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From the *Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Department of Anaesthesiology and Operating Theatre Services, Kwong Wah Hospital, Kowloon, Hong Kong SAR, China.
Address correspondence and reprint requests to Ying Yin Lee, Department of Anaesthesiology, Kwong Wah Hospital, 25, Waterloo Road, Kowloon, Hong Kong. Address e-mail to yyleekwh{at}yahoo.com.
Abstract
BACKGROUND: The dose–response relationship for spinal ropivacaine in patients undergoing surgery of the lower extremity has not been fully determined.
METHODS: We performed a prospective, randomized, double-blind study of 60 patients scheduled for lower limb surgery under combined spinal–epidural anesthesia. Patients were assigned to receive 1 of 5 doses of intrathecal ropivacaine: 2, 4, 7, 10, or 14 mg diluted to 2.8 mL with normal saline. A dose was considered successful if a sensory block to cold was achieved bilaterally at the T12 dermatome within 20 min and surgery proceeded without supplementation for at least 50 min.
RESULTS: Anesthesia was successful in 0, 0, 42, 83, and 100% of the 2, 4, 7, 10, and 14 mg groups, respectively. The derived value for ED50 was 7.6 mg (95% CI: 6.2–8.7 mg) and for ED95 was 11.4 mg (95% CI: 9.7–18.3 mg). The cephalic level of sensory block and the degree of motor block increased with larger doses of ropivacaine.
CONCLUSION: The ED50 and ED95 for spinal ropivacaine in lower limb surgery of 50 min duration or less were 7.6 and 11.4 mg, respectively. This provides a useful guide for clinicians to choose the optimal dose of spinal ropivacaine under different clinical situations.
Many reports have described the use of intrathecal ropivacaine (1–9). However, a number of different doses of ropivacaine have been used for spinal anesthesia, and the dose–response relationship has not been fully determined. Khaw et al. described the dose–response relationship for spinal ropivacaine in obstetric patients (10), but their findings cannot be fully extrapolated to the general surgical population because of differences in pharmacodynamic response and block requirement between pregnant and nonpregnant patients. The objective of this study was to define the dose–response relationship for ropivacaine in patients having spinal anesthesia for lower limb surgery. Traditional dose–response methodology was used and values for ED50 and ED95 were determined.
METHODS
This study was a prospective, randomized, double-blind trial of 60 patients scheduled for a range of lower limb surgeries under combined spinal–epidural anesthesia. No attempt was made to select or stratify patients according to the operation or the use of a tourniquet. Approval was obtained from the Ethics Committee, Kowloon West Cluster, Hospital Authority, Hong Kong, China, and all patients gave written informed consent. Inclusion criteria were ASA physical status I–III, age 
18 yr, body weight 45–85 kg, and height 150 cm. Exclusion criteria were known hypersensitivity to amide local anesthetics, contraindications to spinal or epidural anesthesia and inability to understand English or Chinese.
After enrollment, patients were randomly assigned to receive 1 of 5 doses of intrathecal ropivacaine using a combined spinal–epidural technique: 2, 4, 7, 10, or 14 mg (n = 12 per group). A combined kit (BD Durasafe plus variable extension set, Becton Dickinson Medical Devices Co Ltd., Suzhou, China) was used for the spinal–epidural injection. Randomization was performed according to computer-generated random numbers using the sealed envelope technique. All study solutions were prepared in identical syringes by mixing ropivacaine 10 mg/mL (Naropin, Astra Zeneca Pty. Ltd, Sodertalje, Sweden) and normal saline to a final volume of 2.8 mL. Study solutions were prepared by an anesthesiologist not involved with subsequent administration and patient assessment.
All patients received IV prehydration with 500 mL lactated Ringer’s solution. With patients in the lateral position, under aseptic conditions, the epidural space was identified at the L3–4 or L2–3 interspace using a 17-gauge Tuohy needle and loss-of-resistance to air. A 25-gauge Whitacre spinal needle was passed through the epidural needle and observed for free flow of cerebrospinal fluid before injecting the study solution intrathecally with the orifice facing cephalad. The spinal needle was removed and an epidural catheter was inserted. The epidural catheter was gently aspirated and observed for the presence of blood or cerebrospinal fluid, but no test dose was administered. Patients were placed in the supine position and were monitored using continuous electrocardiography and pulse oximetry and noninvasive arterial blood pressure, cycled every 5 min, until the end of surgery.
Sensory block was assessed using the loss of cold sensation with ethyl chloride spray, and motor block using a 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; 3, unable to flex ankle, knee, and hip) every 2.5 min for 20 min (11). Surgery was initiated when the level of sensory block reached the 12th thoracic dermatome or above. If the block did not reach the required level or if pain occurred during surgery, epidural supplementation using ropivacaine 7.5 mg/mL was given at the anesthesiologist’s discretion.
Our primary end-point was the success or failure of spinal anesthesia. For the purposes of the study, 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.
Hypotension defined as a decrease in systolic blood pressure by more than 30% from baseline or to <100 mm Hg was treated with incremental IV doses of ephedrine 5 mg or phenylephrine 50 µg and further boluses of IV fluid as required. Bradycardia defined as heart rate <50 bpm was treated with IV atropine 0.3–0.6 mg. The incidence of adverse effects, such as nausea, vomiting, and shivering, was recorded. All patients received a follow-up visit on the day after the operation and were assessed for complete recovery of sensory and motor function.
