- Email: [email protected]
Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose 8%) for spinal anaesthesia for elective surgery†
British Journal of Anaesthesia 90 (3): 304±8 (2003)
DOI: 10.1093/bja/aeg077
Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose 8%) for spinal anaesthesia for elective surgery² J. B. Whiteside1, D. Burke1
2
and J. A. W. Wildsmith1*
1
University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 2
*Corresponding author. E-mail: [email protected] Background. Hyperbaric solutions of ropivacaine have been used successfully to provide spinal anaesthesia. This study was designed to compare the clinical ef®cacy of hyperbaric ropivacaine with that of the commercially available hyperbaric preparation of bupivacaine. Methods. Forty ASA grade I±II patients undergoing lower-abdominal, perineal or lower-limb surgery under spinal anaesthesia were recruited and randomized to receive ropivacaine 5 mg ml±1 (with glucose 50 mg ml±1), 3 ml or bupivacaine 5 mg ml±1 (with glucose 80 mg ml±1), 3 ml. The level and duration of sensory block, intensity and duration of motor block, and time to mobilize and micturate were recorded. Patients were interviewed at 24 h and at 1 week to identify any residual problems. Results. All blocks were adequate for the proposed surgery, but there were signi®cant differences between the two groups in mean time to onset of sensory block at T10 (ropivacaine 5 min; bupivacaine 2 min; P<0.005), median maximum extent (ropivacaine T7; bupivacaine T5; P<0.005) and mean duration of sensory block at T10 (ropivacaine 56.5 min; bupivacaine 118 min; P=0.001). Patients receiving ropivacaine mobilized sooner (ropivacaine mean 253.5 min; bupivacaine 331 min; P=0.002) and passed urine sooner (ropivacaine mean 276 min; bupivacaine 340.5 min; P=0.01) than those receiving bupivacaine. More patients in the bupivacaine group required treatment for hypotension (>30% decrease in systolic pressure; P=0.001). Conclusions. Ropivacaine 15 mg in glucose 50 mg ml±1 provides reliable spinal anaesthesia of shorter duration and with less hypotension than bupivacaine. The recovery pro®le for ropivacaine may be of interest given that more surgery is being performed in the day-case setting. Br J Anaesth 2003; 90: 304±8 Keywords: anaesthetics local, bupivacaine; anaesthetics local, ropivacaine; anaesthetic techniques, subarachnoid Accepted for publication: October 17, 2002
Introduction Ropivacaine, a relatively new amino-amide local anaesthetic agent similar in chemical structure to bupivacaine, is not licensed for intrathecal use and has been little studied in that application. Early evaluation of the drug included two studies of glucose-free solutions performed primarily to allay concern regarding the safety of ropivacaine should accidental intrathecal injection occur during epidural block.1 2 Sensory block of variable extent and intermediate
duration was produced. More recently, two studies, one clinical and the other in volunteers, compared ropivacaine and bupivacaine and concluded that ropivacaine offers no advantage, primarily because of a shorter duration of action.3 4 However, the conclusions of these studies are ² This work was presented in abstract form at the European Society of Regional Anaesthesia meeting, Rome, September 20±23, 2000, and at the Anaesthetic Research Society, Newcastle, UK, March 29±30, 2001.
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
Present address: Department of Anaesthetics, St John's Hospital, Livingston, West Lothian, UK
Hyperbaric ropivacaine and bupivacaine
contrary to other experience of intrathecal ropivacaine, where this shorter duration has been identi®ed as a potential bene®t.5 6 Thus, the current study was designed to compare the clinical ef®cacy of a hyperbaric solution of ropivacaine with that of the commercially available preparation of hyperbaric bupivacaine.
Materials and methods
Statistical analysis The sample size was chosen to show a difference in extent of sensory block of two dermatomes (SD one dermatome) between the groups, based on an a risk of 0.05 and a b risk of 0.10 using data from a previous study of intrathecal ropivacaine.5 Data are presented as median (range), mean (SD) or frequencies, as appropriate. Patient characteristics and the duration of surgery were compared using the twotailed, two-sample t-test except for sex (c2-test). Block characteristics were compared using the two-tailed Mann±Whitney U-test or Fisher's exact test (number of patients with complete motor block). A Bonferroni correction was applied for multiple two-way testing. In all categories P<0.05 was considered statistically signi®cant. Data were analysed using Arcus Quickstat version 1.0 (Research Solutions Ltd, UK).
Results The groups were comparable with regard to age, sex, height, weight and ASA status (Table 2). The onset of pinprick analgesia at T10 was more rapid with bupivacaine (P<0.005), although the time to maximum extent of cephalad spread was similar in both groups (Table 3). Median block height with time was slightly higher throughout in the bupivacaine group (Fig. 1), and the maximum block height achieved was signi®cantly higher (P<0.001). The total duration of sensory block was shorter with ropivacaine (P=0.0001). The degree and duration of motor block were signi®cantly greater with bupivacaine than with ropivacaine (Table 3). Median time to complete regression of motor block was 180 min (range 120±210 min) with bupivacaine compared with 90 min (60±180 min) with ropivacaine (P<0.0001).
