (28). In contrast to these results, however, no adverse effects on neonatal Apgar scores, acid-base status, or the Early Neonatal Neurobehavioral Scale were observed (29) after the single-shot administration of 359 ± 27 mg of epidural mepivacaine in parturients undergoing cesarean delivery.

For spinal anesthesia, however, only small quantities of mepivacaine are used and the rate of drug absorption from the subarachnoid space is slow. Mean total mepivacaine dose administered intrathecally in the present study was 0.7 ± 0.32 mg/kg, reducing the potential fetal drug load to about one-tenth of that given epidurally (26). Neonatal Apgar scores as well as umbilical cord blood analysis, as a biochemical marker of neonatal outcome, showed no evidence of neonatal depression after the intrathecal administration of 60 mg of hyperbaric mepivacaine 2% alone or in combination with opioids to parturients undergoing elective cesarean delivery.

In conclusion, 60 mg of hyperbaric mepivacaine 2% is an appropriate local anesthetic for spinal anesthesia in parturients undergoing elective cesarean delivery with respect to anesthetic as well as recovery profiles. Combined intrathecal fentanyl or sufentanil markedly improved postoperative maternal analgesia with sufentanil 5 µg providing the longest duration of complete and effective analgesia. Neonatal outcome was not affected by intrathecal opioid administration. Adverse effects within the first 72 hours after surgery were comparable in all groups.

	Footnotes

 
Presented, in part, at the International Anesthesia Research Society, 74th Clinical and Scientific Congress, Honolulu, HI, March 14, 2000 and the International Anesthesia Research Society, 75th Clinical and Scientific Congress, Ft. Lauderdale, FL, March 16–20, 2001.

	References

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