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© 2000 International Anesthesia Research Society
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Abstract |
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We compared the toxicity of systemic local anesthetics bupivacaine and ropivacaine administered at equivalent and equipotent doses. In the first experiments, 18 male Wistar rats were anesthetized with thiopental and maintained under positive controlled ventilation. Electrocardiogram, electroencephalogram, and invasive arterial blood pressure were continuously recorded. The animals were randomly assigned to receive 3 mg · kg-1 · min-1 bupivacaine, 3 mg · kg-1 · min-1 ropivacaine IV (equivalent group), or 4.5 mg · kg-1 · min-1 ropivacaine (equipotent group). The timing of the occurrence of local anesthetic-induced toxic events (defined as the first QRS modification, dysrhythmia, seizures, moderate and severe bradycardia and hypotension, final systole) was recorded and the dose calculated. Eighteen additional rats, treated according to the same protocol were killed at the time of moderate, severe, and final hypotension for blood sampling and plasma bupivacaine and ropivacaine concentration measurement. In a third experiment, 15 awake rats (5 per group) received IV bupivacaine or ropivacaine (same infusion as in the first experiments) until seizure. At this moment, rats were allowed to recover from local anesthetic intoxication. In the first experiment, except for the first QRS modification, all the other toxic manifestations occurred at significantly larger doses (P < 0.05) in the two ropivacaine groups in comparison to the bupivacaine group. In awake rats, all the animals intoxicated by ropivacaine easily recovered. In the bupivacaine group, two animals required cardiopulmonary resuscitation before any seizure activity could be detected, and only three rats survived. We conclude that, in the model used, ropivacaine, even at an equipotent dose, is less toxic than bupivacaine.
Implications: Our results clearly demonstrate that ropivacaine, even used at an equipotent dose, has a wider therapeutic index than bupivacaine.
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Introduction |
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Ropivacaine is a new amide local anesthetic that was initially marketed as having therapeutic properties similar to those of bupivacaine but associated with less motor blockade and toxicity (1). In contrast with this assertion, recent investigations demonstrate that ropivacaine is at least 40% less potent than bupivacaine (2,3). Moreover, concerning the beneficial effect of ropivacaine on motor blockade, there are no data in the literature that highlight the difference between a specific drug effect versus a potency-related epiphenomenon. This study was designed to compare the cardio- and neurotoxic effects of the local anesthetic ropivacaine with bupivacaine when the two drugs are administered not only at equivalent doses but also at equipotent doses. The aim of this investigation was to determine whether the reduced toxicity of systemic ropivacaine is a specific drug property or an effect related to its reduced potency.
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Methods |
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Approval from the Institutional Animal Care and Use Committee was obtained. In the first experiment, designed to determine the timing of the occurrence of local anesthetic-induced toxic events, 18 male Wistar rats, 5 mo old, weighing 260–320 g were used. Anesthesia was induced with diethyl ether, followed by intraperitoneal thiopental (20 ± 5 mg/kg). A tracheotomy was performed, and controlled ventilation (modified Spiromat 650 ventilator; Dräger, Lübeck, Germany) was started with air (fraction of inspired oxyge): 21%; VT: ±10 mL/kg; respiratory rate ±55 breaths/min). Ventilation was adjusted for an end-tidal CO2 of approximately 25–30 mm Hg (AS3; Datex, Helsinki, Finland). A femoral artery and vein were cannulated. Arterial blood pressure, electrocardiogram (lead II), and frontooccipital electroencephalogram were continuously recorded (Hellige Servomed electrocardiogram and pressure monitor with three-channel recorder, and OTE Biomedica electroencephalogram continuous monitor 1264, Firenze, Italy). The rats were observed for 5 min. After this period, arterial blood gases were measured. A colloid (polygeline Hemaccel; Behring, Marbrug, Germany, 10 ± 2 mL/kg) was infused to compensate for blood retrieved for sample analysis and relative hypovolemia after the start of mechanical ventilation. The rats were again observed for 5 min. After this period, the animals were randomly assigned to receive an IV infusion of 3 mg · kg-1 · min-1 bupivacaine (bupivacaine group), 3 mg · kg-1 · min-1 ropivacaine (equivalent ropivacaine group), or 4.5 mg · kg-1 · min-1 ropivacaine (equipotent ropivacaine group). All the animals received the same volume of infusion per hour by a calibrated electronic infusion pump (Terumo, Tokyo, Japan).