Table 1 Constituents of solutions used (ropivacaine prepared to 10 ml, 3 ml administered). Densities of solutions at 37°C (n=5 for each solution) measured with DE50 density meter (Mettler-Toledo Laboratories, UK) Solution
Ropivacaine 10 mg ml±1 (ml)
Glucose 100 mg ml±1 (ml)
Bupivacaine Heavyâ
Density (g ml±1) [mean (SD)]
Bupivacaine Ropivacaine
0 5
0 5
3 0
1.02098 (0.00001) 1.01531 (0.00002)
305
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
Forty patients gave written informed consent for the study, which was approved by the local research ethics committee. Patients of ASA grade I±II undergoing lower-abdominal, perineal or lower-limb surgery under spinal anaesthesia were recruited and randomized (using shuf¯ed, sealed, opaque, numbered envelopes) to receive ropivacaine 5 mg ml±1 (with glucose 50 mg ml±1), 3 ml or bupivacaine 5 mg ml±1 (with glucose 80 mg ml±1), 3 ml. Premedication consisted of oral temazepam, 10±20 mg. On arrival in the anaesthetic room, continuous monitoring with ECG, non-invasive arterial pressure and pulse oximetry were started, and a suitable peripheral vein was cannulated. No ¯uid was administered and the patient was placed in the left lateral position for lumbar puncture, which was performed using a midline approach at the second or third interspace. A 25-swg Whitacre needle (Vygon, UK) was inserted with the distal port facing laterally, and the appropriate local anaesthetic solution was injected over 10±15 s. The ropivacaine solutions were prepared aseptically immediately before injection (by an anaesthetist who was not one of the investigators) using equal volumes of ropivacaine 10 mg ml±1 and glucose 100 mg ml±1 (Table 1). The bupivacaine solution used was commercially available in the UK (Marcain 0.5% Heavyâ, AstraZeneca). The patient was placed supine immediately after injection. The development of the block was recorded by an investigator who did not know which solution had been injected. The extent of sensory block (analgesia to pinprick with a 27-swg short-bevel dental needle), degree of lowerlimb motor block (modi®ed Bromage scale: 0=full movement; 1=inability to raise extended leg, can bend knee; 2=inability to bend knee, can ¯ex ankle; 3=no movement), arterial pressure and heart rate were recorded at 2, 5, 10, 15, 20, 25 and 30 min, and at 30 min intervals thereafter until complete regression of the block. The caudad limit of sensory block assessment was restricted to S2 and, where there was a difference in height of block between left and right, the mean of the two was recorded. After 30 min the patient was transferred to the operating room for surgery.
Sedation was provided with a target-controlled propofol infusion within the dose range 0.5±2.0 mg ml±1 (titrated to maintain verbal contact at all times), if the patient requested it. Hypotension, de®ned as a decrease in systolic pressure >30% from baseline, was treated with i.v. ephedrine 3 mg. Fluids were only administered to replace intraoperative losses. Bladder catheterization was performed only if surgically indicated. After surgery, patients were encouraged to mobilize under supervision only when the sensory block had regressed beyond S2. All patients were visited at 24 h and telephoned at 3±7 days.
Whiteside et al.
Discussion
This study has con®rmed the ®ndings of a previous study5 that a glucose-containing solution of ropivacaine, hyperbaTable 2 Patient characteristics and types of surgery. Data are mean (SD or range) or frequencies
Number of patients Female/male ASA status (I/II) Age (yr) Weight (kg) Height (cm) Type of surgery Lower limb Perineal Inguinal hernia
Ropivacaine
Bupivacaine
20 9/11 11/9 51 (00±00) 83 (20) 172 (13)
20 11/9 8/12 56 (00±00) 77 (16) 170 (12)
13 4 3
12 8 0
ric relative to cerebrospinal ¯uid,7 can produce predictable and reliable spinal anaesthesia for a wide range of surgical procedures. This is in contrast to the results of the two early clinical studies, which described blocks that varied widely in extent, many of which were inadequate for surgery.1 2 However, those studies used glucose-free solutions of ropivacaine, and the difference con®rms that the addition of glucose to solutions of ropivacaine has the same effect as with other drugsÐit reduces the proportion of very limited blocks without producing signi®cantly more extensive blocks, an effect that has been found previously in studies of both tetracaine8 and bupivacaine.9±12 Comparison of our previous work with that of van Kleef and colleagues5 demonstrates this clearly for ropivacaine. The results of the current study are also in contrast with the general conclusions of two more recent studies of intrathecal ropivacaine, both of which questioned its suitability for spinal anaesthesia compared with bupivacaine.3±4 Gautier and colleagues3 used plain glucose-free preparations, but in larger volumes of less concentrated solutions than are normally used in clinical practice. When equal doses of ropivacaine and bupivacaine were compared, the onset and extent of sensory block were similar, but both the duration of that sensory block and the degree of motor block produced were less with ropivacaine. These ®ndings, particularly the shorter duration of sensory block, led the authors to claim that ropivacaine is less potent than bupivacaine and that it offers no signi®cant advantage, even though the patients who received ropivacaine passed urine and mobilized sooner than those who received bupivacaine. In the other recent study, McDonald and colleagues4 compared hyperbaric preparations of ropivacaine and bupivacaine in volunteers not undergoing surgery. Their solutions were also less concentrated than those normally used clinically, and the total doses injected were lower.
