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Total plasma concentrations of bupivacaine, levobupivacaine and ropivacaine after combined psoas compartment–sciatic nerve block

de Leeuw, Marcel Aa,b; Bet, Pierre Mc; Wilhelm, Abraham Jc; Vos, Rene Mc; Hoeksema, Martijna,b; de Lange, Jaap Ja; Zuurmond, Wouter WAa; Perez, Roberto SGMa

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European Journal of Anaesthesiology: December 2009 - Volume 26 - Issue 12 - p 1083-1085
doi: 10.1097/EJA.0b013e3283308e07

Editor,

To achieve extended anaesthesia and analgesia, a psoas compartment–sciatic nerve block (PCSNB) requires administration of large volumes of potentially cardiotoxic local anaesthetics. Due to the anatomic location of the lumbar plexus [1], mostly within muscle tissue, initial absorption of the administered local anaesthetics after a psoas compartment block could result in relatively high early plasma concentrations. This phenomenon theoretically enhances the risk of local anaesthetic toxicity of this anaesthetic technique.

The primary aim of this study was to analyse total plasma concentrations after administration of the maximum recommended doses of bupivacaine, levobupivacaine and ropivacaine in a PCSNB and to compare these data with described ‘threshold plasma concentration values’ producing local anaesthetic toxicity. The second aim was to require more insight into pharmacokinetic profiles of used local anaesthetic administered in a PCSNB. Both aims should lead to a better understanding of the safety assessment of a PCSNB.

The present study was approved by the Medical Ethics Review Committee of the VU University Medical Centre. Patients participating in a randomized controlled trial [2], comparing the clinical efficacy of PCSNB using levobupivacaine, ropivacaine and bupivacaine, with ASA status I–III, age above 18 and scheduled for total hip replacement under general anaesthesia, were included in this study. Exclusion criteria were patients' refusal, coagulation disorders, infections at the puncture site, known allergy to local anaesthetics and preexisting neurological disorders. Patient information was given at the preoperative screening clinic and written informed consent was obtained one day prior to surgery.

Patients were randomly allocated to receive a combined PCSNB with one of three local anaesthetics: 50 ml bupivacaine 0.3% (group BUPI), 50 ml levobupivacaine 0.3% (group LEVO) or 50 ml ropivacaine 0.45% (group ROPI), which are maximal recommended doses (manufacturer's indication) for a single injection peripheral nerve blockade (PNB). Patients were assigned to the treatment modalities using a block-wise randomization procedure in blocks of three. Epinephrine 1: 200.000 (5 μg ml−1) was added to all solutions. After induction of general anaesthesia, PCSNB was performed according to the landmarks described by Labat [3] and Chayen et al. [4], with the aid of a nerve stimulator and special coated, short-beveled, stimulating needles (Stimuplex HNS 11, needle 150 mm/20G, Braun Medical, Melsungen, Germany). Ten millilitre of local anaesthetic solution was administered to the sciatic nerve and 40 ml was injected incrementally with gentle aspiration into the psoas compartment. The time at which all of the local anaesthetic solution had been injected was taken as time zero. Arterial plasma samples for local anaesthetic total plasma concentration analysis were taken (via radial artery catheter) before block (reference) and at 2, 5, 10, 30, 60, 90, 120, 180 and 240 min after PCSNB. Serum concentrations of bupivacaine, levobupivacaine and ropivacaine were determined by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) after liquid–liquid extraction. Cmax (maximum plasma concentration), Tmax (time to reach Cmax) and area under the curve (AUC, total absorption of local anaesthetics) were determined. The AUC was calculated for T0–240 min using the trapezium rule. Based on standard power calculation of the clinical efficacy study [2], 15 patients were needed per group. Differences between different local anaesthetics with respect to pharmacokinetic indices were analysed using the Kruskal–Wallis and the Mann–Whitney U-tests. Relationships between Cmax and age, length, weight and BMI of the patient were assessed by the Spearman's ρ correlation coefficient, and the Mann–Whitney U-test was used to assess sex-related differences in Cmax. For all analyses, an α value less than 0.05 was considered statistically significant.

Forty-five patients were included in the study, equally divided over the three intervention groups. All patients completed the trial. There were no differences between groups concerning patients' characteristics (Table 1). PCSNBs were all technically successful and time between sciatic nerve and psoas compartment blocks was less than 7 min. Total plasma concentration data of one patient within the bupivacaine group were excluded because there was an unexplained, pharmacologically impossible variation in different plasma concentration values measured at different time frames (t = 0 min: 0.0 μg ml−1, t = 2 min: 12.5 μg ml−1, t = 5 min: 0.26 μg ml ). There was no correlation between Cmax values and sex, age, length, bodyweight and BMI.

