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Anesth Analg 2003;97:412-416
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Central Nervous System and Cardiovascular Effects of Levobupivacaine and Ropivacaine in Healthy Volunteers

Jonathan Stewart, MBChB*, Norma Kellett, MBChB*, and Dan Castro, MD{dagger}

*Inveresk Research, Edinburgh, Scotland, United Kingdom; and {dagger}Abbott Laboratories, Abbott Park, Illinois

Address correspondence and reprint requests to Dr. Jonathan Stewart, Chugai Pharma Europe Ltd., Mulliner House, Flanders Rd., Turnham Green, London, W4 1NN. Address e-mail to jgs{at}doctors.org.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the central nervous system (CNS) and cardiovascular effects of levobupivacaine and ropivacaine when given IV to healthy male volunteers (n = 14) in a double-blinded, randomized, crossover trial. Subjects received levobupivacaine 0.5% or ropivacaine 0.5% after a test infusion with lidocaine to become familiar with the early signs of CNS effects (e.g., tinnitus, circumoral paresthesia, hypesthesia). The development of CNS symptoms was assessed at 1-min intervals and study drug administration was terminated when the first CNS symptoms were recognized. Thereafter, symptoms were recorded at 1-min intervals until symptom resolution. Hemodynamic variables were assessed by transthoracic electrical bioimpedance. Continuous 12-lead electrocardiogram monitoring was also performed. There was no significant difference between levobupivacaine and ropivacaine for: the mean time to the first onset of CNS symptoms (P = 0.870), mean total volume of study drug administered at the onset of the first CNS symptom (P = 0.595), stroke index (P = 0.678), cardiac index (P = 0.488), acceleration index (P = 0.697), PR interval (P = 0.213), QRS duration (P = 0.637), QT interval (P = 0.724), QTc interval (P = 0.737), and heart rate (P = 0.267). Overall, fewer CNS symptoms were reported for levobupivacaine than ropivacaine (218 versus 277). This study found that levobupivacaine and ropivacaine produce similar CNS and cardiovascular effects when infused IV at equal concentrations, milligram doses, and infusion rates.

IMPLICATIONS: This study compared directly, for the first time, the toxicity of levobupivacaine and ropivacaine in healthy volunteers. Levobupivacaine and ropivacaine produced similar central nervous system and cardiovascular effects when infused IV at equal concentrations, milligram doses, and infusion rates.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Concern over reports of serious toxicity and deaths associated with the accidental IV injection of racemic bupivacaine has highlighted the need for a safer local anesthetic. Bupivacaine possesses a single asymmetric carbon atom and exists as a 50:50 mixture of two stereoisomers, termed S(-)- and R(+)-bupivacaine. Early experiments which showed S(-)-bupivacaine to be less toxic than the R-isomer in mice, rats, and rabbits, with no apparent loss of anesthetic potency (1), led to the development of the S(-)-isomer (levobupivacaine) as a potentially safer alternative to racemic bupivacaine. Similarly, ropivacaine, the S(-)-isomer of 1-propyl-2',6'-pipecoloxylidide (the propyl homolog of bupivacaine), has also been developed as a potentially less toxic alternative to bupivacaine.

A wide variety of animal experiments have shown that levobupivacaine and ropivacaine are significantly less toxic than bupivacaine (2,3). In addition, several double-blinded, randomized, crossover volunteer studies have been performed comparing levobupivacaine and bupivacaine, and ropivacaine and bupivacaine (4–6). These trials showed that levobupivacaine and ropivacaine were less toxic than bupivacaine. However, there have been no studies directly comparing the toxicity of levobupivacaine and ropivacaine in humans.