Table 3 Characteristics of neural block and frequency of adverse events. Data are median (range). NS, not signi®cant
Sensory block Onset at T10 (min) Maximum cephalad spread (dermatome) Time to maximum cephalad spread (min) Block height at 90 min (dermatome) Duration at T10 (min) Total duration (min) Motor block Grade 3 block, n (%) Time to maximum degree (min) Total duration (min) Adverse events, n (%) Hypotension Mild back tenderness Post-dural puncture headache Transient neurological symptoms Other factors Time to mobilization (min) Time to ®rst micturation (min)
Bupivacaine (n=20)
Ropivacaine (n=20)
P-value
2 (2±10) T5 (T3±T11) 20 (5±30) T7/8 (T6±L1) 118 (80±238) 255 (150±420)
5 (2±25) T7 (T4/5±T11) 20 (10±30) T10/11 (T6±S2) 56.5 (28±145) 180 (120±270)
0.0046 0.0007 NS <0.0001 0.001 0.0001
20 (100) 10 (2±15) 180 (120±210)
14 (70) 15 (10±25) 90 (60±180)
0.02 <0.0001 <0.0001
14 (70) 2 (10) 1 (5) 0
3 (15) 3 (15) 1 (5) 0
0.001 NS NS NS
331 (219±475) 340.5 (268±497)
254 (151±359) 276 (177±494)
0.0019 0.01
306
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
There were marked differences in cardiovascular changes between the groups (Fig. 2). In the bupivacaine group, 14 (70%) patients required ephedrine for a per protocol decrease in systolic pressure, compared with only three (15%) patients in the ropivacaine group (P=0.001). Twelve patients in the ropivacaine group and ten in the bupivacaine group requested intra-operative sedation, but verbal contact was maintained at all times and the block was suitable for surgery in all patients. Patients in the ropivacaine group were able to mobilize (P=0.002) and pass urine (P=0.01) sooner than those in the bupivacaine group (Table 3). Three patients in the ropivacaine group and two in the bupivacaine group developed mild, localized, self-limiting tenderness at the site of lumbar puncture at 24 h, but there were no neurological symptoms in any patients. One patient in each group developed a mild post-dural puncture headache, treated with bed rest, ¯uids and analgesia. Neither patient required an epidural blood patch.
Hyperbaric ropivacaine and bupivacaine
Fig 1 Sensory block (median dermatoses) characteristics with time in two groups of 20 patients receiving spinal anaesthesia with either ropivacaine 5 mg ml±1 (with 50 mg ml±1 glucose), 3 ml or bupivacaine (with 80 mg ml±1 glucose), 3 ml.
ropivacaine containing glucose 50 mg ml±1,5 which, in the absence of a commercially available glucose-containing solution, is easily prepared before spinal anaesthesia. Second, previous work with bupivacaine had suggested that lower concentrations of glucose than are present in the commercially available hyperbaric solution may be suf®cient to provide the previously stated bene®ts over plain solutions.9 10 Compared with the commercial preparation of bupivacaine, the ropivacaine preparation used in this study produced a somewhat slower onset of slightly less extensive sensory block, which regressed more rapidly. These differences could be the result of the different glucose concentrations on intrathecal spread, differences between the drugs themselves, or a combination of the two. Currently, many consider that ropivacaine has a less potent sensory blocking effect than bupivacaine because of the conclusions of the two studies referred to above.3 4 However, in both of those studies solutions apparently equal in baricity produced sensory blocks of the same rate of onset and extent of block, which suggests that the differences we observed in those aspects of block were the result of the difference in the baricities of our solutions, but further study is needed to establish the exact position. That intrathecal ropivacaine has a shorter duration of sensory effect than bupivacaine is a general ®nding, but this does not support de®nitively the conclusion that it is less potent, and certainly not that it is unsuitable for clinical use by this route. The potency of a drug relates to the effect produced (not the duration of that effect), and both the preparations we studied produced blocks that were effective for the surgery undertaken. There is general agreement that ropivacaine has a less potent effect on motor nerves, con®rmed in this study, with both the degree and duration of motor block produced by ropivacaine being less, although still adequate for the projected surgery. This adds to the now considerable body
Fig 2 Mean systolic pressure plotted against time in two groups of 20 patients receiving spinal anaesthesia with either ropivacaine 5 mg ml±1 (with 50 mg ml±1 glucose), 3 ml or bupivacaine (with 80 mg ml±1 glucose), 3 ml.
