Anesthesia & Analgesia:
Regional Anesthesia: Research Reports
The Median Effective Dose of Bupivacaine, Levobupivacaine, and Ropivacaine After Intrathecal Injection in Lower Limb Surgery
Lee, Ying Y. MBChB, FFARCSI, MScPainM*†; Ngan Kee, Warwick D. MBChB, MD, FANZCA*; Fong, Siu Y. MBBS, FHKCA†; Liu, John T. C. MBBS, FFARCSI, FHKCA†; Gin, Tony MBChB, MD, FANZCA, FRCA*
From the *Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin; and †Department of Anaesthesiology and Operating Theatre Services, Kwong Wah Hospital, Kowloon, Hong Kong SAR, China.
Accepted for publication May 8, 2009.
Supported by the Tung Wah Group of Hospitals Doctors’ Association Research Fund.
Tony Gin is Section Editor of Anesthetic Clinical Pharmacology for the Journal. This manuscript was handled by Terese T. Horlocker, Section Editor of Regional Anesthesia, and Dr. Gin was not involved in any way with the editorial process or decision.
Presented in part at the XXVII Annual European Society of Regional Anesthesia Congress, Genoa, Italy, September 24–27, 2008.
Reprints will not be available from the author.
Address correspondence to Ying Yin Lee, MBChB, FFARCSI, MScPainM, Department of Anesthesiology, Kwong Wah Hospital, 25, Waterloo Rd., Kowloon, Hong Kong SAR, China. Address e-mail to firstname.lastname@example.org.
BACKGROUND: Intrathecal anesthesia is commonly used for lower limb surgery. Bupivacaine, levobupivacaine, and ropivacaine have all been used as intrathecal drugs, but their relative potency in this context has not been fully determined. In this study, we determined the median effective dose (ED50) of these three local anesthetics for intrathecal anesthesia in lower limb surgery and hence their relative potencies.
METHODS: Seventy-five patients scheduled for lower limb surgery under combined spinal-epidural anesthesia were randomly allocated to one of three groups receiving intrathecal bupivacaine, levobupivacaine, or ropivacaine. The dose of local anesthetic was varied using up-down sequential allocation technique. The dose for the first patient in each group was 8 mg, and the dosing increment was set at 1 mg. Subsequent doses in each group were determined by the outcome in the previous patient using success or failure of the spinal anesthesia as the primary end point. A success was recorded if a bilateral T12 sensory block to cold was attained within 20 min after intrathecal injection, and the surgery proceeded successfully until at least 50 min after the intrathecal injection without supplementary epidural injection. The ED50 was calculated using the method of Dixon and Massey.
RESULTS: The ED50s were 5.50 mg for bupivacaine (95% confidence interval [CI]: 4.90–6.10 mg), 5.68 mg for levobupivacaine (95% CI: 4.92–6.44 mg), and 8.41 mg for ropivacaine (95% CI: 7.15–9.67 mg) in intrathecal anesthesia. The relative anesthetic potency ratios are 0.97 (95% CI: 0.81–1.17) for levobupivacaine/bupivacaine, 0.65 (95% CI: 0.54–0.80) for ropivacaine/bupivacaine, and 0.68 (95% CI: 0.55–0.84) for ropivacaine/levobupivacaine.
CONCLUSION: This study suggests that in intrathecal anesthesia for lower limb surgery, ropivacaine is less potent than levobupivacaine and bupivacaine, whereas the potency is similar between levobupivacaine and bupivacaine.
Levobupivacaine and ropivacaine have been described as alternatives to bupivacaine for spinal anesthesia.1–5 The relative potencies of these drugs when given intrathecally for labor analgesia have been determined,6,7 but, because there are differences in pharmacodynamic response and block requirement between pregnant and nonpregnant patients, the results of these studies may not be applicable to other surgical populations. This study compared the potencies of levobupivacaine, ropivacaine, and bupivacaine when given intrathecally using a combined spinal-epidural technique in patients having lower limb surgery. For each local anesthetic, the up-down sequential allocation method8 was used to determine and then compare the median effective dose (ED50), which is also referred to as the minimum local anesthetic dose.9,10
This study was a prospective, randomized, double-blind trial of 75 patients scheduled for lower limb surgery under combined spinal-epidural anesthesia. Approval was obtained from the Clinical Research Ethics Committee, Kowloon West Cluster, Hospital Authority, Hong Kong Special Administrative Region, China. All patients gave written informed consent. Inclusion criteria were 1) ASA physical status I–III; 2) age ≥18 yr; 3) body weight 40–90 kg; 4) height ≥145 cm; and 5) lower limb surgery involving the hip or knee area. Exclusion criteria were 1) known hypersensitivity to amide local anesthetics; 2) contraindications to spinal or epidural anesthesia; 3) inability to speak English or Chinese; and 4) body mass index >35 kg/m2. After enrollment, the patients were randomly assigned into one of three groups (n = 25 per group) to receive an intrathecal dose of bupivacaine, levobupivacaine, or ropivacaine according to computer-generated random numbers using the sealed envelope technique.
