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Anesth Analg 2003;97:893-897
© 2003 International Anesthesia Research Society

REGIONAL ANESTHESIA

Pulmonary Uptake of Ropivacaine and Levobupivacaine in Rabbits

Shigeo Ohmura, MD, Akiko Sugano, MD, Masayuki Kawada, MD, and Ken Yamamoto, MD

Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

Address correspondence and reprint requests to Shigeo Ohmura, MD, Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Address e-mail to ohmura{at}med.kanazawa-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local anesthetic toxicity produced by an inadvertent IV injection is attenuated by the pulmonary uptake of local anesthetics. We compared the pulmonary uptake of ropivacaine and levobupivacaine after a bolus injection in rabbits. Sixteen anesthetized rabbits were randomly assigned to either a ropivacaine group or a levobupivacaine group. A bolus containing ropivacaine or levobupivacaine 0.5 mg/kg and indocyanine green (an intravascular indicator) 0.25 mg/kg was injected rapidly into the vena cava. Arterial blood samples were collected serially at 1.2-s intervals for 30 s. Concentrations of local anesthetic and indocyanine green in each sample were determined for the calculation of first-pass uptake of a local anesthetic in the lung. The first-pass uptake of levobupivacaine (31.4% ± 8.3%; mean ± SD) was larger than that of ropivacaine (22.9% ± 5.6%), and the maximum arterial concentration of ropivacaine (21.2 ± 2.8 µg/mL) was larger than that of levobupivacaine (18.6 ± 1.9 µg/mL). We conclude that the pulmonary uptake of levobupivacaine is larger than that of ropivacaine after a bolus injection. Therefore, the advantages of ropivacaine over levobupivacaine in terms of less cardiovascular toxicity may be offset by the smaller pulmonary uptake after an inadvertent IV injection.

IMPLICATIONS: Local anesthetic toxicity produced by an inadvertent IV injection is attenuated by the pulmonary uptake of local anesthetics. The extent of pulmonary uptake may influence the occurrence of local anesthetic toxicity. We compared the pulmonary uptake of ropivacaine and levobupivacaine after a bolus injection in rabbits.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Since Albright (1) published an alarming editorial in 1979 about the severity of cardiovascular (CV) toxicity of bupivacaine, ropivacaine (2–5), and then recently levobupivacaine (6–8), were developed as alternative long-acting amide local anesthetics with less potential for CV toxicity. The choice between these local anesthetics in clinical practice requires investigations as to whether levobupivacaine is superior to ropivacaine. We have reported that the central nervous system (CNS) toxicities of levobupivacaine and ropivacaine are similar and that the CV toxicity of levobupivacaine is more than that of ropivacaine when they are administered at equivalent doses in rats (9). However, the clinical relevance of that report was limited because CNS and CV toxicity were induced by a constant IV infusion of each local anesthetic. In clinical practice, by contrast, local anesthetic toxicity is most likely produced by an inadvertent bolus injection.

Local anesthetics injected IV should pass through the lung before entering the systemic circulation. The lung has important nonrespiratory functions other than gas exchange (10). The uptake of a large number of drugs, including local anesthetics, is one of them (11–14). As a result, the lung has a dampening effect on the arterial concentrations of accidentally injected local anesthetics (12–14), and the extent of pulmonary uptake may influence the occurrence of local anesthetic toxicity. The pulmonary uptake of a local anesthetic depends mainly on its physicochemical prop- erties (15). The physicochemical properties of ropivacaine are essentially the same as those of levobupivacaine except for lipid solubility (16). The lower lipid solubility of ropivacaine would predict its smaller uptake into the lung compared with levobupivacaine. If this is true, the apparent advantages of ropivacaine over levobupivacaine in terms of less CV toxicity may be offset by the smaller pulmonary uptake after an inadvertent IV injection. We designed this study to compare the pulmonary uptake of ropivacaine and levobupivacaine after a bolus injection in rabbits.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All surgical procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee. Sixteen male Japanese white rabbits weighing 2.7–3.5 kg were studied. The animals were randomly assigned to either a ropivacaine group (n = 8) or a levobupivacaine group (n = 8). Anesthesia was induced with 5% isoflurane in oxygen. A posterior auricular vein was cannulated, and lactated Ringer’s solution was infused at a rate of 10 mL · kg-1 · h-1. Tracheostomy was performed, and the lungs were mechanically ventilated after pancuronium 1 mg IV. The PaCO2 was maintained between 30 and 40 mm Hg. Needle electrodes were placed for recording lead II of the electrocardiogram. Body temperature was measured rectally and was maintained at 37°C to 38°C by using a heating lamp.

