Epidural administration of local anesthetics during labor produces analgesia, anesthesia, and motor block, depending on the volume, concentration, and doses of drug used. New formulations of local anesthetics have been marketed with theoretical clinical benefits over the gold standard, bupivacaine, in terms of toxicity (1) and motor-blocking properties (2–5).
These end-points have not been considered fully in relation to the likely true relative efficacies or potencies for analgesia and, hence, therapeutic benefits or indexes. In addition, the relative motor-blocking potencies began to be addressed only recently, when it was demonstrated that ropivacaine was significantly less potent than bupivacaine for motor blockade, at 66% of bupivacaine (6). This finding allows improved comparisons of motor-blocking capabilities between drugs.
The minimum local analgesic concentration (MLAC) (7) has been defined as the median effective concentration (EC50), and a clinical model was developed to determine the epidural analgesic potencies of local anesthetics in the first stage of labor. The relative analgesic potencies (8) have been determined for racemic bupivacaine and the S-enantiomer, levobupivacaine. There are no reports of the relative motor-blocking potencies of these drugs. The MLAC model has been adapted to determine the motor-blocking potencies (6) for local anesthetics (MMLAC). The aim of this study was to determine the motor block EC50 estimates for racemic bupivacaine and levobupivacaine in first-stage labor and then, by comparing the MMLAC estimates, to determine the relative potency ratio.
This research was conducted at the Pontificia Universidad Católica de Chile. After IRB approval and written, informed consent, 62 parturients of mixed parity, who were classified as ASA physical status I and II and who requested epidural analgesia, were enrolled. Participants had singleton pregnancies of more than 36 wk gestation with vertex fetal presentation. All women were in first-stage induced labor, at <7 cm dilation, when the epidural catheters were placed. Those who had received opioids or sedative medication in the previous hours were excluded.
Participants were allocated to one of two groups in a double-blinded, randomized, prospective study design. After IV prehydration with 500 mL of lactated Ringer’s solution, patients were placed in the flexed lateral position. The epidural space was identified by using loss of resistance to saline at the L2-3 or L3-4 level; injection was limited to 2 mL to minimize dilution of local anesthetic. Each patient received a 20-mL fractioned bolus through the needle, given within 5 min of either bupivacaine (Bupivan®; Abbott Laboratories, North Chicago, IL) or levobupivacaine (Chirocaine®; Abbott Laboratories, Rome, Italy) according to the group allocation. A multiport epidural catheter was advanced 5 cm into the epidural space with the needle bevel facing in the cephalad direction. For the purpose of the study, no epidural test dose was used.
The concentration of local anesthetic received by a particular patient was determined by the response of the previous patient in that group to a larger or smaller concentration, by using an up-down sequential allocation technique. The testing interval was 0.025% wt/vol. The first woman in each group received 0.25% wt/vol bupivacaine or levobupivacaine; this was based on an estimate of MLAC from a previous pilot study (9).
After catheters were inserted, patients were placed in the supine position with left uterine displacement and 30° elevation of the head of the bed. Patients were monitored with tococardiography and a Dinamap 8100® blood pressure monitor (Critikon, Tampa, FL).
The anesthesiologist performing the procedure and subsequent assessments was blinded to the concentration used and to group allocation. A baseline measurement of pain and muscle strength was made in all patients. Motor strength was assessed for both legs with a four-point Bromage scale (Table 1). Pain was evaluated with a 100-mm visual analog pain score (VAPS) during a painful uterine contraction, where 0 represented no pain and 100 represented the worst possible pain. Thirty minutes after the bolus injection, patients were assessed for motor blockade, pain scores, and sensory level to pinprick. A Bromage score of 4 was considered ineffective. Any other response on either leg was effective. Outcomes for motor blockade were defined as follows:
- Effective: Bromage score <4 at 30 min of injection on either leg. A result defined as effective directed a 0.025% wt/vol decrement for the next patient randomized to that group.
- Ineffective: Bromage score unchanged at 4 within 30 min of injection on both legs. A result defined as ineffective directed a 0.025% wt/vol increment for the next patient randomized to that group.
After the evaluation at 30 min, the study was complete. Patients were dosed through the epidural catheter on request, and the usual epidural analgesia practice of the labor ward was continued.
Fetal heart rate was monitored continuously by tococardiography, and any adverse events were recorded. A midwife or a perinatologist blinded to the study group allocation reviewed fetal heart rate tracings obtained during the study by using the National Institutes of Health research guidelines for interpretation of electronic fetal heart rate monitoring (11). Obstetric outcome data were also collected.
Demographic and obstetric data were collected and are presented as mean (sd), median (interquartile range), and numbers, as appropriate. Means (sd) were analyzed with unpaired Student’s t- or Welch’s t-tests for differing variances, medians (interquartile ranges) were analyzed with the Mann-Whitney U-test, and numbers or proportions were analyzed with Fisher’s exact test. The EC50 values were estimated from the up-down sequences by analyzing independent paired reversals, which enabled MLAC with 95% confidence intervals (CI) to be derived. The sequences were also subjected to Wilcoxon and Litchfield probit regression analyses as backup or sensitivity tests. Analyses were performed with the following software: Excel 2000 (Microsoft Corp., Redmond, WA), NCSS 2000 (NCSS Inc., Kaysville, UT), GraphPad Prism 3.02 (GraphPad Software Inc., San Diego, CA), and Pharmacological Calculation System 4.2 (Microcomputer Specialists, Wynewood, PA). Statistical significance was defined for an overall α error at the 0.05 level. All P values were two sided. Sample-size estimations were based on the sd (0.08% wt/vol) from prior pilot data for bupivacaine. Power was given at 0.9, with a minimum difference of 0.1% wt/vol in potency to be significant. It was then estimated that a minimum of 30 women would be required per group.
