Anesth Analg 2001;93:1560-1564
© 2001 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
Neostigmine Combined with Bupivacaine, Clonidine, and Sufentanil for Spinal Labor Analgesia
Robert D’Angelo, MD,
Laura S. Dean, MD,
Greg C. Meister, MD, and
Kenneth E. Nelson, MD
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Robert D’Angelo, MD, Obstetric Anesthesia, Forsyth Medical Center, 3333 Silas Creek Pkwy., Winston-Salem, NC 27103. Address e-mail to rdangelo{at}wfubmc.edu
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Abstract
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We previously found that spinal clonidine prolongs labor analgesia when combined with spinal bupivacaine and sufentanil. We sought to determine whether the addition of spinal neostigmine to these drugs would further enhance labor analgesia. By use of a combined spinal/epidural technique, 36 patients were randomized to receive a hyperbaric spinal injection of bupivacaine 2.5 mg plus clonidine 50 µg and sufentanil 10 µg with or without neostigmine 10 µg. Pain, maternal hemodynamics, fetal heart rate, nausea, pruritus, sedation, motor block, sensory levels to pinprick, and maternal oxygen saturation were assessed at regularly specified intervals after spinal injection until additional analgesia was requested. The duration of spinal analgesia was similar between groups (215 ± 60 min in the Control group versus 205 ± 62 min in the Neostigmine group). Likewise, pain scores, the duration of labor, Apgar scores, and side effects were similar between groups except that patients administered neostigmine experienced significantly more nausea and vomiting (53% vs 7%, P = 0.01). We conclude that spinal neostigmine 10 µg produces severe nausea and does not potentiate the duration of spinal analgesia in laboring women from spinal bupivacaine, clonidine, and sufentanil.
IMPLICATIONS: Spinal neostigmine 10 µg as an adjunct to spinal bupivacaine, clonidine, and sufentanil produces severe nausea and fails to potentiate analgesia in laboring women.
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Introduction
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The combined spinal/epidural technique is being increasingly used in obstetric anesthesia (1). Despite this increased popularity, drugs administered in both the spinal and epidural portions of the technique produce side effects such as hypotension, motor block, and pruritus (2). In addition, spinal labor analgesia typically lasts 2–3 h, after which analgesia is produced by the epidural infusion, which is more likely than the spinal portion to result in inadequate analgesia. Prolonging the duration of spinal analgesia will allow more patients to deliver without requiring epidural analgesia. It is hoped that a combination of spinal drugs can be found that produces longer lasting labor analgesia while minimizing side effects.
Spinal clonidine prolongs labor analgesia from spinal bupivacaine and sufentanil (3). These three drugs each provide analgesia but have distinct side effects when administered alone in large concentrations. Combining them enhances analgesia without producing significant side effects (3–10). Neostigmine may further enhance spinal labor analgesia from these drugs. Although spinal neostigmine alone produces analgesia in humans and animals at doses larger than 100 µg (11–14), dose-dependent nausea has also been observed (13,14). Animal studies suggest a synergistic antinociceptive effect of spinal 
2-adrenergic agonists and cholinesterase inhibitors (14), and volunteer studies have shown an enhancement of spinal 2-adrenergic agonists by neostigmine (15). Additionally, spinal neostigmine has been associated with a reduction in the dose of spinal narcotics required to produce postoperative analgesia (16,17). The purpose of this study was to determine whether neostigmine as a spinal adjunct to bupivacaine, clonidine, and sufentanil would further potentiate the duration of spinal labor analgesia without producing serious side effects.
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Methods
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After Food and Drug Administration (IND 52,156) and IRB (BG97-343) approval, informed written consent was obtained from 36 ASA status I or II nulliparous women, 30 of whom were included in the final data analysis. Patients were excluded if they were obese (>114 kg), had contraindications to regional anesthesia, had a nonreassuring fetal heart rate tracing, or had allergies to any of the study drugs. All patients were at term (38–41 wk gestational age), were in early established labor (2–5 cm cervical dilation), and had received no parenteral medications within 1 h of spinal injection. The patients were randomized, on the basis of a computer-generated table of random numbers, by using a double-blinded technique, to receive a hyperbaric mixture of bupivacaine 2.5 mg, clonidine 50 µg, and sufentanil 10 µg with or without neostigmine 10 µg. D10 was added to each solution to total 2.5 mL and to achieve an approximate 4% concentration of glucose. Hyperbaric solutions reduce the risk of nausea if neostigmine is administered with patients in the lateral position (11). All study solutions were prepared by an anesthesiologist not involved in the patient’s care by using standardized, written instructions for study drug preparation. TB syringes were used to minimize the risk of dilutional errors.
