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Locoregional anaesthesia

The median effective analgesic dose (ED50) of ropivacaine in ultrasound-guided transversus abdominis plane block for analgesia in reversal of ileostomy

A double-blind up-down dose-finding study

Lahlou-Casulli, Maria; Chaize-Avril, Cécile; Pouliquen, Emmanuel; Desfourneaux, Véronique; Mazoit, Jean-Xavier; Malledant, Yannick; Beloeil, Hélène

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European Journal of Anaesthesiology (EJA): September 2015 - Volume 32 - Issue 9 - p 640-644
doi: 10.1097/EJA.0000000000000198
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Abstract

Introduction

The increasing application of ultrasound in regional anaesthesia has helped the transversus abdominis plane (TAP) block to become very popular.1 It has been adopted by many anaesthesiologists because it is easy to perform. The TAP block has been shown to be effective for postoperative analgesia after surgical procedures involving the lower abdominal wall. Several clinical studies and meta-analyses have demonstrated a morphine-sparing effect and an improvement in postoperative analgesia.2,3 The technique involves a single injection of a dose and volume of local anaesthetic in the TAP plane. Neither the volume nor the dose required for successful analgesia with a TAP block in adults has been determined. Reported doses and volumes used vary widely,3 and toxic plasma concentrations (4 and 5.5 μ ml−1 for ropivacaine and lidocaine, respectively) have been reported after a TAP block.4,5 Griffiths et al.5 reported a potentially toxic plasma concentration after a bilateral ultrasound-guided TAP block using 3 mg kg−1 of ropivacaine diluted in 40 ml. In patients at a higher risk, such as pregnant women, the same group confirmed clinical signs of neurotoxicity after a bilateral TAP block using 2.5 mg kg−1 of ropivacaine diluted in 40 ml.6 One report described seizures 3 h after a bilateral TAP block using 3.75 mg kg−1 of ropivacaine diluted in 40 ml.7 In order to ensure that local anaesthetic spreads into the plane, the administration of a large volume (>20 ml) seems necessary, although it has never been quantified. In children undergoing herniorrhaphy, a TAP block with 0.43 mg kg−1 of levobupivacaine was shown to provide successful perioperative analgesia in 95%.8

The aim of this study was to assess the median effective analgesic dose (ED50 = effective dose in 50% of patients) of ropivacaine required for successful analgesia with a unilateral subcostal TAP block. The volume was fixed within 20 to 25 ml and the doses varied according to the up-and-down technique. We chose a surgical procedure involving dermatomes that are anaesthetised by a TAP block,9 the reversal of ileostomy, which unlike most intra-abdominal procedures involves mostly somatic pain from the abdominal wall. The accompanying visceral pain from the anastomosis does not appear to cause distress.

Materials and methods

This double-blind prospective study (EudraCT: 2011-003817-41) was approved by the Ethics Committee (Ethics Committee approval on 4 October 2011, number: 11/27-816, University Hospital of Rennes, Rennes, France) and written informed consent was obtained from all ASA (American Society of Anesthesiology) physical status I to III patients undergoing elective reversal of ileostomy. Exclusion criteria were patients under the age of 18, pregnancy, allergy to local anaesthetics, analgesic treatment taken within 12 h before surgery and patients whose weight required an assigned dose with a volume higher than 25 ml.

Lateral ileostomy is usually performed in order to protect a colorectal anastomosis. It is placed at the umbilical level and involves the T9, T10 and T11 dermatomes. The ileostomy reversal incorporating intestinal stroma closure is performed 2 months after the initial surgery and begins with the mobilisation of the ileostomy from the skin. The afferent and efferent loops are then positioned together to perform a side-to-side anastomosis.

Patients received 1.5 mg kg−1 hydroxyzine 1 h before surgery. General anaesthesia was induced with sufentanil 0.3 μg kg−1, propofol 3 mg kg−1 and cisatracurium 0.15 mg kg−1. Anaesthesia was maintained with desflurane or sevoflurane (MAC 1). During the surgical procedure, sufentanil (0.01 μg kg−1) was given if the heart rate or arterial pressure increased by 15% relative to the baseline measurement. A unilateral subcostal TAP block was performed after the induction of general anaesthesia as described by Barrington et al.9 Briefly, the probe was placed inferior to the costal margin with the needle tip (Pajunk sonoTAP 22G × 80 mm) between the transversus abdominis and the internal oblique muscles lateral to the linea semilunaris. After the needle tip was correctly placed in the TAP using an ‘in-plane’ technique, a widespread application of 20 to 25 ml of a predefined dose of ropivacaine was injected. Investigators visualised the ropivacaine spread in two planes, anterior-posterior and cranial-caudal, in the correct space. The blocks were performed by the study investigators (M.L.C., E.P., C.C.A., H.B.). We chose to have four experienced investigators involved to avoid the bias of having only one physician performing all of the blocks. Investigators performing the TAP blocks were neither involved in the management of the general anaesthesia nor in the postoperative care and the pain assessment of the patients. Patients were blind to the dose injected.

