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Pharmacology

Potentially toxic concentrations in blood of total ropivacaine after bilateral transversus abdominis plane blocks; a pharmacokinetic study

Torup, Henrik; Mitchell, Anja U.; Breindahl, Torben; Hansen, Egon G.; Rosenberg, Jacob; Møller, Ann M.

Author Information
European Journal of Anaesthesiology: May 2012 - Volume 29 - Issue 5 - p 235-238
doi: 10.1097/EJA.0b013e328350b0d5
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Abstract

Introduction

The innervation of the abdominal wall is derived from the anterior divisions of spinal nerves T6 to L1. These nerves are accessible to transversus abdominis plane (TAP) blocks. The TAP is localised using ultrasound guidance or with a blind ‘double pop’ technique, and local anaesthetic is injected into the neurofascial plane between the internal oblique and transversus abdominis muscles, either just before or immediately after surgery. Usually, the TAP block is performed in the anaesthetised patient, but case reports have shown efficacy of the TAP block in sedated patients.1 Since the first TAP block was described by Rafi,2 several prospective randomised, blinded and controlled TAP block trials have been published.3–9 Most of these studies have shown a reduction in opioid consumption and improved pain relief compared with placebo.10

The type, strength and amount of local anaesthetic to be used, and the potentially toxic plasma levels following TAP block continue to be discussed. Two recent studies have shown high blood levels of lidocaine11 and ropivacaine12 after TAP block. The aim of this observational study was to estimate peak ropivacaine concentrations (Cmax) in blood after ultrasound-guided TAP blocks with bilateral injections of 20 ml ropivacaine 0.5% w/v.

Patients and methods

Patients

The local ethics committee waived formal approval because the study was regarded as quality assurance and not biomedical research (Protocol number: H-A-2009-FSP32). The study was registered in http://www.ClinicalTrials.gov (NCT01024868). Patients aged at least 18 years and scheduled for TAP block before abdominal or gynaecological surgery were included. Patients with known allergies to local anaesthesia or with a BMI less than 17 or more than 40 kg m−2 were excluded. Written informed consent for enrolment in the study was obtained from the patients.

Transversus abdominis plane block procedure

The patients were brought to the operating room 1 h before the operation. Standard monitoring with ECG, noninvasive arterial pressure and pulse oximetry was applied. TAP block was performed by one of two experienced senior anaesthesiologists with the patient awake. For facilitation of the TAP-block, 4 ml of lidocaine 1% w/v was administered subcutaneously at the insertion sites 5–10 cm lateral to the umbilicus on each side. Ropivacaine 0.5% w/v 20 ml (Naropin, AstraZeneca, UK) was injected under ultrasound guidance (GE Medical Systems LOGIQe, UK) bilaterally in the TAP between the internal oblique and the transversus abdominis muscles using a Stimoplex 80 mm needle (B-Braun Medical, Bethlehem, PA, USA). Aspiration after injection of each 5 ml of ropivacaine was used to detect accidental intravascular injection. The extent of the TAP blocks was assessed using cold and pin-prick sensation, and these data are to be reported elsewhere [unpublished observations]. General anaesthesia was induced 30–60 min after the TAP blocks.

Blood samples

Blood samples were obtained just before and 10, 30 and 60 min after ropivacaine injection from a venous cannula placed in the antecubital fossa. Serum samples were kept frozen at −80°C for 3–6 months prior to analysis. Two-dimensional liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) after direct injection of diluted serum without further cleanup pretreatment were used. Free ropivacaine concentrations were analysed by injection of ultrafiltrated serum. The method and validation characteristics have been described elsewhere.13

Statistics

Data were analysed using Statistical Package for Social Sciences (SPSS) 18.0 for Windows (SPSS Inc., Chicago Illinois, USA). Results are presented as median (range).

Results

Twenty-one patients were enrolled. One patient was excluded as she felt uncomfortable during the subcutaneous needle insertion prior to local anaesthetic injection and did not want to continue with the TAP block awake. Data from two patients showed cross-contamination between sampling and drug delivery syringes. In one case, a high concentration of ropivacaine was detected in blood sample taken before the block and in another case the total ropivacaine concentration exceeded 28 μg ml−1. Consequently, the data from these two patients were excluded from the study. Personal and Cmax data for the remaining n = 18 patients are shown in Table 1. Age, weight, BMI and dose of ropivacaine were 53 (range, 32–81) years, 75 (48–106) kg, 24.5 (17–31) kg m−2 and 2.7 (1.9–4.2) mg kg−1, respectively. The pharmacokinetic profiles for total ropivacaine concentrations are shown in Fig. 1.

Table 1
Table 1:
Patient characteristics and peak ropivacaine concentrations (total and free)
Fig. 1
Fig. 1:
no caption available.

All (n = 18) total ropivacaine concentrations measured before performing the TAP block were less than 0.002 μg ml−1. Peak free ropivacaine concentrations were 0.024 (0.006–0.19) μg ml−1. Free fraction of ropivacaine varied from 1.4% at 10 min to 2.6% at 60 min. Total ropivacaine concentrations were 1.0 (0.14–3.6), 1.6 (0.46–4.5) and 1.7 (0.51–5.1) μg ml−1 at 10, 30 and 60 min, respectively. Six patients out of 18 (33%) had levels above 2.2 μg ml−1 at some time. Four of these patients received less than 3 mg kg−1 of ropivacaine. The highest concentration was 5.1 μg ml−1 60 min after injection (ropivacaine 2.7 mg kg−1). The highest dose of ropivacaine given was 4.2 mg kg−1and levels for this patient remained below 2.2 μg ml−1 at all times. Except for one patient, blood pressure, pulse rate and oxygen saturation remained stable for the 30 min observation time. One patient had a 33% drop in mean arterial blood pressure 10 min after injection of ropivacaine with a normal heart rate and was asymptomatic. This patient had a total ropivacaine level of 3.6 μg ml−1 at 10 min, a free level of 0.14 μg ml−1 at 30 min.

