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Anesth Analg 1999;89:727
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Comparison of Ropivacaine 0.2% and Lidocaine 0.5% for Intravenous Regional Anesthesia in Volunteers

Maximilian W. B. Hartmannsgruber, MD*, David G. Silverman, MD*, Thomas M. Halaszynski, DMD, MD*, Vonda Bobart, MD*, Sorin J. Brull, MD{dagger}, Carlos Wilkerson, MD, PhD{ddagger}, Andreas W. Loepke, MD{ddagger}, and Peter G. Atanassoff, MD*

Departments of Anesthesiology, *Yale University School of Medicine, New Haven, Connecticut; {dagger}University of Arkansas Medical Center, Little Rock, Arkansas; and {ddagger}Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence and reprint requests to David G. Silverman, MD, Department of Anesthesiology, Yale University School of Medicine, PO Box 208051, New Haven, CT 06520-8051. Address e-mail to david.silverman{at}yale.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
A longer acting local anesthetic such as ropivacaine may offer advantages over lidocaine for IV regional anesthesia (IVRA). The objective of this investigation was to determine whether the use of ropivacaine improves the quality and duration of IVRA. In a randomized, double cross-over design, 10 volunteers received lidocaine 0.5% or ropivacaine 0.2% for IVRA of the upper extremity on two separate days with a standard double-cuff technique. Sensation to pinprick, response to tetanic stimuli, and tourniquet pain were assessed on a 0–10 verbal numeric score scale at 5-min intervals throughout the period of tourniquet inflation. Motor function was evaluated by grip strength. After release of the second (distal) cuff, pinprick sensation, motor strength, and systemic side effects were evaluated at 3, 10, and 30 min. No significant differences were observed for onset times of anesthesia and times to proximal (38 ± 3 and 36 ± 3 min) or distal (34 ± 13 and 36 ± 13 min) tourniquet release after the administration of ropivacaine and lidocaine, respectively. However, postdeflation hypoalgesia and motor blockade were prolonged with ropivacaine, and postdeflation lightheadedness, tinnitus, and drowsiness were more prominent with lidocaine. We conclude that ropivacaine may be an alternative to lidocaine for IVRA. It may result in prolonged analgesia and fewer side effects after tourniquet release.

Implications: In this study, volunteers received lidocaine 0.5% or ropivacaine 0.2% for IV regional anesthesia on two study days. Ropivacaine and lidocaine provided similar surgical conditions. However, after release of the distal tourniquet, prolonged sensory blockade and fewer central nervous system side effects were observed with ropivacaine.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
IV regional anesthesia (IVRA) is a technically simple and reliable technique, with success rates between 94% and 98% (1,2). However, the local anesthetic most often used in the United States (lidocaine 0.5%) has a relatively brief duration of action, which may affect the duration of intraoperative analgesia, tourniquet tolerance, and redistribution of drug after tourniquet release. Theoretically, it would be beneficial to use a longer acting drug such as bupivacaine, but it is considered too risky for IVRA because it binds tightly to myocardial sodium channels and may cause irreversible cardiac arrest if the drug escapes into the systemic circulation (3,4).

Ropivacaine, a newer amide local anesthetic, is structurally related to bupivacaine with almost as long a duration of action (5,6); however, ropivacaine causes less depression of cardiac conduction (7–11), presumably because it is a pure s-enantiomer. Clinical use of ropivacaine is well established for epidural anesthesia and peripheral nerve blocks, but the drug has not been used for IVRA. The potential use of a local anesthetic that could provide anesthesia of greater duration than lidocaine with less toxicity than bupivacaine prompted the present comparison of ropivacaine and lidocaine for IVRA in healthy volunteers. The potency of ropivacaine is approximately 3 times that of lidocaine (7). A 0.2% solution was used because it is the commercially available concentration of ropivacaine that most closely achieves equipotency with the concentration of lidocaine typically used for IVRA.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval of the Yale University Institutional Human Investigations Committee, 10 unpremedicated healthy volunteers (age 19–48 yr; two women, eight men) participated in a randomized, double-blinded, cross-over comparison of lidocaine 0.5% and ropivacaine 0.2%. Forty milliliters of lidocaine 0.5% or ropivacaine 0.2% was injected IV into the dorsal surface of the nondominant hand in two separate study sessions at least 4 days apart. A second IV line was placed into an antecubital vein of the dominant arm to draw blood samples and to provide a route for emergency drug administration. Throughout the investigation, volunteers were monitored continuously with noninvasive blood pressure measurements, electrocardiogram, and pulse oximetry.