Postoperative analgesia consisted of 1 g paracetamol given every 6 h. Systematic postoperative nausea and vomiting (PONV) prophylaxis was provided with droperidol. The NPS (numeric pain scale) was recorded every 10 min in the postanaesthesia care unit (PACU) by a nurse blind to the ropivacaine study dose, then once upon arrival in the ward and finally at the end of the study 6 h after the TAP block. Heart rate, oxygen saturation and blood pressure were monitored.

To assess the ropivacaine ED50, we used the up-and-down sequential allocation method.10 After reviewing different doses used in previous reports,2 the dose chosen to be administered to the first patient was 1.6 mg kg−1 of ropivacaine diluted in 20 ml. The dose of ropivacaine received by the subsequent patients was determined by the response of the previous patient. For successful responses, the dose was reduced by 0.2 mg kg−1, and for unsuccessful responses, the next patient received a dose increased by the same margin. For doses above 200 mg, the volume required exceeded 20 ml and was capped at 25 ml. In order to keep the volume within the predefined range of 20 to 25 ml, we did not include patients whose weight and assigned dose would result in a volume higher than 25 ml. Before recruiting any patient, the investigator (M.L.) verified that the next assigned dose when adjusted for the weight resulted in a volume lower than 25 ml. The success or failure of the study dose of ropivacaine was assessed using the NPS at rest 6 h after the TAP block. Two outcomes were considered: effective: NPS of 3 or lower out of 10 (directing a decrement for the next patient); and ineffective: NPS greater than 3 out of 10 (directing an increment for the next patient). In case of NPS greater than 3 out of 10 within the 6 h of the study, the dose was considered ineffective, and the patient was given rescue analgesia (morphine titration or 20 mg of nefopam at the physician's discretion). Because of the potential toxicity of ropivacaine, we set the maximum dose to 3 mg kg−1.5 The duration of the analgesia associated with a TAP block has never been studied per se. On the basis of previous studies, which reported the time of the first need for analgesics, and on our experience, we chose to assess the NPS 6 h after the TAP block.2

Adverse effects

Known adverse effects of ropivacaine (visual and hearing disturbances, dysguesia, dizziness, muscular twitching, arrhythmia, QRS modification) and of sufentanil (vomiting, nausea, pruritus, sedation, urinary retention, respiratory depression) were sought in the PACU and on the ward, and noted.

Statistical analysis

We determined the ED50: the median dose leading to the probability of 0.5 for a patient having an NPS less than 3 on a 0 to 10 numeric pain scale using the up-and-down method.11,12 This estimates the threshold for an all-or-none response, usually defined as the point above which 50% of the individuals respond to the stimulus and below which 50% of the individuals do not respond. The number of individuals needed was estimated to be 24 at most.12,13. Because we set the maximum dose at 3 mg kg−1, the ED50 (and its 95% confidence interval, 95% CI) may be considered as a lower limit. The calculation was based on the success of the doses given. Because the number of successful doses was lower than the number of failures and because the difference between the number of successes at any level and the number of failures at the preceding lower level was always equal to –1, the conditions leading to the calculation of the approximate maximum likelihood were met.10 We also calculated the ED50 imputing successful doses of 3.2 mg kg−1 for individuals 9 and 22, that is dummy doses above the 3 mg kg−1 maximum permitted. This allowed us to calculate the upper limit of the ED50 and the corresponding 95% CI.14 In addition, because the number of successes was small, we calculated the 95% CI using the Student correction. The statistical analysis was performed using R.15

Results

Two patients were excluded because of analgesic protocol violation. The study was stopped after the enrolment of 24 consecutive patients, with eight independent up-and-down deflections. Patient characteristics are presented in Table 1.

Table 1
Table 1:
Patient characteristics

In all patients, the TAP and the spread of ropivacaine were visualised, and the block was performed without complications. No adverse effects of either ropivacaine or sufentanil were observed. No PONV was recorded.

