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OBSTETRIC ANESTHESIA

The Relative Potencies for Motor Block After Intrathecal Ropivacaine, Levobupivacaine, and Bupivacaine

Michela Camorcia, MD^*, Giorgio Capogna, MD^*, Cristiana Berritta, MD^*, and Malachy O. Columb, FRCA

From the *Department of Anesthesia, Città di Roma Hospital, Roma, Italy; and Department of Anaesthesia and Intensive Medicine, South Manchester University Hospital, Wythenshawe, Manchester, UK.

Address correspondence and reprint requests to Michela Camorcia, MD, Department of Anesthesia, Città di Roma Hospital, Via Maidalchini 20, 00152 Roma, Italy. Address e-mail to michela_camorcia{at}yahoo.it.

	Abstract

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BACKGROUND: In this study, we sought to determine the median effective dose (ED₅₀) for motor block of intrathecal ropivacaine, levobupivacaine, and bupivacaine and to define their motor-blocking potency ratios.

METHODS: We enrolled 104 parturients undergoing elective cesarean delivery with combined spinal-epidural anesthesia and randomized them to one of three groups to receive intrathecal 0.5% (wt/vol) ropivacaine, levobupivacaine, or bupivacaine. The initial dose was 4 mg, and the testing interval was set at 1 mg. Efficacy was determined by the occurrence of any motor block in either lower limb (modified Bromage and hip motor function scale) within 5 min after the spinal injection.

RESULTS: As assessed using up-down analysis, intrathecal ED₅₀ for motor block was 5.79 mg for ropivacaine (95% CI 4.62–6.96), 4.83 mg for levobupivacaine (95% CI 4.35–5.32) and 3.44 mg for bupivacaine (95% CI 2.55–4.34) (P < 0.0007). The relative motor blocking potency ratios were ropivacaine/bupivacaine 0.59 (95% CI, 0.42–0.82), ropivacaine/levobupivacaine 0.83 (95% CI 0.64–1.09), and levobupivacaine/bupivacaine 0.71 (95% CI 0.51–0.98).

CONCLUSIONS: There is a clinical profile of potency for motor block for the pipecolylxylidines when administered spinally: low, intermediate, and high for ropivacaine, levobupivacaine, and bupivacaine, respectively.

	Introduction

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To evaluate the pharmacodynamic contributions of various epidural and intrathecal drugs, a clinical model was developed to determine the relative potencies of local anesthetics (1,2). This involves the estimation of the median effective dose (ED₅₀) to determine the spinal potency ratios for sensory and motor block. Ropivacaine, levobupivacaine, and bupivacaine belong to the pipecolylxylidine homologous series of local anesthetics that have an ability to cause differential sensory and motor neural blockade. We (2) have investigated the ED₅₀ for motor block with spinal ropivacaine and levobupivacaine, determining a relative potency ratio of 0.83 for ropivacaine/levobupivacaine. However, there are no reports of the ED₅₀ for motor block with intrathecal bupivacaine. Furthermore, we (3) previously determined the minimum local analgesic doses of the three local anesthetics for intrathecal analgesia in the first stage of labor. The results showed ropivacaine to be 35% less potent than bupivacaine and 19% less potent than levobupivacaine. The aim of our present study was to determine the ED₅₀ values for motor block with intrathecal ropivacaine, levobupivacaine, and bupivacaine, and then to estimate the motor blocking potency ratios of these three drugs.

	METHODS

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After institutional ethical approval and written informed patient consent, we enrolled 104 parturients, undergoing elective cesarean delivery with combined spinal-epidural (CSE) anesthesia in this prospective, randomized, double-blind, parallel group, up-down sequential allocation study. All parturients were at full-term gestation (>36 and <41 wk) with singleton pregnancies and were ASA physical status I or II.

Parturients underwent a CSE anesthetic technique in the left lateral decubitus position. The epidural space was identified using loss of resistance to saline at the L3–4 or L4–5 interspace with a 16-gauge Tuohy needle. A 26-gauge Whitacre spinal needle was then placed through the Tuohy needle until the dura mater was punctured. Once a free flow of clear cerebrospinal fluid was obtained in the hub of the spinal needle, the study drug was injected into the intrathecal space in 15 s. The spinal needle was then withdrawn and a closed-end, triple-port epidural catheter was threaded through the epidural needle. After the placement of the epidural catheter, parturients were placed in the supine position with left uterine displacement.