Discussion

This study shows that potentially toxic blood concentrations of ropivacaine can be obtained when using a dose that is normally considered safe. There are no evidence-based criteria describing how much local anaesthetic should be used for TAP blocks or other peripheral nerve blocks. Ropivacaine is often used as a drug of choice. It is effective, long-acting and considered to be less toxic than the bupivacaine enantiomers. In some TAP block studies, a fixed volume of ropivacaine is given, for example 15–20 ml bilaterally,6–10 whereas other studies have specified the given volume or dose per kilogram, usually 1.5–3.0 mg kg−1.11,12 The concentration of ropivacaine used in these studies varies from 0.375 to 0.75% w/v. Most recommendations are based on extrapolations from animal experiments, case reports, pharmacokinetic results and measurements of blood concentrations. Rosenberg et al.14 suggested that recommended doses of local anaesthetics should be block and site specific.

We measured free ropivacaine in serum after ultrafiltration, which is a routine method for determination of unbound drug concentrations. In one case, the free concentration did exceed the generally accepted reference value for toxicity of free ropivacaine, (0.15 μg ml−1)15 with a value of 0.19 μg ml−1 after 60 min. The patient was anaesthetised at this time and no sign of toxicity was reported. In another case, the patient had a drop in mean arterial blood pressure 10 min after injection of ropivacaine. However, this patient did not exceed the 0.15 μg ml−1 value for free ropivacaine, but showed a different profile in total ropivacaine, in that the peak value and decay were earlier than for the other individuals (see Fig. 1). This profile may be suggestive of some immediate systemic injection with early clearance.

The free concentrations reported in this study were determined in thawed serum without control of pH and temperature during ultrafiltration. The values are comparable with data from Griffiths et al.,12 but the free ropivacaine concentrations in both studies might not have been correctly determined if pH and temperature were not controlled during ultrafiltration. Arvidsson and Eklund16 observed a decrease in the free fraction of ropivacaine by a factor of two when serum pH was adjusted from 7.2 to 7.6 prior to ultrafiltration. Although it is recognised that it is essential to control pH and temperature during ultrafiltration in order to obtain correct free-drug concentrations, it is not certain that such measures are always practiced.

Total ropivacaine concentrations can be found in published reports. According to Knudsen et al.,15 the threshold total ropivacaine for neurological symptoms after intravenous injection of ropivacaine in healthy volunteers is 2.2 μg ml−1. However, it is uncertain whether neurological and cardiac symptoms would occur at the same serum concentration when local anaesthetics are absorbed from tissues rather than injected intravenously.

In our study, we did not reach a Cmax in all patients even after 60 min. The patients in this study were anaesthetised 30–60 min after TAP block. In the Australian study by Griffiths et al.,12 the TAP blocks were performed after anaesthesia. The reason for the prolonged time to Cmax in our study is unclear, but anaesthesia may influence the absorption of ropivacaine, and propofol shows competitive inhibitory effects on metabolism by human cytochrome P450 enzyme systems in vitro.17 More studies are needed to analyse the possible effect of anaesthesia on absorption of local anaesthetics in vivo.

Of the one-third patients who had peak total ropivacaine concentrations exceeding 2.2 μg ml−1, just one showed cardiovascular symptoms with a 33% drop in mean arterial blood pressure 10 min after TAP block. There were no sequelae. It is uncertain if this episode was caused by a systemic effect of ropivacaine. A constant problem is that potential signs of toxicity following local anaesthesia might be hidden, as most TAP-blocks are performed in anaesthetised patients. Only two other studies have investigated serum concentrations of local anaesthetics after TAP blocks with lidocaine11 and ropivacaine.12 Both studies found that the peak total concentration occurred 30 min postinjection, exceeded the therapeutic range and could lead to potential toxicity. Griffiths et al.12 found a mean total ropivacaine concentration of 2.54 μg ml−1 30 min postinjection using 3 mg kg−1 ropivacaine diluted to 40 ml. No seizures or persistent cardiovascular instability were observed, but all of the patients were anaesthetised at this time. In our study, the patients were awake for at least 30 min after TAP block insertion and no neurological symptoms of toxicity were observed.

Other studies that measured serum levels after administration of regional anaesthesia, found lower mean values of serum ropivacaine, for example 1.5 μg ml−1 after scalp block for awake craniotomy18 and median values of 0.9 μg ml−1 after combined psoas compartment and sciatic nerve block.19 In both studies one out of five patients had peak values exceeding the 2.2 μg ml−1 level for total ropivacaine, but without any signs of toxicity. We do not know the exact toxic level for a given patient. The correlation between blood levels and signs of toxicity is considered multifactorial as physiological, anatomical and pharmacokinetic factors all contribute.14 However, it seems that total mean serum values after TAP-block may be higher than after other regional blocks, but more studies are needed to verify this.

In conclusion, we demonstrated that TAP blocks with bilateral 20 ml injections of ropivacaine 0.5% w/v gave rise to potentially toxic levels of total ropivacaine in blood in one third of patients.

Acknowledgements

This work was supported by the Department of Clinical Biochemistry, Vendsyssel Hospital, Aalborg University, Denmark, and the Department of Anaesthesiology, Herlev Hospital, Copenhagen, Denmark.

None of the authors has any conflict of interest.

References

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Keywords:

ropivacaine; toxicity; transversus abdominis plane block

© 2012 European Society of Anaesthesiology