In this study, we investigated the doses of ropivacaine and levobupivacaine required to elicit the first signs of central nervous system (CNS) symptoms in healthy volunteers, and the type and severity of these symptoms. The effects of these drugs on selected hemodynamic variables (stroke index, cardiac index, acceleration index) and selected ECG (electrocardiogram) variables (PR interval, QRS duration, QT interval, QTc interval, and heart rate) at specified time points throughout the study are also reported.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The underlying rationale for this study was to enable a proper direct comparison of the toxic effects of the two S(-)-isomer anesthetics, levobupivacaine and ropivacaine. We compared the time to onset of CNS symptoms and the cardiovascular effects in male volunteers when levobupivacaine and ropivacaine were infused IV at equal concentrations, milligram doses, and infusion rates.

This study was conducted within the guidelines of good clinical practice, according to the provisions of the Declaration of Helsinki (and its subsequent revisions) with the approval of an Independent Ethics Committee. Written informed consent to participate in the study was obtained from all subjects.

Subjects
The target study population consisted of 14 healthy male subjects, with an age range of 18–40 yr and a body mass index <=30. Subjects were required to undergo a full medical examination and meet the following inclusion criteria: no clinically significant abnormal physical finding from the screening examination; no clinically relevant abnormalities from the laboratory screening evaluation; normal ECG results; normal arterial blood pressure (systolic 100–150 mm Hg, diastolic 50–90 mm Hg) and heart rate (50–90 bpm) at screening; human immunodeficiency virus negative; and a nonsmoker. Subjects were also required to not consume caffeine or alcohol and to not engage in strenuous exercise in the 48-h period before each dosing session.

Subject exclusion criteria included: administration of any investigational new drug within the 4 mo before entering the study; a need for any medication during the 14-day period before entering the trial (excluding aspirin or paracetamol); existence of any surgical or medical condition that, in the judgment of the investigator, might interfere with the absorption, distribution, metabolism, or excretion of study drugs; history of allergies requiring treatment or known allergies to the study drugs; history of, or familial history of, any unusual responses to amide local anesthetics; loss of >400 mL of blood during the 12-wk period before entering the trial; serious adverse reaction or hypersensitivity to any drug; history of seizure or other neurological, neuromuscular, or psychiatric disorders; history of blood clotting disorders or blood dyscrasias.

Subjects who met the study criteria were deemed eligible to undergo a lidocaine test session to become familiar with the early symptoms of CNS toxicity of local anesthetics. Subjects were administered a test dose of IV lidocaine infused at 15 mg/min, with a maximal allowable dose of 200 mg, until the subject was aware of the early signs of CNS effect (e.g., tinnitus, circumoral paresthesia, hypesthesia). Subjects were asked to grade the symptoms as mild, moderate, or severe at the initial detection of the CNS symptoms and at 1-min intervals thereafter until the symptoms completely resolved. Subjects who experienced CNS symptoms without major sequelae during the lidocaine test session were eligible to continue the study.

Infusion and Monitoring
The study period was divided into 2 dosing sessions in which subjects received levobupivacaine 0.5% or ropivacaine 0.5%, in a double-blinded manner and a randomized order separated by a minimal 7-day washout period. The first study drug dosing session began immediately after a minimal 18-h washout period after the lidocaine test session.

For both the levobupivacaine and ropivacaine dosing sessions, study drug was administered at a rate of 10 mg/min by continuous IV infusion. At 1-min intervals from the start of study drug infusion, subjects were asked, "Do you have any symptoms?" Study drug administration was terminated on recognition of CNS symptoms by the investigator. Subjects were asked to grade the symptoms as mild, moderate, or severe. Symptom grading continued at 1-min intervals until the symptom resolved. Study drug administration procedures for the second dosing session were identical to those followed during the first dosing session, except that upon entry to the clinic facility, the subject underwent an abbreviated physical examination, provided updated medical information, and verified no alcohol or caffeine consumption in the previous 48-h period. The maximal allowable dose of either study drug was 150 mg, regardless of whether or not the subject reported any CNS symptoms.

CNS effects were measured by recording the time to onset of the first CNS symptom and the total dose of study drug administered at the onset of the first CNS symptom.