During surgical preparation, anesthesia was maintained with 3% isoflurane in oxygen. The inspired concentration of isoflurane was continuously monitored with a calibrated anesthetic gas monitor. The left internal carotid artery was cannulated for arterial blood pressure monitoring and blood sampling. A cannula was placed through the right external jugular vein into the superior vena cava for bolus drug administration. Arterial pressure and electrocardiogram were continuously recorded.

After surgical preparation, anesthesia was maintained with 2% isoflurane in oxygen. After a stabilization period of approximately 20 min, arterial blood was obtained for blood gas analysis and to establish standard curves for sample analysis. Then a bolus containing ropivacaine 0.5 mg/kg and indocyanine green (ICG; an intravascular indicator) 0.25 mg/kg in 0.2 mL/kg of normal saline was injected rapidly into the superior vena cava of animals in the ropivacaine group. Animals in the levobupivacaine group received the same amount of levobupivacaine instead of ropivacaine. Arterial blood samples were serially withdrawn from the internal carotid artery at 20 mL/min by means of a peristaltic pump (Minipuls 3®; Gilson, Middleton, WI) and collected in 1.2-s fractions in a fraction collector (Type 203; Gilson). Tubes in the fraction collector contained 8 µL of heparin (1000 U/mL). A total of 24 blood samples were collected from the time of injection.

After collection, 250 µL of each blood sample was diluted with 2.75 mL of water and vortexed vigorously to lyse the red cells. After centrifugation at 3000 rpm for 10 min, the supernatant was decanted. By using the diluted blood samples, the ICG concentrations in the whole blood were determined by spectrophotometry from its absorbance at 805 nm. A linear standard curve was obtained over a range of 0.2 to 30 µg/mL. The diluted blood samples were frozen at -80°C until the day of analysis of local anesthetics. The concentrations of local anesthetics in the whole blood were determined by high-performance liquid chromatography on the basis of the method reported by Adams et al. (17). A linear standard curve was obtained over a range of 0.2 to 24 µg/mL for each of the local anesthetics. The coefficients of variation for the assay of ropivacaine and levobupivacaine were 2.1% and 2.8%, respectively.

The fractional concentration of ICG (FCICG) or a local anesthetic (FCLA) in each arterial blood sample was calculated as the measured concentration divided by the total amount injected. Cardiac output (CO) was measured by a dye dilution method as described by Ross (18). It was calculated by the formula


where 0 is the time of bolus injection and FCICG(corrected) is the FCICG corrected for recirculation (Fig. 1).



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  		Figure 1. Typical fractional concentration (FC) versus time curves of indocyanine green (FCICG; •) and a local anesthetic (FCLA; {circ}). FCICG or FCLA in each sample was calculated as the measured concentration divided by the total amount injected as a bolus at 0 s. Two peaks were observed in the curve of FCICG. The first corresponds to the first pass of ICG through the lung. The second corresponds to the recirculation of ICG through the lung. The dashed line represents the FC versus time curve of ICG corrected for recirculation. The correction for recirculation was performed by monoexponential extrapolation of the early part of the downward slope to infinity. The arrow indicates the time at which 95% of the total amount of ICG had passed through the lung.

 
The first-pass uptake (FPU) of a local anesthetic in the lung was measured by the double-indicator dilution method reported by Bertler et al. (12). It was calculated by the formula


where 0 is the time of bolus injection and t is the time when 95% of the total amount of ICG had passed through the lung.

Data are presented as mean ± SD. Between-group comparisons were performed by using the unpaired Student’s t-test. Categorical data were analyzed with Fisher’s exact test and are presented as frequency and percentage. A P value <0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The physiological data at the time of bolus injection are shown in Table 1. There were no significant differences in body weight, arterial blood gases, heart rate, systolic blood pressure, diastolic blood pressure, or CO between the groups.


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  		Table 1. Physiological Data
 
In the early phase of the first pass of the injectate through the lung, FCICG was larger than FCLA, indicating that there was uptake of a local anesthetic into the lung during this period (Fig. 1). In the late phase, by contrast, FCLA was larger than FCICG, indicating that there was back diffusion of a local anesthetic from the lung into the blood.

The FPU of levobupivacaine (31.4% ± 8.3%) was significantly larger than that of ropivacaine (22.9% ± 5.6%) (Fig. 2). The maximum arterial concentration of ropivacaine (21.2 ± 2.8 µg/mL) was significantly larger than that of levobupivacaine (18.6 ± 1.9 µg/mL) (Fig. 3). There was no significant difference in the number of animals that developed ventricular dysrhythmias after bolus injection: one (12.5%) and two (25.0%) animals in the ropivacaine and levobupivacaine groups, respectively.