The women were randomized to one of three groups, by using a computer-generated list, to receive spinal 0.5% (wt/vol) ropivacaine, levobupivacaine, or bupivacaine. We used commercially available 0.5% (wt/vol) bupivacaine and levobupivacaine solutions. The 0.5% (wt/vol) ropivacaine solution was prepared by combining 1% (wt/vol) ropivacaine with 0.9% (wt/vol) sterile saline solution as the diluent to achieve the required 0.5% (wt/vol) concentration. All solutions were made by an investigator who did not have subsequent involvement in data collection. The initial dose of local anesthetic solution was 4 mg and the testing interval was set at 1 mg for all the three groups, according to our previous investigation (2). Subsequent doses of the drug in each group were determined by the outcome in the previous parturient, according to the up-down sequential allocation technique.

Efficacy of the study drug was assessed by using a modified Bromage scale (4) and the hip motor function scale (5) every minute for 5 min and again at 10 min (Table 1). Time 0 was considered to be the end of the injection of spinal local anesthetic solution. Parturients were asked to perform all motor block tests before the CSE block to exclude those who were not able to do them from the study. The end point was considered to be the occurrence of any motor block in either lower limb as assessed by at least one of the two scales within 5 min after spinal injection of study solution. We defined an effective outcome to be the occurrence of a motor block score >0 in any of the two scales in either leg within 5 min and this directed a 1 mg decrement of the study drug for the next parturient randomized to that group. We defined an ineffective outcome to be the occurrence of motor block score = 0 with both scales within 5 min, and this directed a 1 mg increment of the study drug for the next parturient assigned to that group. To ascertain that the local anesthetic solution was administered correctly in the subarachnoid space, we evaluated the presence of sensory block every minute for 5 min and at 10 min. The absence of any sign of intrathecal injection was considered a technical failure. In this case, the dose was repeated for the next parturient randomized to the same group and the outcome was considered a reject.

Sensory block was tested at lumbar and sacral dermatomes bilaterally for loss to pinprick sensation using the sharp tip of a sterile 25-gauge pencil-point spinal needle, and the parturients were instructed to report when the sharpness of the needle felt the same when compared with the sensation tested over an unanesthetized area. Parturients were monitored for heart rate, noninvasive arterial blood pressure, pulse oximetry, and tococardiography. Hypotension was defined as a 20% decrease in mean arterial blood pressure when compared with baseline values and treated, if necessary, with a 5-mg IV boluses of ephedrine. All assessments were made by an anesthesiologist who was not involved in the patient’s care and was blinded to the group assignment as well as to the drug injected. After completion of the study, all parturients received incremental epidural boluses of 2% (wt/vol) lidocaine with epinephrine 1:200,000, and sodium bicarbonate 1 mEq to achieve a satisfactory anesthetic level for cesarean delivery.

Demographic and obstetric data were collected and are presented as mean ± SD, median and interquartiles, and count as appropriate. Means ± SD were analyzed using one-way analysis of variance (ANOVA) and medians and interquartiles by Kruskal–Wallis one-way analysis. Additional analyses included Tukey post-tests and logistic regression. The median effective doses were estimated using up-down reversals and probit regression, which enabled ED₅₀ with 95% confidence intervals (95% CI) to be derived (6). The number of parturients enrolled was based on a previous study (2). Assuming a coefficient of variation of 0.25 and to detect a 30% change in ED₅₀ with 80% power at a Bonferroni corrected threshold P = 0.017 to maintain overall P < 0.05, a minimum of 29 subjects in each of the three groups was required for an up-down sequential allocation design. Analyses were performed using the following software; Excel 2000 (Microsoft, Redmond, VA), Number Crunching Statistical System (NCSS) 2004 (NCSS, Kaysville, UT), Minitab 14 (Minitab, State College, PA) and GraphPad Prism 4.01 (GraphPad Software, San Diego, CA). Statistical significance was defined at P < 0.05 (two-sided).

	RESULTS

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Of the 104 women enrolled in the study, 99 remained for the analysis. Five subjects (one in the levobupivacaine group and two in both the ropivacaine and bupivacaine groups) were rejected according to the study protocol. Demographic and obstetrical data were similar in the groups (Table 2).

The sequences of effective and ineffective outcomes are shown in Figure 1. As found using up-down analysis, the intrathecal ED₅₀ for motor block was 5.79 mg for ropivacaine (95% CI 4.62–6.96), 4.83 mg for levobupivacaine (95% CI 4.35–5.32) and was 3.44 mg for bupivacaine (95% CI 2.55–4.34), (ANOVA P < 0.0007). The ED₅₀ values for motor block as calculated using both the up-down analysis and probit regression are reported in Table 3. The relative motor blocking potency ratios were ropivacaine/bupivacaine 0.59 (95% CI 0.42–0.82), ropivacaine/levobupivacaine 0.83 (95% CI 0.64–1.09), and levobupivacaine/bupivacaine 0.71 (95% CI 0.51–0.98).