Cardiovascular effects were determined by measuring changes from baseline to the end of study drug infusion in stroke index, cardiac index, and acceleration index using transthoracic electrical bioimpedance. For the baseline measurements, 3 consecutive measures of each index were taken 15 min before dosing, with the mean of these 3 measurements used as the baseline figure. Measurements were taken at 5, 10, 15, 20, 25, and 30 min after the start of infusion and at the end of study drug infusion.

In addition, cardiovascular effects were further determined by measuring PR, QRS, QT, and QTc intervals and heart rate derived from ECG recordings. Continuous ECG monitoring was performed from approximately 1 h before dosing to 6 h after dosing. A 12-lead ECG was recorded 1 h before dosing (baseline), and at 5, 10, 15, 20, 30 min and 1, 2, and 8 h after the start of infusion. A 12-lead ECG was also recorded at the end of study drug infusion.

Adverse events, vital signs, and oxygen saturation were monitored at specific time points during the study. Adverse events were monitored from the time of study enrollment until a 7-day telephone follow-up evaluation.

For the purposes of sample size calculation, cardiac output and stroke volume were used as the primary end-points. It was assumed that the mean cardiac output in supine healthy subjects was approximately 8.0 L/min, and that the study was aiming to detect a 10% difference in cardiac output between the 2 formulations. Based on a relevant estimate of the within-subject variability (SD = 0.9 L/min), power calculations showed that a minimum of 11 subjects were required to show a treatment difference with an 80% power at a significance level of 95%. It was assumed that mean stroke volume in healthy supine subjects was approximately 126 mL and the study was aiming to detect a 10% difference in cardiac output between treatments. Based on a relevant estimate of within-subject variability (SD = 14.3 mL), power calculations showed a minimum of 12 subjects were required to show a treatment difference with an 80% power at a significance level of 95%. Therefore, it was recommended that 14 subjects be recruited for the study.

All statistical tests were two-tailed, and a P value < 0.05 was considered statistically significant. Statistical analyses were performed using SAS(version 6.12, or a more recent version; SAS Institute Inc., Cary, NC). The time-normalized area under the curve (AUC), change from baseline to the worst value obtained after the start of infusion up to 8 h after the start of infusion, and the change from baseline to the end of infusion were calculated for all end-points. An analysis of variance (ANOVA) was performed on the time-normalized AUC, change from baseline to worst value, and change from baseline to end of dosing with effect of sequence, subject of sequence, period, and treatment regimen. Within the framework of the ANOVA model, a 95% confidence interval was obtained for the difference between regimens. The minimal total volume of drug and the total volume of study drug administered at the time of the first CNS symptom were analyzed using a similar ANOVA model. In addition, regimen differences in the time to first CNS symptom were assessed using a survival analysis appropriate for a crossover design. The time-normalized AUC, change from baseline to the worst value obtained after the start of infusion up to 8 h after the start of infusion, and the change from baseline to the end of infusion were calculated for vital signs, pulse, and oxygen saturation.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 14 subjects enrolled in the study, 13 were eligible to continue the study after the lidocaine test session. (One subject was withdrawn because of a prolonged PR interval [221 ms] during the lidocaine test session.) The 13 subjects who received both the levobupivacaine and ropivacaine infusions completed the dosing sessions according to the protocol and without experiencing serious adverse events.

The mean total volume ± SD of study drug administered at the onset of the first CNS symptom was similar for levobupivacaine and ropivacaine (36.9 ± 8.55 and 39.2 ± 17.54 mg, respectively; P = 0.595). The larger standard deviation observed with ropivacaine compared with that of levobupivacaine is unlikely to be significant, given the small number of subjects in the study. The mean time ± SD to the first onset of CNS symptom was also similar for levobupivacaine and ropivacaine (3.7 ± 0.85 and 3.9 ± 1.75 min, respectively; P = 0.870).