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  		Figure 2. First-pass uptake of ropivacaine (open bar; n = 8) and levobupivacaine (solid bar; n = 8) in the lung. Each bar represents mean ± SD. *P < 0.05 compared with ropivacaine.

 


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  		Figure 3. Maximum arterial concentrations of ropivacaine (open bar; n = 8) and levobupivacaine (solid bar; n = 8). Each bar represents mean ± SD. *P < 0.05 compared with levobupivacaine.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study demonstrate that the FPU of levobupivacaine is larger than that of ropivacaine. Ropivacaine differs from levobupivacaine in that it has a propyl group on the piperidine nitrogen, whereas levobupivacaine has a butyl group. With regard to the physicochemical properties of ropivacaine and levobupivacaine, plasma protein binding and the pKa values of the two drugs are essentially the same (16). However, ropivacaine has an intermediate lipid solubility among local anesthetics that is approximately one third that of levobupivacaine (16). Therefore, the decreased lipid solubility of ropivacaine compared with levobupivacaine may account for our finding that the FPU of ropivacaine is smaller than that of levobupivacaine. Concerning the effects of lipid solubility on the uptake of drugs into the lung, it has been reported that the pulmonary FPU of morphine in humans is only a small percentage of the injected dose, compared with 75% for the more lipophilic fentanyl (19).

Our results also demonstrate that the maximum arterial concentration of ropivacaine is larger than that of levobupivacaine after a bolus injection. We have previously reported that there are no differences between the plasma concentrations of ropivacaine and levobupivacaine at the onset of seizures and asystole when they are administered at equivalent doses (9). Therefore, ropivacaine may produce CNS and CV toxicity more easily than levobupivacaine when injected as a bolus. In our previous study (9), we also reported that the plasma concentration of ropivacaine at the onset of ventricular dysrhythmias is larger than that of levobupivacaine. In this study, however, no difference was seen between the frequency of ropivacaine- and levobupivacaine-induced ventricular dysrhythmias. The finding suggests that the advantage of ropivacaine over levobupivacaine in terms of lower dysrhythmogenicity may be lost after a bolus injection.

We used the time when 95% of the total amount of ICG had passed through the lung for the calculation of FPU. The time has been previously used for the calculation of the pulmonary FPU of lidocaine (12,13), narcotic analgesics (19), and propofol (20). By using this time for the calculation, FPU could be compared regardless of CO. Rothstein et al. (14) calculated the pulmonary FPU of bupivacaine by the double-indicator dilution method, as was used in this study. However, their calculation was confined to the peak of the outflow curve of ICG, reflecting only the earliest phase of the first pass of the injectate through the lung.

In this study, isoflurane was used for basal anesthesia. With regard to the effects of inhaled anesthetics on the pulmonary FPU of drugs, Jorfeldt et al. (21) reported no significant difference in the pulmonary FPU of lidocaine between awake and anesthetized patients. In addition, Matot et al. (20) reported that the pulmonary FPU of propofol in cats was not affected by 1% halothane, although it was significantly reduced in cats exposed to 1.5% halothane. The concentration of isoflurane used in this study was 2%, corresponding to the minimum alveolar anesthetic concentration of isoflurane in rabbits (22). Therefore, we suppose that isoflurane had no influence on the FPU of ropivacaine and levobupivacaine in this study. With regard to the effects of inhaled anesthetics on local anesthetic toxicity, isoflurane has been reported to attenuate bupivacaine-induced ventricular dysrhythmias (23). Therefore, the frequency of ventricular dysrhythmias induced by ropivacaine or levobupivacaine may have been affected by isoflurane. In this study, animals were ventilated in a hyperoxic condition. Concerning the effects of inspiratory oxygen concentration on the pulmonary uptake of local anesthetics, it has been reported that there is no significant difference in the pulmonary uptake of lidocaine between hyperoxic and hypoxic dogs (24).

In summary, we conclude that the pulmonary FPU of levobupivacaine is larger than that of ropivacaine and that the maximum arterial concentration of ropivacaine is larger than that of levobupivacaine after a bolus injection in rabbits. Although ropivacaine has been reported to have less CV toxicity than levobupivacaine, attention should be paid to the potential hazard of an unexpected increase of ropivacaine concentration in the arterial blood when ropivacaine is accidentally injected as a bolus.


   Acknowledgments
 
The authors thank Chiroscience Ltd., Cambridge, UK; Maruishi Pharmaceutical Co., Ltd., Osaka, Japan; and Astra Pain Control AB, Södertälje, Sweden, for supplying the local anesthetics. The authors also thank Keiko Yachi for her technical support and assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979; 51: 285–7.[Web of Science][Medline]
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Accepted for publication April 23, 2003.




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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 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press