The following events were recorded and the dose of bupivacaine required to produce them was calculated:
- First QRS modification (QRS-MOD) that consisted of an increased duration of the QRS complex (>20%) consecutive to a narrowing of the S wave;
- First dysrhythmia, defined as the first dysrhythmia accompanied by an abnormal systole on the blood pressure trace;
- Twenty-five percent reduction of basal heart rate (predrug infusion; HR-25%);
- Fifty percent reduction of basal heart rate (predrug infusion; HR-50%);
- Twenty-five percent reduction of basal mean arterial blood pressure (predrug infusion; MABP-25%);
- Fifty percent reduction of basal MABP (predrug infusion; MABP-50%); and
- Final systole (Asys), defined as the absence of a pressure pulse on the arterial blood pressure trace, and absence of end-tidal CO2 detection after 2 min.
- First dysrhythmia, defined as the first dysrhythmia accompanied by an abnormal systole on the blood pressure trace;
Time between the first QRS-MOD and MABP-25% was measured (MABP-25% - QRSmod) to evaluate the time elapsed between rhythmologic manifestations of local anesthetic overdose and the toxic effects of the drugs on myocardial inotropy and systemic vascular resistance.
The central nervous system (CNS) toxicity was evaluated by the dose of local anesthetic requested to produce seizure activity (SZ) defined as a sudden burst of electrical activity recorded on the electroencephalogram monitoring.
In a second experiment, designed to measure plasma local anesthetic concentrations at various threshold events, 18 Wistar male rats were studied by using the same protocol as previously described. They also received, in a randomized fashion, either bupivacaine (same dose) or ropivacaine (3 or 4.5 mg · kg-1 · min-1). At the moment of 25% reduction of basal MABP (2 animals per group), 50% reduction of basal MABP (2 animals per group) and Asys (2 animals per group), the infusion of IV local anesthetic was stopped. Three milliliters of whole blood was withdrawn via the femoral arterial catheter for determination of bupivacaine or ropivacaine concentration. Thiopental (20 mg/kg) was injected IV, and the ventilation was stopped.
Bupivacaine and ropivacaine concentrations in plasma were determined with high-performance liquid chromatography and UV-detection in two different runs. Three spiked quality control samples (10 µg/mL) were analyzed, together with the unknown samples in each run.
In a third experiment, designed to observe the capacity of recovery from local anesthetic intoxication, 15 additional Wistar male rats were studied according to the following protocol: a femoral artery and vein were cannulated under diethyl ether anesthesia. Arterial blood pressure was continuously recorded. The rats were allowed to recover for 5 min. After this period, the animals were randomly assigned to receive an IV infusion of 3 mg · kg-1 · min-1 bupivacaine (n = 5), 3 mg · kg-1 · min-1 ropivacaine (n = 5), or 4.5 mg · kg-1 · min-1 ropivacaine (n = 5). The infusions were stopped immediately when clinically observable SZ developed. The dose required to produce SZ and the immediate evolution were recorded. After 30 min, intravascular catheters were removed and the rats were observed for 24 h.
The time required for the appearance of the different local anesthetic-induced toxic manifestations, and the calculated cumulative doses of bupivacaine and ropivacaine at each event time, were compared by using analysis of variance for repeated measures. Post hoc comparisons were achieved according to the Tukey honest test. Normal distribution of the variables were confirmed by using the Kolmogorov-Smirnov test. Fisher’s exact test was used for the comparison of the observed proportion. A P value 
0.05 was considered statistically significant.
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Results |
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In the first experiment, baseline characteristics and arterial blood gases were similar in the three groups and remained in the normal range.
Except for the first QRS-MOD that invariably consisted in the appearance of an S wave with widening of the QRS complex, all the other detectable signs of local anesthetic overdose occurred significantly later and consequently at larger doses in both ropivacaine groups when compared with the bupivacaine group (Figure 1).