307
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Equal doses of ropivacaine and bupivacaine produced sensory blocks of similar onset and extent, but there was less motor block, which regressed faster, with ropivacaine. Again, primarily on the basis of the shorter duration of action and despite equivalence in the onset and extent of sensory block, the authors concluded that ropivacaine is less potent than bupivacaine. Their study also found a higher incidence of backache after ropivacaine and concluded that the incidence of side-effects was higher even though the difference was not statistically signi®cant. Because our initial experience with intrathecal ropivacaine was not in accord with the conclusions of these studies, we decided to compare it directly with bupivacaine, using glucose-containing solutions of both. The concentration of glucose in the ropivacaine solution was lower than that of the bupivacaine for two reasons. First, a previous study had demonstrated the clinical ef®cacy of a solution of
Whiteside et al.
Acknowledgement We would like to thank AstraZeneca, SoÈdertalje, Sweden for ®nancial support.
References 1 van Kleef JW, Veering BT, Burm AGL. Spinal anaesthesia with ropivacaine: A double-blind study on the ef®cacy and safety of 0.5% and 0.75% solutions in patients undergoing minor lower limb surgery. Anesth Analg 1994; 78: 1125±30
308
2 Wahedi W, Nolte H, Klein P. Ropivacaine in spinal anaesthesia. Anaesthesist 1996; 45: 737±44 3 Gautier PE, De Kock M, Van Steenberge A, et al. Intrathecal ropivacaine for ambulatory surgery: A comparison between intrathecal bupivacaine and ropivacaine for knee surgery. Anesthesiology 1999; 91: 1239±45 4 McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine: A comparison to bupivacaine in volunteers. Anesthesiology 1999; 90: 971±7 5 Whiteside J, Burke D, Wildsmith JAW. A comparison of 0.5% ropivacaine (5% glucose) with 0.5% ropivacaine (1% glucose) when used to provide spinal anaesthesia for elective surgery. Br J Anaesth 2001; 86: 241±4 6 McNamee DA, Parks L, McCelleand AM, et al. Intrathecal ropivacaine for total hip arthroplasty: double-blind comparative study with isobaric 7.5 mg ml±1 and 10 mg ml±1 solutions. Br J Anaesth 2001; 87; 743±7 7 Schiffer E, Van Gessel E, Gamulin Z. In¯uence of sex on cerebrospinal ¯uid density in adults. Br J Anaesth 1999; 83: 943±4 8 Lee A, Ray D, Littlwood DG, Wildsmith JAW. Effect of dextrose concentration on the intrathecal spread of amethocaine. Br J Anaesth 1988; 61: 135±8 9 Bannister J, McClure JH, Wildsmith JAW. Effect of glucose concentration on the intrathecal spread of 0.5% bupivacaine. Br J Anaesth 1990; 64: 232±4 10 Chambers WA, Edstrom HH, Scott DB. Effect of baricity on spinal anaesthesia with bupivacaine. Br J Anaesth 1981; 53: 279±82 11 Logan MR, McClure JH, Wildsmith JAW. Plain bupivacaine: an unpredictable spinal anaesthetic agent. Br J Anaesth 1986; 58: 292±6 12 Sanderson P, Read J, Littlewood DG, McKeown D, Wildsmith JAW. Interaction between baricity (glucose concentration) and other factors in¯uencing intrathecal drug spread. Br J Anaesth 1994; 73: 744±6 13 Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JAW. Comparison of extradural ropivacaine and bupivacaine. Br J Anaesth 1991; 66: 31±7 14 Morrisson LMM, Emanuelsson BM, McClure JH, et al. Ef®cacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth 1994; 72: 269±73 15 Schneider M, Ettlin T, Kaufmann M, et al. Transient neurologic toxicity after hyperbaric subarachnoid anaesthesia with 5% lidocaine. Anesth Analg 1993; 76: 1154±7
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
of evidence suggesting that there is a greater degree of sensory±motor separation when using ropivacaine compared with bupivacaine,13 14 and supports our view that ropivacaine is an agent worthy of further study as an agent for spinal anaesthesia. Good sensory blocks were associated with a highly favourable recovery pro®le compared with bupivacaine, with more rapid regression of sensory and motor block, earlier mobilization and shorter time to ®rst micturition. With the current emphasis on ambulatory surgery, such a recovery pro®le may be of bene®t. Hyperbaric lidocaine 5% has been used as a short-acting agent for ambulatory spinal anaesthesia, but concerns about the high incidence of transient neurological symptoms restrict its use currently.15 We found no evidence of any late sequelae such as backache or other transient symptoms in this or a previous study of ropivacaine.5 In conclusion, a solution of ropivacaine that is hyperbaric relative to cerebrospinal ¯uid can be used to provide reliable spinal anaesthesia that is comparable to that with hyperbaric bupivacaine in terms of quality of block, but with a shorter recovery pro®le. The key issue is the difference in the clinical pro®le of the block (onset, extent, suitability for surgery, duration) produced, not the relative potencies of the two drugs. However, further work is required to evaluate the role of hyperbaric ropivacaine for surgical procedures of short-to-intermediate duration, particularly in the ambulatory setting.