Table 1
Table 1:
Patients' characteristics

Total plasma concentrations of ropivacaine (Cmax) were higher than bupivacine and significantly higher than levobupivacaine (Mann–Whitney U-test; P = 0.036) (Fig. 1). The variance of all plasma concentrations was large, regardless of which local anaesthetic was used. A notable observation is a second small increase in local anaesthetic total plasma concentration after 90–110 min postpuncture in all three groups.

Fig. 1
Fig. 1

Systemic absorption of ropivacaine (AUC0–240) is significantly higher than bupivacaine or levobupivacaine (Kruskal–Wallis; P < 0.001; see Table 2).

Table 2
Table 2:
Pharmacokinetics data

Figure 2 displays scatter plots of Cmax versus Tmax. Lowest individual peak plasma concentration values were measured for levobupivacaine compared with bupivacaine and ropivacaine [NB: overall median Cmax values (Table 2) were lowest for bupivacaine] and the Tmax was longer for levobupivacaine compared with the other two local anaesthetics. Three patients within the ropivacaine group and one patient within the bupivacaine group showed large plasma concentrations (ropivacaine: 2.36, 2.76 and 3.06 μg ml−1; bupivacaine: 3.24 μg ml−1). Neither patient-related factors (age, weight, length) nor procedure-related factors (no blood aspiration prior injection or difficult procedure) were correlated with these relatively large plasma concentrations.

Fig. 2
Fig. 2

In this study, measured local anaesthetic total plasma concentrations after a PCSNB, with given dosages of bupivacaine, levobupivacaine or ropivacaine, remained far below described threshold values to produce central nervous system (CNS) or cardiac toxicity [5]. Probably today's dose recommendations provided by pharmaceutical companies may be conservative and the margin of safety is probably much wider than assumed.

The low local anaesthetic total plasma concentrations we found were comparable with those found in other studies concerning local anaesthetic plasma concentrations after lower extremity peripheral nerve blocks [6,7]. Recently, Vanterpool et al.[6] described a mean maximum total plasma concentration of 1.56 mg l−1 ropivacaine after a PCSNB with 300 mg ropivacaine. Higher values of their measured plasma concentrations could be explained by a higher ropivacaine dose and a lower ratio of added epinephrine.

A notable observation was a large interpatient variability in local anaesthetic plasma concentrations. This could be the result of the anatomical variation in the ‘psoas compartment’ [1]. Injecting local anaesthetic within highly vascularized muscle tissue could lead to higher local anaesthetic plasma concentrations than injecting local anaesthetic in a plexus sheath between different muscles. For unknown reasons, we only found high local anaesthetic plasma concentrations in one patient in the bupivacaine group and three patients in the ropivacaine group, suggesting very high initial absorption of the local anaesthetics administrated in muscle tissue. Partial intravasal injection of local anaesthetics is less likely due to the absence of tachycardia and hypertension during injection (epinephrine was added as an ‘intravascular marker’) but could not be ruled out.

The higher maximal plasma concentration of ropivacaine compared with levobupivacaine is probably due to a higher dosage of ropivacaine (225 versus 150 mg).

Although the AUC0–240min of bupivacaine and levobupivacaine were equal, there was a trend towards levobupivacaine having a longer Tmax compared with bupivacaine (see Fig. 2). Probably, initially systemic absorption of levobupivacaine is slower than bupivacaine and could be explained by a more vasoconstrictor effect of levobupivacaine compared with racemic bupivacaine as described by Aps and Reynolds [8]. This difference was not statistically significant and further studies are needed to analyse this phenomenon.

A notable observation was a second, small, increase in plasma concentration, within all three groups after t = 90 min. Planned awakening at that moment from general anaesthesia, which led to a higher heart rate, blood pressure and cardiac output, resulting in a better perfusion of muscles around the psoas compartment could be the reason for this second elevation in the plasma concentrations curve. Further studies are needed to analyse the influence of cardiac output dynamics on systemic absorption of local anaesthetics.

A minor shortcoming of the present study is that only local anaesthetic total plasma concentrations were measured. The unbound local anaesthetic concentrations, which might be more closely associated with toxicity reactions, and α(1)-acid glycoprotein were not measured. Because the unbound fraction has a similar proportional plasma concentration curve and the fact that surgery results in a rise of α(1)-acid glycoprotein (decreasing the unbound fraction) make total local anaesthetic plasma concentration data still valuable for safety assessment.

In conclusion, total plasma concentrations of the maximum recommended doses of bupivacaine, ropivacaine and levobupivacaine used in a PCSNB remain far below the described toxicity thresholds and make the margin of safety probably much wider than current standards, allowing the usage of a higher dose than that recommended by the manufacturer. However, one should be cautious about using high doses of potentially cardiotoxic local anaesthetics in a PCSNB because the anatomic location of the lumbosacral plexus makes high initial systemic absorption possible. Finally, although not statistically significant, levobupivacaine seems to have a slower initial systemic absorption, which could make this local anaesthetic more favourable when using large dosages of local anaesthetics in a PCSNB. Further studies are needed to investigate this phenomenon.

References

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