Table 1 specifies the types of CNS symptoms reported by subjects receiving levobupivacaine and ropivacaine. All patients experienced at least one CNS symptom. The most common CNS symptoms during both study drug infusions were dizziness, paresthesia, and hypesthesia. CNS symptoms that occurred exclusively during the ropivacaine infusion were chest pain, circumoral paresthesia, pain, taste perversion, and vasodilation, whereas only depersonalization and hyperventilation occurred exclusively during the levobupivacaine infusion.


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  		Table 1. Central Nervous System (CNS) Symptoms Reported by Subjects
 
Levobupivacaine had fewer CNS observations recorded than ropivacaine (218 versus 277). The severity gradings of all the reported CNS observations are shown in Table 2. The majority of CNS observations that occurred throughout either the levobupivacaine or ropivacaine dosing sessions were mild in severity. Eight CNS observations with levobupivacaine, which were all reported by the same subject, were graded as severe.


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  		Table 2. Severity Gradings of All Reported Central Nervous System Observations
 
Mean percentage changes from baseline to the end of infusion were similar for levobupivacaine and ropivacaine for stroke index, cardiac index, and acceleration index, as well as for PR interval, QRS duration, QT interval, QTc interval, and heart rate (Table 3). Mean values for stroke index, cardiac index, and acceleration index were similar for levobupivacaine and ropivacaine from baseline through 30 min after the start of infusion, with minor differences between groups. Mean values for PR interval, QRS duration, QT interval, QTc interval, and heart rate were also similar for levobupivacaine and ropivacaine from baseline through 8 h after the start of infusion, with minor differences between the 2 groups. Given the small number of subjects in this study, the large standard deviations shown in Table 3 and the absence of statistically significant results, it is not possible to draw firm conclusions about these cardiovascular findings.


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  		Table 3. Cardiovascular Effects Recorded During the Study: Mean Percentage Change from Baseline to End of Infusion
 
Adverse events were recorded in 6 patients (38.5%) during the ropivacaine session and in 2 patients (15.4%) during the levobupivacaine session (Table 4). There were no serious adverse events. Analyses of arterial blood pressure, pulse, and arterial oxygen saturation showed no significant differences between the levobupivacaine and ropivacaine groups.


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  		Table 4. Adverse Events During the Trial
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This double-blinded, randomized, crossover study is the first to directly compare the doses of ropivacaine and levobupivacaine required to elicit the first signs of CNS symptoms. The results suggest that there is little, if any, difference in the CNS toxicity of levobupivacaine and ropivacaine in volunteers when infused IV at equal concentrations, milligram doses, and infusion rates.

The human studies by Scott et al. (4) and Knudsen et al. (5) demonstrate a larger tolerated CNS dose for ropivacaine (124 and 115 mg, respectively) than for bupivacaine (99 and 103 mg, respectively). In a trial reported by Bardsley et al. (6), a 17% larger dose of levobupivacaine than bupivacaine was tolerated before the first appearance of CNS symptoms (56 and 47 mg, respectively). The earlier trials (4,5) were continued until subjects felt more clearly defined CNS symptoms (not necessarily severe). Later studies, including the trial presented in this report, discontinued anesthetic infusions at the first sign of CNS symptoms (for ethical reasons). This could account for the observed differences in maximal dose between earlier and later studies. It could also explain the lack of change in cardiac measurements detected in this study, because cardiac changes normally become apparent only at larger doses than those required to evoke CNS changes.

In the clinical setting, the comparative safety of drugs can be assessed by comparing therapeutic indices—the margin between the therapeutic and toxic doses. Thus, results of toxicity studies must be considered together with the potency of each anesthetic. Although this study does not address potency directly, the issue has been considered extensively in other studies, including trials that determined the minimal local analgesic concentrations of bupivacaine, levobupivacaine, and ropivacaine. Such potency studies have provided evidence that levobupivacaine and bupivacaine have similar potencies (7,8), while clinical trials have clearly shown that levobupivacaine and bupivacaine have equal clinical efficacy in various indications (9–11).