Of the 62 women enrolled in the study, 60 were used for analysis. Two subjects (both in the bupivacaine group) were rejected: one for protocol violation and the other for inability to perform measurements because of full cervical dilation before 30 min.
Demographic and obstetric data are shown in Table 2 and were similar in both groups. There were significant (P < 0.001) reductions in pain and motor block scores compared with pretest values in both groups (Table 3). The sequences for bupivacaine and levobupivacaine are shown in Figure 1. The MMLAC estimate for bupivacaine was 0.27% wt/vol (95% CI, 0.25–0.30) and for levobupivacaine was 0.31% wt/vol (95% CI, 0.29–0.34) (Table 4). The relative motor-blocking potency was significantly higher for bupivacaine (P = 0.024), with a levobupivacaine/bupivacaine potency ratio of 0.87 (95% CI, 0.77–0.98). The results in molar terms, as described elsewhere (8), due to the difference in the expressed formulation of levobupivacaine were 8.3 mmol/L (95% CI, 7.64–9.12 mmol/L) for bupivacaine and 10.89 mmol/L (95% CI, 9.86–11.91 mmol/L) for levobupivacaine. The molar potency ratio was 0.77 (95% CI, 0.68–0.88).
There were no significant differences in the groups regarding the upper level achieved for pinprick sensation: bupivacaine, T7 (T8 to T5); and levobupivacaine, T7 (T9 to T5). The VAPS are depicted in Table 3. Pain scores were significantly (P < 0.0001) reduced by 30 min, with no differences in the lower absolute pain scores. Satisfactory pain scores (VAPS of ≤30) were recorded in all women at 30 min. The degree of motor block in effective subjects was similar in both groups (Table 3).
Review of the fetal heart rate tracings did not reveal significant differences in the study groups. No clinical obstetric interventions were performed in response to fetal heart rate during the study period. The obstetric outcomes were similar in the groups and are shown in Table 2.
This is the first study using the MMLAC methodology to compare the relative motor-blocking potencies of levobupivacaine and bupivacaine. The MMLAC methodology was described in a previous study (6), where it was demonstrated that the S-enantiomer ropivacaine was 34% less potent than racemic bupivacaine for motor block. In this study, we determined the contribution of enantiomerism of epidural bupivacaine to motor blockade, a concept that was suggested previously (6) but that was not directly demonstrated until now. Our current data confirm that the S-enantiomer levobupivacaine is significantly less potent than the racemate by 13% on a percentage weight per volume basis for motor block.
Our results of a lesser motor-blocking potency for levobupivacaine appear to contrast with the analgesic potency in labor (8). Lyons et al.’s (8) data on analgesic MLAC for levobupivacaine found almost no difference in analgesic MLAC with the racemate (levobupivacaine: 0.083% wt/vol; 95% CI, 0.065–0.101; bupivacaine: 0.081% wt/vol; 95% CI, 0.055–0.108; potency ratio, 0.98; P = not significant), although the CI was wide (95% CI, 0.67–1.41). Our results suggest that levobupivacaine may demonstrate greater apparent sensory-motor dissociation than racemic bupivacaine, especially if we express our results in molar terms. This translates to approximately a 25% reduction in motor block potency due to the difference in the expressed formulation of levobupivacaine (8). In considering the results from representative analgesic and motor block MLAC studies involving three centers (6,8,9,12), it appears that both levobupivacaine and ropivacaine widen the sensory-motor separation (Fig. 2) for the pipecoloxylidine homologous series of local anesthetics that have the ability to cause differential sensory and motor neural blockade (13). However, to determine whether this is a true pharmacological effect, we need to take the ratios rather than the absolute differences. Logarithmic transformation (Fig. 3) shows that the apparent differences may be lost in favor of similar pharmacological behaviors, suggesting that such behaviors are best explained by their respective relative potencies. It is therefore possible to hypothesize that the absolute measured differences in sensory-motor separation do not appear to be preserved in true terms of pharmacological proportionality. However, the profiles of apparent differences in separation should still be clinically useful for the lower-potency pipecoloxylidines, because low motor blockade with excellent analgesia is desirable in obstetric patients.
The current state of knowledge suggests that a clinical profile of potencies for motor block with the pipecoloxylidines is emerging: low, intermediate, and high for ropivacaine, levobupivacaine, and racemic bupivacaine, respectively (6,14,15). Indeed, such a profile has already been described for toxicity in animal models (1).
In conclusion, this study shows that levobupivacaine is less potent than the racemate in causing motor blockade after epidural administration. This further confirms the lesser potency of the S-enantiomeric pipecoloxylidines at inducing motor block.
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