After exsanguination of the nondominant arm by gravity, the proximal cuff of a double-cuff tourniquet placed on the volunteer's upper arm was inflated to a pressure of 250 mm Hg. Limb occlusion pressure was verified by loss of pulse oximetry tracing of the ipsilateral index finger. The local anesthetic was then injected over 1 min. When the proximal tourniquet pressure became unbearably painful (rated as 10 on a verbal numeric scale [VNS] where 0 = no pain and 10 = the worst pain imaginable), the distal cuff was inflated, followed by release of the proximal tourniquet. The VNS was used instead of the more commonly used visual analog scale (VAS) because the former does not require the use of a visual prompt and is considered preferable when visual and motor coordination are impaired (12), i.e., immediately after tourniquet deflation. It has been confirmed that although the VAS has superior ratio scale characteristics, both the VNS and VAS provide consistent measures of experimental and clinical pain intensity and can be used separately to measure pain (13). The distal tourniquet remained inflated until a VNS score of 10 was again reported.

Multiple assessments were obtained at baseline and at 5-min intervals during tourniquet inflation. Response to pinprick was evaluated in the dermatomal sensory distribution of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves with a 0–10 scale (0 = no sensation to 10 = normal sensation). Pain in response to tetanic stimulation (5 s, 50 Hz, 60 mA) delivered via surface electrodes placed over the ulnar nerve at the wrist was evaluated on a VNS scale. This stimulus has been shown to be equivalent to a surgical incision, initially in studies assessing mean alveolar concentrations of volatile anesthetics (14) and subsequently in assessments of regional anesthesia (15). A VNS score <5 was chosen to represent acceptable surgical conditions after this stimulus. Motor function was evaluated by asking the volunteer to squeeze a blood pressure cuff that was preinflated to 40 mm Hg.

The previously described assessments were repeated 3, 10, and 30 min after deflation of the distal tourniquet. The volunteers were asked to rate central nervous system (CNS) side effects such as dizziness, tinnitus, lightheadedness, and the presence of metallic taste on a 0–10 VNS at these same times. At the conclusion of the second session, the subject was asked to compare the intensity of side effects during the two sessions. In light of the poor ratio scale properties of the VNS (13), this comparison used the method of magnitude estimation. The subject was told to rate the intensity of side effects in Session 2 as a score of 50 and to rate side effects on Day 1 relative to that score; e.g., symptoms perceived to be twice as severe were scored 100, symptoms half as severe were scored 25.

Immediately before release of the distal tourniquet and 3, 10, and 30 min postrelease, venous blood samples were drawn from the volunteer's opposite arm to determine lidocaine and ropivacaine concentrations in the plasma. The samples were immediately centrifuged and frozen at -60°C until measurement of total amount of drug (bound and unbound) by gas chromatography with a nitrogen-phosphorus detector could be performed. All samples were prepared in duplicate, and the reported amount was calculated from their mean. Bupivacaine was chosen as an internal standard for the ropivacaine samples, and prilocaine was chosen as an internal standard for the lidocaine samples.

Data are expressed as mean ± SD (range) and were analyzed by using Wilcoxon's signed rank and paired t-tests for nonparametric and parametric data, respectively; actual P values are presented for all P < 0.05 determinations to permit "corrections" for repetitive testing at multiple time points (i.e., 3, 10, and 30 min after tourniquet release).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All participating volunteers completed the investigation successfully. There were no significant differences between the two local anesthetics with respect to time to loss of pinprick sensation along the individual nerve distributions (Figure 1). Time to complete loss of pinprick sensation corresponded to tolerance of tetanic stimulation (VNS score <5) and occurred at 18 ± 9 min (5–30 min) and 22 ± 11 min (5–35 min) for lidocaine and ropivacaine, respectively (P = not significant [NS]). Complete loss of sensation to tetanic stimulation occurred at 32 ± 12 min (10–45 min) and 33 ± 14 min (10–55 min) for lidocaine and ropivacaine, respectively (P = NS). Tolerance times for the proximal tourniquet were the same for both sessions (36 ± 11 and 38 ± 11 min); additional tolerance times for the distal tourniquet were also equal (36 ± 13 and 34 ± 13 min).