View larger version (12K): [in this window] [in a new window]   Figure 1. Sequences of effective and ineffective outcomes. The sequences of effective and ineffective outcomes are shown in Figure 1. As assessed using up-down analysis the intrathecal ED50 for motor block was 5.79 mg for ropivacaine (95% CI 4.62–6.96), 4.83 mg for levobupivacaine (95% CI 4.35–5.32) and was 3.44 mg for bupivacaine (95% CI 2.55–4.34), (ANOVA P < 0.0007).

None of the parturients had motor impairment before the CSE procedure was performed. All parturients were able to perform the motor block evaluation tests before the anesthetic block. In addition, no parturient with an ineffective outcome (no motor block) at 5 min developed any sign of motor block at the 10 min evaluation. Routine observations were similar in all groups for maternal heart rate, incidence of hypotension, pulse oximetry values, and fetal heart rate tracings.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
In this study, we assessed the ED₅₀ for motor block of ropivacaine, levobupivacaine, and bupivacaine, and established the motor-blocking potency ratios for these three drugs when administered by the intrathecal route. We found that spinal ropivacaine was 41% less potent than bupivacaine and 17% less potent than levobupivacaine, which, in turn, was 29% less potent than bupivacaine. The results of the present study are consistent with our previous study in which we reported spinal ropivacaine to be 17% less potent than levobupivacaine in producing motor block (2).

The S-enantiomers, ropivacaine and levobupivacaine, produce less motor block than racemic bupivacaine when administered by the epidural route (7,8). Lacassie et al. (7,8) found the epidural potency ratios for motor block for ropivacaine/bupivacaine and levobupivacaine/bupivacaine to be 0.66 and 0.87, respectively. According to these (7,8) and other epidural analgesic studies (9–13), it seems that there is a spectrum of potencies from low, intermediate, to high for ropivacaine, levobupivacaine, and racemic bupivacaine, respectively, with regard to analgesia, motor block, and toxicity (14).

The intrathecal potency ratios for motor block obtained in our present study are similar to those for analgesia from our previous study, in which we found ropivacaine to be 35% less potent than bupivacaine and 19% less potent than levobupivacaine.

When considering the ED₅₀ values for sensory analgesia reported in our previous study (2) and the motor block values determined in the present study, it appears that intrathecal ropivacaine exhibits a greater sensory motor dissociation when compared with bupivacaine.

The lesser potential for motor block with intrathecal ropivacaine is supported by a study of day surgery patients (15), which suggested a favorable profile when compared to bupivacaine.

The greater lipid solubility of bupivacaine becomes more apparent in the intrathecal space near the spinal cord, and this means greater partition into the cord with almost inevitable motor-blocking effects. It then follows that the lower potency of ropivacaine is advantageous when minimizing motor block with intrathecal injection. It is noteworthy, however, that the sensory-motor separation observed with intrathecal studies is not as marked when compared with that of previous epidural studies (7,8). Thus, it appears that any advantages due to sensory-motor separation are reduced to some extent with intrathecal administration.

In conclusion, we estimated the ED₅₀ for motor block with ropivacaine, levobupivacaine, and bupivacaine when given intrathecally, supporting the observation that there is a clinical profile of potencies for motor block for the pipecolylxylidines, even when administered spinally: low, intermediate, and high, for ropivacaine, levobupivacaine, and bupivacaine, respectively. These data confirm that potency issues can be used to explain the lesser motor-blocking effects of intrathecal ropivacaine and levobupivacaine.

	Footnotes

 
Accepted for publication December 12, 2006.

Presented in part at the annual meeting of the European Society of Anaesthesiologists, Vienna, Austria, May 28–31, 2005.

	REFERENCES

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3. Camorcia M, Capogna G, Columb MO. Minimum local analgesic doses of ropivacaine, levobupivacaine and bupivacaine for intrathecal labor analgesia. Anesthesiology 2005;102:646–50.[Web of Science][Medline]
4. Bromage PR. A comparison of the hydrochloride and carbon dioxide salt of lidocaine and prilocaine in epidural analgesia. Acta Anaesth Scandinav Suppl 1965;17:55–69.
5. Collis R. Ambulatory analgesia in labour. In: Collis R, Plaat F, Urquart J, eds. Textbook of obstetric anaesthesia. London: GMM Publications, 2002:108.
6. Columb MO, Thomson HE. Confidence with confidence intervals. Br J Anaesth 2005;95:111–12.[Free Full Text]
7. Lacassie HJ, Columb MO, Lacassie HP, Lantadilla RA. The relative motor blocking potencies of epidural bupivacaine and ropivacaine in labor. Anesth Analg 2002;95:204–8.[Abstract/Free Full Text]
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12. Benhamou D, Ghosh C, Mercier FJ. A randomized sequential allocation study to determine the minimum effective analgesic concentration of levobupivacaine and ropivacaine in patients receiving epidural analgesia for labor. Anesthesiology 2003;99:1383–6.[Web of Science][Medline]
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