DOI: 10.1093/bja/aeg077
Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose 8%) for spinal anaesthesia for elective surgery² J. B. Whiteside1, D. Burke1
2
and J. A. W. Wildsmith1*
1
University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 2
*Corresponding author. E-mail: [email protected] Background. Hyperbaric solutions of ropivacaine have been used successfully to provide spinal anaesthesia. This study was designed to compare the clinical ef®cacy of hyperbaric ropivacaine with that of the commercially available hyperbaric preparation of bupivacaine. Methods. Forty ASA grade I±II patients undergoing lower-abdominal, perineal or lower-limb surgery under spinal anaesthesia were recruited and randomized to receive ropivacaine 5 mg ml±1 (with glucose 50 mg ml±1), 3 ml or bupivacaine 5 mg ml±1 (with glucose 80 mg ml±1), 3 ml. The level and duration of sensory block, intensity and duration of motor block, and time to mobilize and micturate were recorded. Patients were interviewed at 24 h and at 1 week to identify any residual problems. Results. All blocks were adequate for the proposed surgery, but there were signi®cant differences between the two groups in mean time to onset of sensory block at T10 (ropivacaine 5 min; bupivacaine 2 min; P<0.005), median maximum extent (ropivacaine T7; bupivacaine T5; P<0.005) and mean duration of sensory block at T10 (ropivacaine 56.5 min; bupivacaine 118 min; P=0.001). Patients receiving ropivacaine mobilized sooner (ropivacaine mean 253.5 min; bupivacaine 331 min; P=0.002) and passed urine sooner (ropivacaine mean 276 min; bupivacaine 340.5 min; P=0.01) than those receiving bupivacaine. More patients in the bupivacaine group required treatment for hypotension (>30% decrease in systolic pressure; P=0.001). Conclusions. Ropivacaine 15 mg in glucose 50 mg ml±1 provides reliable spinal anaesthesia of shorter duration and with less hypotension than bupivacaine. The recovery pro®le for ropivacaine may be of interest given that more surgery is being performed in the day-case setting. Br J Anaesth 2003; 90: 304±8 Keywords: anaesthetics local, bupivacaine; anaesthetics local, ropivacaine; anaesthetic techniques, subarachnoid Accepted for publication: October 17, 2002
Introduction Ropivacaine, a relatively new amino-amide local anaesthetic agent similar in chemical structure to bupivacaine, is not licensed for intrathecal use and has been little studied in that application. Early evaluation of the drug included two studies of glucose-free solutions performed primarily to allay concern regarding the safety of ropivacaine should accidental intrathecal injection occur during epidural block.1 2 Sensory block of variable extent and intermediate
duration was produced. More recently, two studies, one clinical and the other in volunteers, compared ropivacaine and bupivacaine and concluded that ropivacaine offers no advantage, primarily because of a shorter duration of action.3 4 However, the conclusions of these studies are ² This work was presented in abstract form at the European Society of Regional Anaesthesia meeting, Rome, September 20±23, 2000, and at the Anaesthetic Research Society, Newcastle, UK, March 29±30, 2001.
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
Present address: Department of Anaesthetics, St John's Hospital, Livingston, West Lothian, UK
Hyperbaric ropivacaine and bupivacaine
contrary to other experience of intrathecal ropivacaine, where this shorter duration has been identi®ed as a potential bene®t.5 6 Thus, the current study was designed to compare the clinical ef®cacy of a hyperbaric solution of ropivacaine with that of the commercially available preparation of hyperbaric bupivacaine.
Materials and methods
Statistical analysis The sample size was chosen to show a difference in extent of sensory block of two dermatomes (SD one dermatome) between the groups, based on an a risk of 0.05 and a b risk of 0.10 using data from a previous study of intrathecal ropivacaine.5 Data are presented as median (range), mean (SD) or frequencies, as appropriate. Patient characteristics and the duration of surgery were compared using the twotailed, two-sample t-test except for sex (c2-test). Block characteristics were compared using the two-tailed Mann±Whitney U-test or Fisher's exact test (number of patients with complete motor block). A Bonferroni correction was applied for multiple two-way testing. In all categories P<0.05 was considered statistically signi®cant. Data were analysed using Arcus Quickstat version 1.0 (Research Solutions Ltd, UK).
Results The groups were comparable with regard to age, sex, height, weight and ASA status (Table 2). The onset of pinprick analgesia at T10 was more rapid with bupivacaine (P<0.005), although the time to maximum extent of cephalad spread was similar in both groups (Table 3). Median block height with time was slightly higher throughout in the bupivacaine group (Fig. 1), and the maximum block height achieved was signi®cantly higher (P<0.001). The total duration of sensory block was shorter with ropivacaine (P=0.0001). The degree and duration of motor block were signi®cantly greater with bupivacaine than with ropivacaine (Table 3). Median time to complete regression of motor block was 180 min (range 120±210 min) with bupivacaine compared with 90 min (60±180 min) with ropivacaine (P<0.0001).