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Bupivacaine overdose induced significantly more rapid hypotension than ropivacaine. In the present model, 6 mg bupivacaine versus 45 mg ropivacaine in the equipotent group were required to reduce baseline MABP 25%. The time elapsed between rhythmologic and hemodynamic manifestations of local anesthetic overdose are presented in Table 1.
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Concerning the CNS toxicity, significantly larger doses of ropivacaine were required to produce SZ when compared with bupivacaine.
In the second experiment, the doses of local anesthetic required to produce the toxic events (HR-25%, HR-50%, and Asys) are comparable to these observed in the first experiment. The mean plasma concentrations measured are given in Table 2.
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In the third experiment, the doses of local anesthetics required to produce SZ in spontaneously breathing rats are 4.5 ± 0.8 mg in the ropivacaine 3-mg group, 2.9 ± 0.3 in the ropivacaine 4.5-mg group. Two animals in the first and three in the second group presented with cardiopulmonary arrest immediately after SZ and were successfully resuscitated. These 10 rats were alive and healthy after 24 h. In the bupivacaine 3-mg group, 2.8 ± 0.1 mg was necessary to produce SZ in three animals. The two other animals presented with cardiopulmonary arrest before any SZ could be detected. Only one was successfully resuscitated. Two of the three animals with SZ required cardiopulmonary resuscitation after this episode. In all these animals, cardiopulmonary resuscitation was adequate but one animal died at the end of the 24-h period.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our results clearly demonstrate that cardiac and CNS toxicity are significantly delayed in rats receiving equipotent doses of IV ropivacaine than in rats receiving bupivacaine.
In clinical practice, local anesthetic intoxication principally occurs after accidental IV bolus injection. It is a rare but dramatic complication of locoregional anesthesia. Nevertheless, this complication is of special interest because the practice of locoregional techniques is increasing not only for surgical anesthesia but also for acute and chronic pain management. Consequently, the population of patients receiving large-volume infusions of local anesthetics is growing along with the probability of an inadvertent IV administration. In this regard, any improvement in the safety margin of these techniques could be beneficial.
Ropivacaine is an amide local anesthetic only recently available for clinical use. Despite early enthusiastic reports considering potency and motor blockade properties, there is no evidence that this drug is significantly superior to bupivacaine when considering these two variables. Nevertheless, numerous studies in animals and one in volunteers reported reduced neuro- and/or cardiotoxicity of ropivacaine when compared with bupivacaine (4–8). A cardiotoxic potential of 2:1 (up to 6:1, depending on species) for bupivacaine and ropivacaine, respectively, has been reported. The mechanism underlying this differential toxicity is, however, still in question. Differences in uptake (partition coefficient 2.9 for ropivacaine versus 10 for bupivacaine), distribution (volume of distribution: 59 L for ropivacaine versus 73 L for bupivacaine), clearance (0.82 L/min for ropivacaine versus 0.58 L/min for bupivacaine) may account for this observation. The reduced potency of ropivacaine when compared with bupivacaine [equipotent concentrations 0.5 vs 0.25 (2,3)] may be another plausible explanation. For this reason, we decided to evaluate the toxic effects of bupivacaine and ropivacaine overdose using a 50% difference between the dosages of the two local anesthetics. For this purpose, in the first and second experiment, we used a model of anesthetized rats under controlled ventilation and constant IV local anesthetic infusion. By using such a model, it is possible, with a reduced number of animals, to control some variables that interfere with local anesthetic toxicity (hypoxemia, acidosis) and to easily observe the progression of toxic signs (9,10). Nevertheless, this model has its own limitations. First, the concomitant administration of general anesthetics (diethyl ether and thiopental) may have influenced the threshold doses of toxic manifestations (dysrhythmia and seizure activity). Second, in contrast with bolus injection, the slow infusion rate allows the administration of large doses of local anesthetic before toxic symptoms appear. In this regard, it is interesting to note the difference in the dose required to produce SZ in rats of the first experiments compared with rats in the third experiment, particularly in the ropivacaine groups.