The epidural space was identified with patients in the lateral decubitus position via a loss of resistance to air technique by use of a 17-gauge, 3.5-in. Tuohy-Schliff epidural needle. A 27-gauge 411/16-in. Whitacre spinal needle was then inserted through the epidural needle, and after aspiration of cerebrospinal fluid, the study solution was administered. The spinal needle was removed, and an 18-gauge three-holed (B Braun Medical, Bethlehem, PA) epidural catheter was advanced 4–6 cm into the epidural space. The patient was then placed in the supine position with left uterine displacement ensured. Noninvasive maternal blood pressure, tocodynamometry, and continuous fetal heart rate were monitored throughout labor but were recorded at 0, 5, 10, 15, and 30 min after spinal injection and then every 30 min until additional analgesia was requested. Pulse oximetry was monitored for 1 h after subarachnoid injection. Patients not experiencing analgesia within 15 min of study drug administration and those who experienced complete cervical dilation or delivered before requesting additional analgesia were excluded from the final data analysis. Neither a subarachnoid nor an IV test dose was administered to test for accidental intrathecal or IV catheter placement until the patient requested additional analgesia. Patients were asked to rate levels of pain, nausea, pruritus, and sedation on an 11-point scale (0 = none, 10 = worst imaginable) at the time intervals previously indicated. Maternal blood pressure, fetal heart rate, motor block with a four-point scale (0 = lifts legs off bed, 1 = bends knees only, 2 = moves feet only, 3 = no leg movement), and sensory levels to pinprick were also documented at the same time intervals. An additional 250-mL IV fluid bolus and/or ephedrine 5–10 mg was administered for a decrease in maternal blood pressure of >20%, systolic blood pressure of <100 mm Hg, or, in cases of fetal bradycardia (<120 bpm), without evidence of maternal hypotension. The timing and dose of ephedrine was recorded. The study was completed when additional labor analgesia was requested, and at that time, the epidural catheter was tested and labor analgesia was provided according to our standard clinical protocol.
Statistical analyses were performed with SAS version 6.12 (SAS Institute, Inc., Cary, NC). Data are presented as mean ± SD, median (25th, 75th percentiles), or percentages, as indicated. Patient demographics, duration of spinal analgesia, and duration of labor were analyzed by using Student’s t-tests. Side effects, mode of delivery, ephedrine use, and Apgar scores were analyzed with 
2, Fisher’s exact, and Wilcoxon’s ranked sum tests, as appropriate. A value of P < 0.05 was considered significant. Group size (15 patients per group) was determined by power analysis to detect a 30-min difference in analgesia between groups, assuming the Control group would experience a 200-min mean duration of spinal analgesia and with the following assumptions: SD = 28 min, power = 0.8, = 0.05.
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Results
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Thirty-six patients were randomized, and 30 completed the study. Four patients achieved complete cervical dilation, and two patients delivered before requesting additional analgesia and were excluded from the data analysis. The patient groups were similar demographically, except that patients who were administered neostigmine were significantly older (Table 1). Gestational age, cervical dilation before spinal placement, sensory levels to pinprick, and pain relief were similar between groups (Table 1). The duration of labor analgesia from the time of spinal injection until the request for additional analgesia was 215 ± 60 min for patients in the Control group versus 205 ± 62 min for those who received neostigmine and was similar between groups (Fig. 1).
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Figure 1. The duration of spinal labor analgesia from the spinal injection until the patient requested additional analgesia. All patients received bupivacaine 2.5 mg, clonidine 50 µg, sufentanil 10 µg, and D10 with or without neostigmine 10 µg to total 2.5 mL. The duration of spinal labor analgesia was similar between groups.
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Patients who were administered spinal neostigmine experienced significantly more severe nausea (a score of 10 on a 0–10 scale) (Table 2). Nausea was experienced between 60 and 180 min after neostigmine administration, and it peaked at approximately 90 min (Fig. 2). The incidence of other side effects, including pruritus, sedation, motor block, maternal oxygen desaturation, maternal hypotension and bradycardia, fetal bradycardia, and the number of patients who required ephedrine, was similar between groups (Table 2). Likewise, the mean dose of ephedrine administered to patients with hypotension was similar between groups (19 ± 13 vs 18 ± 17 mg for patients in the Control and Neostigmine groups, respectively). All 1- and 5-min Apgar scores were 7 or more except for one neonate in the Neostigmine group, who had 1- and 5-min Apgar scores of 1 and 4, respectively.
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Figure 2. The percentage of patients who experienced severe nausea and vomiting at each 30-min interval. All patients received spinal bupivacaine 2.5 mg, clonidine 50 µg, sufentanil 10 µg, and D10 with or without neostigmine 10 µg to total 2.5 mL. Overall, 53% of patients who were administered spinal neostigmine versus 7% in the Control group experienced severe nausea (P = 0.01).