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  		Figure 1. Onset of decreased sensation to pinprick in the distal nerve distributions and of decreased motor function. Lat Cut = lateral antebrachial cutaneous nerve, Med Cut = medial antebrachial cutaneous nerve.

 
After release of the distal tourniquet, decreased pinprick sensation persisted longer in the ropivacaine session (Figure 2). Significant differences of pinprick sensation persisted for 30 min in the distribution of the lateral antebrachial cutaneous nerve (P = 0.0002). Likewise, the persistence of decreased grip strength was prolonged after ropivacaine administration (P = 0.02).



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  		Figure 2. Recovery from sensory and motor blockade in the distal nerve distributions of the brachial plexus 3, 10, and 30 min after distal tourniquet deflation. *P = 0.0002 for interdrug differences in the distribution of the lateral antebrachial cutaneous nerve. **P = 0.02 for interdrug differences for grip strength. Lat Cut = lateral antebrachial cutaneous nerve, Med Cut = medial antebrachial cutaneous nerve.

 
Venous plasma levels of ropivacaine and lidocaine are shown in Figure 3. Even with the tourniquet inflated, trace amounts of both local anesthetics were present in the plasma (time 0). The maximal concentration (Cmax) of ropivacaine, 1.2 ± 0.3 µg/mL (0.8–1.6 µg/mL), was detected 10 min after distal cuff deflation. The Cmax of lidocaine, 1.7 ± 0.6 µg/mL (1.1–3.0 µg/mL), was detected only 3 min after cuff release.



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  		Figure 3. Venous plasma concentrations of lidocaine and ropivacaine immediately before tourniquet deflation and 3, 10, and 30 min after release of the distal tourniquet.

 
CNS side effects were less intense after release of the tourniquet in the ropivacaine session than in the lidocaine session (Table 1). Three minutes after release during the ropivacaine session, subjects reported less dizziness (P = 0.01), less tinnitus (P = 0.003), less metallic taste (P = 0.01), and less lightheadedness (P = 0.001). Ten minutes after release of the tourniquet, tinnitus was perceived less in volunteers receiving ropivacaine (P = 0.03). One volunteer shivered, and two others complained of nausea within 3 min of tourniquet release during the lidocaine session. When asked to compare the intensity of CNS side effects between the two study days, volunteers rated their intensity 5.3 ± 2.4 times higher with lidocaine than with ropivacaine (P = 0.04). Cardiotoxic events such as arrhythmias or hypotension were not observed with either local anesthetic.


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  		Table 1. CNS Effects Reported After Tourniquet Release
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we demonstrated that, during the period of tourniquet inflation, IVRA with ropivacaine 0.2% provides anesthesia and motor blockade of similar onset and intensity as IVRA with lidocaine 0.5%. Despite its longer duration in other clinical settings, ropivacaine did not prolong tourniquet tolerance compared with lidocaine for IVRA. However, after tourniquet release, ropivacaine had a prolonged residual effect; the interdrug difference was significant for sensation in the distribution of the lateral antebrachial cutaneous nerve and for grip strength at each of the postdeflation test times. Other nerves evaluated tended to have longer residual effects with ropivacaine than with lidocaine, but this trend did not reach statistical significance in our 10 subjects. The longer duration of posttourniquet sensory block after IVRA with ropivacaine may be attributable to more complete and more persistent binding and, hence, slower release into the systemic circulation. The potential for superior postoperative analgesia in the immediate postoperative period remains to be determined.

The rapid return of normal sensation after lidocaine administration was associated with a peak concentration of lidocaine in the plasma approximately three minutes after tourniquet release. This is consistent with the report that, within three minutes of tourniquet release, 58% of a compound similar to lidocaine (0.1 mg of HIDA labeled with 100 mCi of 99mTc in 40 mL of saline) was eliminated from the arm (16). The rapid washout of lidocaine was associated not only with a rapid decline in anesthesia, but also with systemic effects at the three-minute postdeflation time point. Systemic effects with this local anesthetic are not uncommon (17–20) and actually may be underreported because of concomitant sedative medication (21). In one report, 3 of 11,229 patients undergoing IVRA and receiving 30–45 mL of lidocaine 0.5% developed seizures promptly after tourniquet deflation (17).