A standard combined spinal-epidural technique was used with a commercial kit (BD Durasafe plus variable extension set, Becton Dickinson Medical Devices Co., Suzhan, China). An IV infusion of 10 mL/kg of normal saline was given as prehydration. With the patient in the lateral position and using full aseptic precautions, the epidural space was identified at the L3–4 or L2–3 interspaces with a 17-gauge Tuohy needle using the loss of resistance to air technique. A 25-gauge Whitacre spinal needle was then passed through the epidural needle, and free flow of cerebrospinal fluid from the spinal needle indicated the correct position. Intrathecal injection of the study solution was done with the orifice of the Whitacre needle facing cephalad. After the intrathecal injection, the spinal needle was removed, and an epidural catheter was inserted 3–4 cm into the epidural space and then secured with tape. No drug was injected via the epidural catheter. The patient was then returned to the supine position.
The study solutions were prepared by an anesthesiologist, who was not involved with subsequent patient assessment, using 0.5% bupivacaine (AstraZeneca Pty, North Ryde, NSW, Australia), 0.5% levobupivacaine (Nycomed Pharma AS, Elverum, Norway for Abbott Laboratories), or 1% ropivacaine (Naropin, AstraZeneca Pty, Soterlaje, Sweden). A different anesthesiologist, who was blinded to the drug and dose, administered anesthesia and assessed patients. The dose of intrathecal local anesthetic administered to patients was varied according to the up-down sequential allocation method.8 In each group, the dose used for the first patient was 8 mg. For each subsequent patient, the dose was determined by the outcome of the previous patient in the group with the dosing increment set at 1 mg. For the purposes of the study, a successful block was defined using criteria we used in a previous study of patients having lower limb surgery.11 Accordingly, a success was recorded if a bilateral sensory block to the T12 dermatome was attained within 20 min after intrathecal injection, and surgery was completed, or proceeded until at least 50 min after the intrathecal injection, without epidural supplementation. After successful anesthesia, the dose of the study drug for the next patient was decreased by 1 mg in that group. Conversely, if a failure was recorded, the dose of the study drug for the next patient was increased by 1 mg in that group. All study drugs were diluted to a volume of 2.5 mL with normal saline to facilitate blinding.
In cases of failure, patients received top-up epidural injection of local anesthetic as decided by the attending anesthesiologist. If repeated top-up doses of epidural injection failed to provide adequate level of anesthesia, general anesthesia would be given. Patients were followed up on the day after the operation for the complete recovery of sensory and motor function and any adverse events.
The monitored variables included continuous electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure cycled every 5 min from the start of spinal anesthesia until the operation was finished. Sensory blockade was monitored using loss of sensation to cold spray of ethyl chloride every 2.5 min for 20 min after the initiation of spinal anesthesia and at the end of operation. Motor blockade was assessed according to the modified Bromage scale (0 = no paralysis, able to flex hip/knee/ankle; 1 = able to flex knee, unable to raise extended leg; 2 = able to flex ankle, unable to flex knee; and 3 = unable to flex ankle, knee, and hip), every 2.5 min for 20 min and at the end of operation.12
Demographic data were collected and are presented as count or mean ± sd as appropriate. Nominal data were analyzed using the χ2 test, and continuous data were analyzed using one-way analysis of variance for intergroup differences. Values for ED50 were calculated using the technique of Dixon and Massey.8 Sample size estimation was determined by the method as recommended by Dixon and Massey and based on the result of previous published studies.9,10 A sample size of 25 patients for each group was determined to account for cases of failure and the potential deviation of the initial test dose from the ED50. Analyses were performed using SPSS 15.0 for Windows (SPSS, Chicago, IL), Excel 2003 (Microsoft Corporation, Redmond, WA), and Graph Pad Prism 4.00 (Graphpad Software, San Diego, CA). Values of P < 0.05 were considered statistically significant.
Demographic data were similar among groups (Table 1). No patient had residual neurologic changes or postdural puncture headache when seen at the follow-up visit on the day after the surgery. The sequences of patients with successes and failures are shown in Figure 1. The calculated values for ED50 were 5.50 mg for bupivacaine (95% confidence interval [CI]: 4.90–6.10 mg), 5.68 mg for levobupivacaine (95% CI: 4.92–6.44 mg), and 8.41 mg for ropivacaine (95% CI: 7.15–9.67 mg). The relative potency ratios among the different drugs were levobupivacaine/bupivacaine 0.97 (95% CI: 0.81–1.17), ropivacaine/bupivacaine 0.65 (95% CI: 0.54–0.80), and ropivacaine/levobupivacaine 0.68 (95% CI: 0.55–0.84). The potency of the local anesthetics was bupivacaine = levobupivacaine > ropivacaine.