In contrast, evidence for the potency of ropivacaine compared with that of bupivacaine is less clear-cut, with several minimal local analgesic concentration studies (12–14) demonstrating that ropivacaine has 60% of the potency of bupivacaine. Although some trials have suggested equal clinical efficacy for ropivacaine and bupivacaine (15,16), data for some applications suggest that larger concentrations of ropivacaine (0.75% or 1.0%) are needed to provide the same sensory block as bupivacaine (0.5% and 0.75%) (17).

If levobupivacaine is proven to be more potent than ropivacaine across a range of applications, and given that the difference in toxicity between ropivacaine and levobupivacaine seems slight—as is supported by this trial—our study provides evidence supporting a higher therapeutic index for levobupivacaine.


   Acknowledgments
 
This research was funded by a grant from Abbott Laboratories.

Abbott Laboratories and the authors gratefully acknowledge the valuable contribution made to this study by the late Dr. Dan Castro.


   Footnotes
 
JS has received sponsorship from Abbott Laboratories, Fujisawa Pharmaceuticals, Merck Sharp & Dohme, and Novartis for attendance at scientific meetings.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Åberg G. Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol 1972; 31: 273–86.[Medline]
  2. Morrison SG, Dominguez JJ, Frascarolo P, Reiz S. A comparison of the electrocardiographic cardiotoxic effects of racemic bupivacaine, levobupivacaine, and ropivacaine in anesthetized swine. Anesth Analg 2000; 90: 1308–14.[Abstract/Free Full Text]
  3. Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg 2001; 93: 743–8.[Abstract/Free Full Text]
  4. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563–9.[Abstract/Free Full Text]
  5. Knudsen K, Suurkula NB, Blomberg S, et al. Central nervous and cardiovascular effects of i. v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78: 507–14.[Abstract/Free Full Text]
  6. Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998; 46: 245–9.[ISI][Medline]
  7. Lyons G, Columb M, Wilson RC, Johnson RV. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901.[Abstract/Free Full Text]
  8. Vladimirov M, Nau C, Mak WM, Strichartz G. Potency of bupivacaine stereoisomers tested in vitro and in vivo: biochemical, electrophysiological and neurobehavioral studies. Anesthesiology 2000; 93: 744–55.[ISI][Medline]
  9. Bader AM, Tsen LC, Camann WR, et al. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology 1999; 90: 1596–601.[ISI][Medline]
  10. Kopacz DJ, Allen HW, Thompson GE. A comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anesth Analg 2000; 90: 642–8.[Abstract/Free Full Text]
  11. Burke D, Henderson DJ, Simpson AM, et al. Comparison of 0.25% (S-)-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour. Br J Anaesth 1999; 83: 750–5.[Abstract/Free Full Text]
  12. Capogna G, Celleno D, Fusco P, et al. Relative potencies of bupivacaine and ropivacaine for analgesia in labour. Br J Anaesth 1999; 82: 371–3.[Abstract/Free Full Text]
  13. Polley LS, Columb MO, Naughton NN, et al. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: implications for therapeutic indexes. Anesthesiology 1999; 90: 944–50.[ISI][Medline]
  14. 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]
  15. Nociti JR, Serzedo PS, Zuccolotto EB, et al. Ropivacaine in peribulbar block: a comparative study with bupivacaine. Acta Anaesthesiol Scand 1999; 43: 799–802.[Medline]
  16. Senard M, Joris JL, Ledoux D, et al. A comparison of 0.1% and 0.2% ropivacaine and bupivacaine combined with morphine for postoperative patient-controlled epidural analgesia after major abdominal surgery. Anesth Analg 2002; 95: 444–9.[Abstract/Free Full Text]
  17. McClellan KJ, Faulds D. Ropivacaine: an update of its use in regional anaesthesia. Drugs 2000; 60: 1065–93.[ISI][Medline]
Accepted for publication March 18, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press