Table 1 Constituents of solutions used (ropivacaine prepared to 10 ml, 3 ml administered). Densities of solutions at 37°C (n=5 for each solution) measured with DE50 density meter (Mettler-Toledo Laboratories, UK) Solution
Ropivacaine 10 mg ml±1 (ml)
Glucose 100 mg ml±1 (ml)
Bupivacaine Heavyâ
Density (g ml±1) [mean (SD)]
Bupivacaine Ropivacaine
0 5
0 5
3 0
1.02098 (0.00001) 1.01531 (0.00002)
305
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on February 9, 2015
Forty patients gave written informed consent for the study, which was approved by the local research ethics committee. Patients of ASA grade I±II undergoing lower-abdominal, perineal or lower-limb surgery under spinal anaesthesia were recruited and randomized (using shuf¯ed, sealed, opaque, numbered envelopes) to receive ropivacaine 5 mg ml±1 (with glucose 50 mg ml±1), 3 ml or bupivacaine 5 mg ml±1 (with glucose 80 mg ml±1), 3 ml. Premedication consisted of oral temazepam, 10±20 mg. On arrival in the anaesthetic room, continuous monitoring with ECG, non-invasive arterial pressure and pulse oximetry were started, and a suitable peripheral vein was cannulated. No ¯uid was administered and the patient was placed in the left lateral position for lumbar puncture, which was performed using a midline approach at the second or third interspace. A 25-swg Whitacre needle (Vygon, UK) was inserted with the distal port facing laterally, and the appropriate local anaesthetic solution was injected over 10±15 s. The ropivacaine solutions were prepared aseptically immediately before injection (by an anaesthetist who was not one of the investigators) using equal volumes of ropivacaine 10 mg ml±1 and glucose 100 mg ml±1 (Table 1). The bupivacaine solution used was commercially available in the UK (Marcain 0.5% Heavyâ, AstraZeneca). The patient was placed supine immediately after injection. The development of the block was recorded by an investigator who did not know which solution had been injected. The extent of sensory block (analgesia to pinprick with a 27-swg short-bevel dental needle), degree of lowerlimb motor block (modi®ed Bromage scale: 0=full movement; 1=inability to raise extended leg, can bend knee; 2=inability to bend knee, can ¯ex ankle; 3=no movement), arterial pressure and heart rate were recorded at 2, 5, 10, 15, 20, 25 and 30 min, and at 30 min intervals thereafter until complete regression of the block. The caudad limit of sensory block assessment was restricted to S2 and, where there was a difference in height of block between left and right, the mean of the two was recorded. After 30 min the patient was transferred to the operating room for surgery.
Sedation was provided with a target-controlled propofol infusion within the dose range 0.5±2.0 mg ml±1 (titrated to maintain verbal contact at all times), if the patient requested it. Hypotension, de®ned as a decrease in systolic pressure >30% from baseline, was treated with i.v. ephedrine 3 mg. Fluids were only administered to replace intraoperative losses. Bladder catheterization was performed only if surgically indicated. After surgery, patients were encouraged to mobilize under supervision only when the sensory block had regressed beyond S2. All patients were visited at 24 h and telephoned at 3±7 days.
Whiteside et al.
Discussion
This study has con®rmed the ®ndings of a previous study5 that a glucose-containing solution of ropivacaine, hyperbaTable 2 Patient characteristics and types of surgery. Data are mean (SD or range) or frequencies
Number of patients Female/male ASA status (I/II) Age (yr) Weight (kg) Height (cm) Type of surgery Lower limb Perineal Inguinal hernia
Ropivacaine
Bupivacaine
20 9/11 11/9 51 (00±00) 83 (20) 172 (13)
20 11/9 8/12 56 (00±00) 77 (16) 170 (12)
13 4 3
12 8 0
ric relative to cerebrospinal ¯uid,7 can produce predictable and reliable spinal anaesthesia for a wide range of surgical procedures. This is in contrast to the results of the two early clinical studies, which described blocks that varied widely in extent, many of which were inadequate for surgery.1 2 However, those studies used glucose-free solutions of ropivacaine, and the difference con®rms that the addition of glucose to solutions of ropivacaine has the same effect as with other drugsÐit reduces the proportion of very limited blocks without producing signi®cantly more extensive blocks, an effect that has been found previously in studies of both tetracaine8 and bupivacaine.9±12 Comparison of our previous work with that of van Kleef and colleagues5 demonstrates this clearly for ropivacaine. The results of the current study are also in contrast with the general conclusions of two more recent studies of intrathecal ropivacaine, both of which questioned its suitability for spinal anaesthesia compared with bupivacaine.3±4 Gautier and colleagues3 used plain glucose-free preparations, but in larger volumes of less concentrated solutions than are normally used in clinical practice. When equal doses of ropivacaine and bupivacaine were compared, the onset and extent of sensory block were similar, but both the duration of that sensory block and the degree of motor block produced were less with ropivacaine. These ®ndings, particularly the shorter duration of sensory block, led the authors to claim that ropivacaine is less potent than bupivacaine and that it offers no signi®cant advantage, even though the patients who received ropivacaine passed urine and mobilized sooner than those who received bupivacaine. In the other recent study, McDonald and colleagues4 compared hyperbaric preparations of ropivacaine and bupivacaine in volunteers not undergoing surgery. Their solutions were also less concentrated than those normally used clinically, and the total doses injected were lower.