The development of fewer systemic effects after ropivacaine administration is consistent with the delayed peak of ropivacaine plasma levels after tourniquet release. However, peak ropivacaine plasma levels were relatively higher than peak lidocaine plasma levels (1.2 vs 1.7 µg/mL) when comparing the same volumes of ropivacaine 0.2% (total of 80 mg) and lidocaine 0.5% (total of 200 mg). This may be explained by differing sensitivities of the assays, as well as initial high uptake of lidocaine in the lungs (22) and efficient extraction of lidocaine by the liver ("high extraction drug") (23). Therefore, the absolute levels of ropivacaine and lidocaine are not directly comparable. Contributing to fewer CNS side effects of shorter duration after ropivacaine may be the fact that only a small fraction (<10%) is unbound in the plasma (10), whereas 20%–40% of lidocaine is unbound.

The highest venous plasma levels of ropivacaine (1.2 µg/mL), noted 10 minutes after tourniquet release, were approximately half as high as total venous plasma levels obtained in a study that established 2.2 µg/mL as the maximal tolerated plasma concentration of ropivacaine during an IV infusion of 10 mg/min (10). Objective signs of lidocaine toxicity are reported to occur at approximately 5 µg/mL. This level is more than twice that used in the present study, consistent with the finding that only one of our volunteers shivered as an objective sign of lidocaine toxicity. However, in the present study, we showed that more subtle effects may be elicited on questioning: 10 of 10 subjects who received lidocaine reported symptoms that were of greater intensity and longer duration than those after ropivacaine administration.

In all study subjects, tourniquets remained inflated for >40 minutes. Hence, we did not examine the potential for adverse effects after shorter tourniquet times or in cases of tourniquet failure. There are two reported cases in which an inadvertent intravascular injection of ropivacaine (150 and 200 mg) was followed by convulsions (24,25). Neither patient showed signs of cardiotoxicity, and both recovered uneventfully. In his review, McClure (25) noted that four other cases of inadvertent IV injection during the administration of 75 to 200 mg of ropivacaine were not accompanied by convulsions or signs of cardiotoxicity. If ropivacaine were used for IVRA in a volume and concentration equivalent to those in the present investigation, the maximal dose that could be released is 80 mg.

The margin of safety with ropivacaine may be greater than that with bupivacaine. IV infusions of ropivacaine caused less severe CNS symptoms than equivalent infusions of bupivacaine (10). In that study, which compared toxicity during IV infusions of ropivacaine and bupivacaine, both drugs produced a similar spectrum of symptoms, but the symptoms were more tolerable and of shorter duration after ropivacaine administration; only 1 of 12 subjects tolerated the maximal dose (150 mg) of bupivacaine, compared with 7 of 12 subjects who tolerated ropivacaine (10). This may be attributable to the finding that the lipid solubility of ropivacaine is <50% of that of bupivacaine (8). Ropivacaine's lipid solubility is intermediate between lidocaine and bupivacaine. The fact that ropivacaine is only one-half to one-third as lipid-soluble as bupivacaine explains the higher threshold for CNS symptoms with ropivacaine, but this does not fully explain bupivacaine's greater cardiotoxicity. In an isolated rabbit purkinje fiber-ventricular muscle preparation, the conduction block was less in response to ropivacaine and lidocaine than bupivacaine, a finding that suggests a greater effect on calcium channels by the latter drug (8). In contrast to bupivacaine, cardiovascular toxicity with ropivacaine does not usually occur without warning, i.e., without preceding signs of CNS toxicity (9).

In conclusion, based on the findings of equivalent anesthesia, prolonged hyposensation after tourniquet release, and reduced CNS side effects, it seems reasonable to consider ropivacaine as a potential alternative for IVRA. The advantages of ropivacaine 0.2% warrant further investigation, particularly under surgical conditions.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 26, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press