A sample size of 12 patients in each group was determined using Tallarida’s suggestion for efficient design of a dose–response study (12). Data for age and height of the patients are presented as mean and standard deviation. Intergroup comparisons were performed using one-way analysis of variance. Data on the type of surgery were analyzed using Fisher’s exact test. Levels of sensory and motor block are presented as median values. The dose–response relationship for spinal ropivacaine was determined using probit analysis. Data for successful responses in each group were used to construct a working probit-log10(dose) plot. Linear regression was performed and interpolation was used to determine values for ED50 and ED95 (13). Data were analyzed using SPSS 10.0 for Windows (Chicago, IL), PharmTools Pro 1.1.27 (The McCary Group, Emmaus, PA), and GraphPad Prism 4.00 (GraphPad Software, San Diego, CA). P < 0.05 was considered statistically significant.
RESULTS
Sixty patients completed the study and were included for data analysis. In one additional case, both spinal injection (intrathecal ropivacaine 7 mg) and epidural supplementation failed to produce adequate sensory block and general anesthesia was required. This case was regarded as a technical failure and while maintaining blinding, another patient was recruited as a replacement. There were no differences in age and height of the patients as well as type of surgery (Tables 1 and 2). The spinal needle was inserted at the L3–4 interspace in 58 patients and the L2–3 interspace in two patients.
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The cephalic level of sensory block and the degree of motor block increased with larger doses of ropivacaine (Figs. 3 and 4). No patient had bradycardia. Four patients (1 in 7 mg group, 1 in 10 mg group, and 2 in 14 mg group) had hypotension, which recovered promptly with IV boluses of ephedrine and phenylephrine. Three patients (1 in 10 mg group and 2 in 14 mg group) had shivering. No patient experienced nausea or vomiting. There were no residual neurologic changes and no postdural puncture headaches in any patient at the follow-up visit on the day after the surgery.
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In this study, we investigated the dose–response relationship for intrathecal ropivacaine for patients having lower limb surgery of 50 min or less which required sensory block to the T12 dermatome. We determined the ED50 to be 7.6 mg (95% CI: 6.2–8.7 mg) and the ED95 to be 11.4 mg (95% CI: 9.7–18.3 mg).
The estimation of dose requirements for intrathecal ropivacaine from this study was surprisingly small. Sell et al. (14) used the technique of continuous spinal anesthesia with spinal catheters and up–down sequential analysis to define the ED50 of ropivacaine for patients having hip replacement surgery as 12.8 mg (95% CI: 12.2–13.4 mg). Nevertheless, their criteria for success included loss of sensation to pinprick and tetanic electrical stimulation at the T12 dermatome; complete motor block at 20 min after intrathecal injection; and the use of a spinal catheter that would produce a different spread of local anesthetic compared with injection through needle. These differences in successful criteria and the technique of intrathecal injection of study solutions render the direct comparison of our results impossible. The doses used in previous reports of the use of ropivacaine for spinal anesthesia for lower extremity surgery have ranged from 15 mg to 33.75 mg, which are larger than our calculated value for the ED95 (11.4 mg) (1,6,15–17). This suggests that commonly used doses may be larger than required. With the construction of the dose–response curve, our data may be a useful guide for clinicians to choose the optimal dose for spinal anesthesia under different clinical situations; for example, a dose equal to or more than the ED95 when a single-injection technique is used, and a smaller dose nearer to the ED50 when a catheter technique is used.
The ED50 and ED95 of spinal ropivacaine defined in our study only gave an approximation of the true values as our sample size was small and the confidence intervals were wide. Because one potential benefit of the use of spinal ropivacaine would be for ambulatory surgery of short duration, we used successful conduct of surgery up to 50 min as one of the criteria for defining success. Unfortunately, we did not monitor the progression and regression of sensory and motor block after the first 20 min of intrathecal injection. Further studies, defining the time course of the sensory and motor block with different doses of ropivacaine, would be of interest. Because patients were chosen from the routine operating lists, the study included a range of surgeries for which there was variation in the use of tourniquets. A better design may have been to apply more stringent selection criteria in order to reduce the heterogeneity among patients. Thus, although our results provide an indication of dose requirement for spinal ropivacaine for lower limb surgery, this should be considered a generalized estimate. Actual dose requirements for different subsets of lower limb surgery may vary.
In conclusion, the ED50 and ED95 for spinal ropivacaine in lower limb surgery of 50 min duration or less were 7.6 and 11.4 mg, respectively.
ACKNOWLEDGMENTS
The authors thank the operating theater nurses of Kwong Wah Hospital for their assistance in the conduct of the study and Dr. Anna Lee, MPH, PhD (Associate Professor, Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, China), for her statistical advice.
Footnotes
Accepted for publication April 5, 2007.
Supported by the Department of Anaesthesiology and Operating Theatre Services, Kwong Wah Hospital and Tung Wah Group of Hospitals Doctors’ Association Research Fund.
Presented in part at the 8th Biennial Congress Asian & Oceanic Society of Regional Anesthesia and Pain Medicine, Chiba, Japan, December 7–10, 2005.
REFERENCES
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