Table 3 Characteristics of neural block and frequency of adverse events. Data are median (range). NS, not signi®cant
Sensory block Onset at T10 (min) Maximum cephalad spread (dermatome) Time to maximum cephalad spread (min) Block height at 90 min (dermatome) Duration at T10 (min) Total duration (min) Motor block Grade 3 block, n (%) Time to maximum degree (min) Total duration (min) Adverse events, n (%) Hypotension Mild back tenderness Post-dural puncture headache Transient neurological symptoms Other factors Time to mobilization (min) Time to ®rst micturation (min)
Bupivacaine (n=20)
Ropivacaine (n=20)
P-value
2 (2±10) T5 (T3±T11) 20 (5±30) T7/8 (T6±L1) 118 (80±238) 255 (150±420)
5 (2±25) T7 (T4/5±T11) 20 (10±30) T10/11 (T6±S2) 56.5 (28±145) 180 (120±270)
0.0046 0.0007 NS <0.0001 0.001 0.0001
20 (100) 10 (2±15) 180 (120±210)
14 (70) 15 (10±25) 90 (60±180)
0.02 <0.0001 <0.0001
14 (70) 2 (10) 1 (5) 0
3 (15) 3 (15) 1 (5) 0
0.001 NS NS NS
331 (219±475) 340.5 (268±497)
254 (151±359) 276 (177±494)
0.0019 0.01
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There were marked differences in cardiovascular changes between the groups (Fig. 2). In the bupivacaine group, 14 (70%) patients required ephedrine for a per protocol decrease in systolic pressure, compared with only three (15%) patients in the ropivacaine group (P=0.001). Twelve patients in the ropivacaine group and ten in the bupivacaine group requested intra-operative sedation, but verbal contact was maintained at all times and the block was suitable for surgery in all patients. Patients in the ropivacaine group were able to mobilize (P=0.002) and pass urine (P=0.01) sooner than those in the bupivacaine group (Table 3). Three patients in the ropivacaine group and two in the bupivacaine group developed mild, localized, self-limiting tenderness at the site of lumbar puncture at 24 h, but there were no neurological symptoms in any patients. One patient in each group developed a mild post-dural puncture headache, treated with bed rest, ¯uids and analgesia. Neither patient required an epidural blood patch.
Hyperbaric ropivacaine and bupivacaine
Fig 1 Sensory block (median dermatoses) characteristics with time in two groups of 20 patients receiving spinal anaesthesia with either ropivacaine 5 mg ml±1 (with 50 mg ml±1 glucose), 3 ml or bupivacaine (with 80 mg ml±1 glucose), 3 ml.
ropivacaine containing glucose 50 mg ml±1,5 which, in the absence of a commercially available glucose-containing solution, is easily prepared before spinal anaesthesia. Second, previous work with bupivacaine had suggested that lower concentrations of glucose than are present in the commercially available hyperbaric solution may be suf®cient to provide the previously stated bene®ts over plain solutions.9 10 Compared with the commercial preparation of bupivacaine, the ropivacaine preparation used in this study produced a somewhat slower onset of slightly less extensive sensory block, which regressed more rapidly. These differences could be the result of the different glucose concentrations on intrathecal spread, differences between the drugs themselves, or a combination of the two. Currently, many consider that ropivacaine has a less potent sensory blocking effect than bupivacaine because of the conclusions of the two studies referred to above.3 4 However, in both of those studies solutions apparently equal in baricity produced sensory blocks of the same rate of onset and extent of block, which suggests that the differences we observed in those aspects of block were the result of the difference in the baricities of our solutions, but further study is needed to establish the exact position. That intrathecal ropivacaine has a shorter duration of sensory effect than bupivacaine is a general ®nding, but this does not support de®nitively the conclusion that it is less potent, and certainly not that it is unsuitable for clinical use by this route. The potency of a drug relates to the effect produced (not the duration of that effect), and both the preparations we studied produced blocks that were effective for the surgery undertaken. There is general agreement that ropivacaine has a less potent effect on motor nerves, con®rmed in this study, with both the degree and duration of motor block produced by ropivacaine being less, although still adequate for the projected surgery. This adds to the now considerable body
Fig 2 Mean systolic pressure plotted against time in two groups of 20 patients receiving spinal anaesthesia with either ropivacaine 5 mg ml±1 (with 50 mg ml±1 glucose), 3 ml or bupivacaine (with 80 mg ml±1 glucose), 3 ml.