In the two models tested (controlled and spontaneous ventilation), the results obtained confirm the data obtained by others: ropivacaine, even at equipotent doses, is significantly less toxic than bupivacaine. Like bupivacaine, it produces widening of the QRS complex width as a result of conduction disturbances by inhibition of voltage-gated sodium channels. It also produces hemodynamic changes mainly by direct negative inotropic effects. The decrease in myocardial contractility may be attributed to the following mechanisms resulting from the complex effects of local anesthetics: decrease in Ca2+ release from sarcoplastic reticulum, disturbance of membrane Na+-Ca2+ pump, disturbance of cellular energy metabolism, and inhibition of the basal and epinephrine-stimulated cyclic adenosine monophosphate production.
When considering neurotoxicity, in the first experiments, SZ appears to be a relatively late manifestation of ropivacaine overdose when compared with bupivacaine. This is in contrast with the reports of inadvertent intravascular administration in which most of the patients developed convulsions as an early symptom (11–13). In the third experiment, using awake rats, convulsions developed earlier in both ropivacaine groups than in the model using anesthetized rats under controlled ventilation. It implies that in the anesthetized model methodologically related factors have delayed the apparition of this symptom.
Interestingly, in the third experiment, all the ropivacaine-treated rats presented convulsion before cardiovascular arrest. This was not the case in the bupivacaine group, in which two animals had cardiac arrest before any sign of neurotoxic effect. The postintoxication evolution of the ropivacaine-treated rats was also significantly easier in this group when compared with the bupivacaine group.
In conclusion, our results demonstrate a wider therapeutic use of ropivacaine, even at equipotent doses, than bupivacaine.
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Footnotes |
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The cost of this work was exclusively supported by the Department of Anesthesiology of the University of Louvain, St. Luc Hospital.
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References |
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- Markham A, Faulds D. Ropivacaine: a review of its pharmacology and therapeutic use in regional anesthesia. Drugs 1996; 52: 429–49.[Web of Science][Medline]
- Mc Donald S, Liu S, Kopacz D, Stephenson CA. Hyperbaric spinal ropivacaine: a comparison to bupivacaine in volunteers. Anesthesiology 1999; 91: 971–7.
- Gautier Ph, De Kock M, Fanard L, Van Steenberge A. Intrathecal ropivacaine or bupivacaine for ambulatory knee arthroscopy. Anesthesiology 1999;91:1239–45.
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Nancarrow C, Rutten AJ, Runciman WB, et al. Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine and ropivacaine in the sheep. Anesth Analg 1989; 69: 276–83.
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Rutten A, Mather LE, Nancarrow C, et al. Cardiovascular effects and regional clearance of intravenous ropivacaine in sheep. Anesth Analg 1990; 70: 577–82.
[Abstract/Free Full Text] - Kohane DS, Sankar WN, Shubina M, et al. Sciatic nerve blockade in infant, adolescent, and adult rats: a comparison of ropivacaine with bupivacaine. Anesthesiology 1998; 89: 1199–208.[Web of Science][Medline]
- Danielsson BR, Danielson MK, Boo EL, et al. Toxicity of bupivacaine and ropivacaine in relation to free plasma concentrations in pregnant rats: a comparative study. Pharmacol Toxicol 1997; 81: 90–6.[Medline]
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Scott D, 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] - De Kock M, Henin D, Gautier PH. Endogenous digoxin enhances bupivacaine toxicity in rats. Reg Anesth 1993; 18: 369–73.[Medline]
- De Kock M, Le Polain B, Henin D, et al. Clonidine pretreatment reduces the systemic toxicity of intravenous bupivacaine in rats. Anesthesiology; 1993;79:282–9.
- Korman B, Riley RH. Convulsions induced by ropivacaine during interscalene brachial plexus block. Anesth Analg 1997; 85: 1128–9.[Web of Science][Medline]
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Abouleish EJ, Ellas M, Nelson C. Ropivacaine-induced seizure after extradural anesthesia. Br J Anaesth 1998; 80: 843–4.
[Abstract/Free Full Text] - Selander D, Sjövall J, Waldenlind L. Accidental i.v. injections of ropivacaine: clinical experiences of six cases [abstract]. Reg Anesth 1997; 22 Suppl: 70.
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