This study investigated the ED50 of intrathecal ropivacaine, levobupivacaine, and bupivacaine for lower limb surgery with a duration of up to 50 min. Under these study conditions, the potency determined was bupivacaine = levobupivacaine > ropivacaine.
Two previous studies have compared ED50 values of levobupivacaine/ropivacaine and ropivacaine/ bupivacaine when given intrathecally for surgical anesthesia. Sell et al.10 defined the ED50 of intrathecal levobupivacaine and ropivacaine for hip replacement surgery by continuous spinal anesthesia using spinal catheters. The calculated values were 11.7 mg (95% CI: 11.1–12.4 mg) and 12.8 mg (95% CI: 12.2–13.4 mg), and they concluded that there was no significant difference among the drugs, which conflicts with our finding that levobupivacaine was more potent than ropivacaine. However, of note, Sell et al. based their conclusion on the overlapping of 95% CIs for the two sets of calculated values of ED50. This is a conservative comparison that lacks power for detecting a significant difference between the two drugs. It has been suggested that nonoverlapping of 83% or 84% CIs is more appropriate for rejecting the null hypothesis at an α of approximately 0.05.13,14 Michalek-Sauberer et al.15 defined the ED50 of intrathecal bupivacaine and ropivacaine for brachytherapy of the lower abdomen by continuous spinal anesthesia. The ED50 of intrathecal bupivacaine and ropivacaine were 11.2 and 22.6 mg, respectively, with a potency ratio of 0.5 for ropivacaine/bupivacaine. This is comparable with our finding that ropivacaine was less potent than bupivacaine. Parpaglioni et al.9 defined the ED50 of intrathecal levobupivacaine and ropivacaine for cesarean delivery. Similar to our findings, they determined that levobupivacaine was more potent than ropivacaine, with calculated values for ED50 of 10.58 and 14.22 mg for levobupivacaine and ropivacaine, respectively.
Several studies have also compared the potencies of these three local anesthetics when given intrathecally for labor analgesia, with conflicting results. Sia et al.16 performed a random dose allocation dose-response study of levobupivacaine and ropivacaine and consistent with our results, noted that levobupivacaine was more potent than ropivacaine, with calculated values for ED50 of 1.07 and 1.4 mg, respectively. Camorcia et al.7 using up-down sequential allocation determined ED50 values for ropivacaine, levobupivacaine, and bupivacaine as 3.64, 2.94, and 2.37 mg, respectively. Their results suggested a potency hierarchy of bupivacaine > levobupivacaine > ropivacaine. Van de Velde et al.6 determined the full dose-response relation of the three local anesthetics given with sufentanil 1.5 μg. Their calculated values for ED95 of bupivacaine, levobupivacaine, and ropivacaine were 3.3, 5.0, and 4.8 mg, respectively. Their results suggested a potency hierarchy of bupivacaine > levobupivacaine = ropivacaine, although of note the ED95 values for levobupivacaine and ropivacaine were larger than the maximum doses actually given (3.5 mg) and were estimated by extrapolation.
A comparison of local anesthetic potency in different studies is made difficult by differences among the studies in criteria defining success, type of surgery, and patient population. However, the ED50 of ropivacaine defined in our present study is comparable with that determined by dose-response methodology in our previous study in which we used similar criteria to define success.11 In both these studies, we defined success as bilateral sensory block to the T12 dermatome within 20 min and ability for surgery to be performed for at least 50 min after intrathecal injection. These were relatively objective and well-defined criteria, which were chosen to minimize subject and observer bias.
Up-down sequential allocation study is a simple and efficient method to define ED50. It allows the estimation of ED50 with greater precision and requires fewer subjects compared with traditional dose-response studies.8,17 Although ED50 is commonly used to define and compare the potency of different local anesthetics,7,9,10,15 values of ED50 estimated in up-down sequential allocation studies represent only a single point (quantile) along the dose-response curve. Higher quantiles such as ED90 or ED95 that may be of more clinical relevance are not defined, and when comparing potencies of drugs, the assumption is often made that their dose-response curves are parallel. The potency ratio of local anesthetics may vary at different points on the dose-response curve or when different responses are measured, which might partly explain the differences between our result and the finding of those studies for labor analgesia.6,7
In summary, this study suggests that for intrathecal anesthesia for lower limb surgery, ropivacaine is less potent than levobupivacaine and bupivacaine, whereas the potency is similar between levobupivacaine and bupivacaine. Although it is controversial whether calculated values for ED50 can be directly translated to clinical practice when doses closer to ED9517 are usually used, the information is useful for planning of future studies.
The authors thank the operating theater nurses of Kwong Wah Hospital for their assistance in the conduct of the study.
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