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Equal doses of ropivacaine and bupivacaine produced sensory blocks of similar onset and extent, but there was less motor block, which regressed faster, with ropivacaine. Again, primarily on the basis of the shorter duration of action and despite equivalence in the onset and extent of sensory block, the authors concluded that ropivacaine is less potent than bupivacaine. Their study also found a higher incidence of backache after ropivacaine and concluded that the incidence of side-effects was higher even though the difference was not statistically signi®cant. Because our initial experience with intrathecal ropivacaine was not in accord with the conclusions of these studies, we decided to compare it directly with bupivacaine, using glucose-containing solutions of both. The concentration of glucose in the ropivacaine solution was lower than that of the bupivacaine for two reasons. First, a previous study had demonstrated the clinical ef®cacy of a solution of
Whiteside et al.
Acknowledgement We would like to thank AstraZeneca, SoÈdertalje, Sweden for ®nancial support.
References 1 van Kleef JW, Veering BT, Burm AGL. Spinal anaesthesia with ropivacaine: A double-blind study on the ef®cacy and safety of 0.5% and 0.75% solutions in patients undergoing minor lower limb surgery. Anesth Analg 1994; 78: 1125±30
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2 Wahedi W, Nolte H, Klein P. Ropivacaine in spinal anaesthesia. Anaesthesist 1996; 45: 737±44 3 Gautier PE, De Kock M, Van Steenberge A, et al. Intrathecal ropivacaine for ambulatory surgery: A comparison between intrathecal bupivacaine and ropivacaine for knee surgery. Anesthesiology 1999; 91: 1239±45 4 McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine: A comparison to bupivacaine in volunteers. Anesthesiology 1999; 90: 971±7 5 Whiteside J, Burke D, Wildsmith JAW. A comparison of 0.5% ropivacaine (5% glucose) with 0.5% ropivacaine (1% glucose) when used to provide spinal anaesthesia for elective surgery. Br J Anaesth 2001; 86: 241±4 6 McNamee DA, Parks L, McCelleand AM, et al. Intrathecal ropivacaine for total hip arthroplasty: double-blind comparative study with isobaric 7.5 mg ml±1 and 10 mg ml±1 solutions. Br J Anaesth 2001; 87; 743±7 7 Schiffer E, Van Gessel E, Gamulin Z. In¯uence of sex on cerebrospinal ¯uid density in adults. Br J Anaesth 1999; 83: 943±4 8 Lee A, Ray D, Littlwood DG, Wildsmith JAW. Effect of dextrose concentration on the intrathecal spread of amethocaine. Br J Anaesth 1988; 61: 135±8 9 Bannister J, McClure JH, Wildsmith JAW. Effect of glucose concentration on the intrathecal spread of 0.5% bupivacaine. Br J Anaesth 1990; 64: 232±4 10 Chambers WA, Edstrom HH, Scott DB. Effect of baricity on spinal anaesthesia with bupivacaine. Br J Anaesth 1981; 53: 279±82 11 Logan MR, McClure JH, Wildsmith JAW. Plain bupivacaine: an unpredictable spinal anaesthetic agent. Br J Anaesth 1986; 58: 292±6 12 Sanderson P, Read J, Littlewood DG, McKeown D, Wildsmith JAW. Interaction between baricity (glucose concentration) and other factors in¯uencing intrathecal drug spread. Br J Anaesth 1994; 73: 744±6 13 Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JAW. Comparison of extradural ropivacaine and bupivacaine. Br J Anaesth 1991; 66: 31±7 14 Morrisson LMM, Emanuelsson BM, McClure JH, et al. Ef®cacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth 1994; 72: 269±73 15 Schneider M, Ettlin T, Kaufmann M, et al. Transient neurologic toxicity after hyperbaric subarachnoid anaesthesia with 5% lidocaine. Anesth Analg 1993; 76: 1154±7
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of evidence suggesting that there is a greater degree of sensory±motor separation when using ropivacaine compared with bupivacaine,13 14 and supports our view that ropivacaine is an agent worthy of further study as an agent for spinal anaesthesia. Good sensory blocks were associated with a highly favourable recovery pro®le compared with bupivacaine, with more rapid regression of sensory and motor block, earlier mobilization and shorter time to ®rst micturition. With the current emphasis on ambulatory surgery, such a recovery pro®le may be of bene®t. Hyperbaric lidocaine 5% has been used as a short-acting agent for ambulatory spinal anaesthesia, but concerns about the high incidence of transient neurological symptoms restrict its use currently.15 We found no evidence of any late sequelae such as backache or other transient symptoms in this or a previous study of ropivacaine.5 In conclusion, a solution of ropivacaine that is hyperbaric relative to cerebrospinal ¯uid can be used to provide reliable spinal anaesthesia that is comparable to that with hyperbaric bupivacaine in terms of quality of block, but with a shorter recovery pro®le. The key issue is the difference in the clinical pro®le of the block (onset, extent, suitability for surgery, duration) produced, not the relative potencies of the two drugs. However, further work is required to evaluate the role of hyperbaric ropivacaine for surgical procedures of short-to-intermediate duration, particularly in the ambulatory setting.