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Discussion
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In this study, spinal neostigmine 10 µg as an adjunct to bupivacaine, clonidine, and sufentanil did not potentiate spinal labor analgesia but did significantly increase the incidence of severe nausea. The lack of enhanced spinal analgesia is in contrast to a recent study by Owen et al. (18) that found neostigmine significantly prolongs spinal analgesia when combined with bupivacaine, clonidine, and fentanyl. Although the nonequipotent doses of opioids administered by Owen et al. and the current study (fentanyl 25 µg versus sufentanil 10 µg, respectively) may explain some of this discrepancy, the differences in findings between studies are most likely related to the dose of clonidine administered in each study. Owen et al. (18) administered clonidine 30 µg and found that neostigmine prolonged labor analgesia from 123 to 165 minutes. The current study administered 67% more clonidine, which when combined with bupivacaine and sufentanil produced approximately 210 minutes of labor analgesia. Whereas the analgesic effect of neostigmine 10 µg probably lasts no longer than three hours, analgesia from clonidine 50 µg lasts approximately 3.5 hours (3). It is possible that increasing the dose of neostigmine may further potentiate the duration of labor analgesia from clonidine 50 µg. However, doses of neostigmine larger than 20 µg have not been investigated in pregnant patients (19), and the severe nausea reported both in the current study and in that of Owen et al. precludes administering larger doses of neostigmine to laboring women.
Spinal neostigmine 10 µg alone does not produce labor analgesia but does reduce the dose of sufentanil required to produce 60 minutes of analgesia by 25% (19). In animal models, acetylcholine has intrinsic analgesic properties, and its concentration in cerebrospinal fluid (CSF) is increased during painful electrical stimulation (20). The mechanism of spinal neostigmine-induced analgesia is proposed to be an inhibition of acetylcholinesterase that indirectly increases acetylcholine levels released from spinal cholinergic neurons deep in the dorsal horn (12,21,22). The analgesic effect is thought to be mediated via spinal muscarinic receptors (14). However, as previously discussed, any analgesic effect may be of a relatively short duration.
Hypotension from spinal bupivacaine and clonidine in animals has been reduced by the addition of neostigmine (23–25). Enhanced amounts of acetylcholine released from preganglionic sympathetic neurons may counteract the sympatholytic actions of local anesthetics or 2-adrenergic agonists (20). In contrast, patients administered spinal neostigmine in this study did not experience less hypotension than patients in the Control group (Table 2); this may reflect the small doses of spinal neostigmine we used. Nevertheless, any protective effect on the development of hypotension in humans would not outweigh the increased incidence of nausea produced by spinal neostigmine in laboring women.
Spinal neostigmine alone uniformly produces analgesia in large doses (100–200 µg), but it also results in significant dose-dependent nausea (11–14). Nausea associated with spinal neostigmine is thought to result from spread in CSF to brainstem sites and is not responsive to standard antiemetics (14). The incidence of nausea can be reduced in volunteers with the addition of glucose to the neostigmine solution, but only if this is administered with patients in the lateral position (11), which is why both of these variables were included in this study design. In contrast to our findings, neostigmine 10 µg did not produce nausea in volunteers (11,13,14) or when administered alone to laboring women (19). It is possible the drugs used in this study interacted to enhance nausea or enhance the spread of neostigmine within the spinal fluid. Also, a larger spinal injectate was administered in the current study (2.5 mL versus 2.0 mL in previous studies), and this may have enhanced spread within the CSF. Of interest, the nausea produced by neostigmine in this study exhibited an all or none phenomenon: patients either did not develop nausea (47%) or developed severe nausea with vomiting (53%) that was unresponsive to IV promethazine 12.5 mg. The severe nausea and vomiting occurred at approximately 90 minutes after study drug injection (Fig. 2), and this is consistent with previously demonstrated delays of 60–120 minutes in onset of nausea after spinal injection of neostigmine (11,14). There was no correlation between women who experienced hypotension and those who subsequently developed nausea.
Although patients administered spinal neostigmine were older than women in the Control group, we are unaware of any data suggesting that age affects neostigmine analgesia or side effects. This most likely reflects a statistical anomaly related to the study’s power. The study was designed to detect differences in duration of spinal analgesia between groups rather than to test for all demographic variables and side effects.
Although neostigmine failed to enhance spinal analgesia in this study, we believe that a combination of spinal drugs will ultimately be found that produces long lasting analgesia with minimal side effects. It is also important to stress that we do not condone the routine mixing of four or five spinal drugs that can potentially lead to mixing errors. Although this may be acceptable in a study setting, it is hoped that if a successful combination is found it will become commercially available or will be prepared in the hospital pharmacy. In addition, we do not currently administer clonidine in our clinical practice because it both is expensive and has a Food and Drug Administration "black box warning" against its routine use in obstetrics (26).
In summary, neostigmine 10 µg failed to enhance spinal labor analgesia when combined with bupivacaine, clonidine, and sufentanil but did significantly increase the incidence of nausea and vomiting. On the basis of these findings, we do not recommend the use of spinal neostigmine in labor patients.
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Accepted for publication August 1, 2001.
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Abstract
Introduction