As shown in Fig. 1, the first eight doses of ropivacaine were unsuccessful, and the maximum dose of 3 mg kg−1 was reached three times. The highest total dose of ropivacaine administered in one patient was 252 mg. The corresponding concentrations varied from 5.2 to 10 mg ml−1.

Fig. 1
Fig. 1:
Sequence of dosing. The quality of analgesia was measured on a numeric pain scale (from 0 to 10) and was defined as ineffective (numeric pain scale score ≤3) or effective (numeric pain scale score >3). Squares are failures (ineffective analgesia), and circles are successes (effective analgesia). The horizontal line is the median effective dose (thick line) and its 95% confidence interval (dashed lines).

Using the raw data (eight successes), the ED50 (95%CI) was 2.70 mg kg−1 (2.37 to 3.03 mg kg−1). When we analysed the data with one and two additional dummy successful values at 3.2 mg kg−1, the ED50s (95% CI) were 2.95 mg kg−1 (2.60 to 3.30 mg kg−1) and 2.99 mg kg−1 (2.63 to 3.35 mg kg−1), respectively.

Discussion

To our knowledge, this is the first study to determine the ED50 of a local anaesthetic in a TAP block. Although the ED50 is not as clinically relevant as the ED95, it is a simple rigorous pharmacologic approach. It could help define the best local anaesthetic concentration needed for a successful TAP block, as it has previously been defined for other blocks.16 Indeed, there are currently no recommendations regarding effective concentrations for this technique.

In our study, the ED50 of ropivacaine in TAP blocks in patients undergoing reversal of ileostomy was 2.71 mg kg−1 (2.05 to 3.37 mg kg−1). This is close to the maximum dose of 3 mg kg−1, which was reached three times. We chose to not administer higher doses because of potential toxicity;5 in the TAP block as in all peripheral nerve blocks, systemic local anaesthetic absorption cannot be avoided. Indeed, the TAP is a neurovascular plane in which the course of thoracolumbar nerves is close to vessels such as the deep circumflex iliac artery.17

Unlike lidocaine, ropivacaine has a long-lasting action that leads to a delayed absorption.18 Griffiths et al.5 showed that the mean plasma concentration in 28 patients using ropivacaine 3 mg kg−1 peaked at 2.54 μg ml−1, 30 min after bilateral TAP blocks. This concentration reached 4.4 μg ml−1 in some patients, higher than the 2.2 μg ml−1 threshold that has been shown to induce minor central nervous system symptoms.18 This threshold was established from samples taken from healthy volunteers without consideration for age, sex, renal function, adiposity or the impact of general anaesthesia on the emergence of neurotoxicity.18 Serum local anaesthetic concentrations measured in healthy volunteers will not necessarily reflect what happens in clinical practice following overdosage and accidental intravascular injection. Despite these limitations, there is justification for using the threshold defined by Knudsen et al.18 for comparison. In patients at risk (i.e. pregnant women), clinical signs of neurotoxicity associated with high venous ropivacaine concentrations (≥2.2 μg ml−1)6 have been reported even if the dose was lower (2.5 mg kg−1). In most studies, the dose administered is fixed regardless of the patients’ weight. Thus, for some patients, the dose of ropivacaine could be higher than 3 mg kg−1. In the most recent study, the protocol was amended after the first four patients because of neurotoxicity associated with ropivacaine use. These four patients received a 200 mg bolus followed by a continuous infusion of ropivacaine (14 mg h−1 for 72 h) via bilateral TAP catheters. The authors switched to a weight-based regimen after these incidents.19 These reports and our results both call for adapting the dose of local anaesthetic, especially for a bilateral TAP block, to the patient's weight. Indeed, our blocks were unilateral and reversal of ileostomy requires anaesthesia of a limited number of dermatomes. The dose required to achieve a successful bilateral block would be much higher and its safety could be questioned. If adherence to well tolerated limits of local anaesthetic result in insufficient dosing and failure of the block, the fundamental usefulness of the TAP block is also brought into question.

There are several limitations in our study. We chose the up-and-down method because it allows the determination of ED50 with a lower number of patients than conventional techniques. Pain was reduced, and its duration was negligible thanks to systematic rescue analgesia administration when NPS was higher than 3. This technique has been well described in many previous studies,14 but we were obliged to modify the initial method because of an upper limit of the allowed dose. Therefore, the ED50 was calculated with relative uncertainty, and we reported the worst eventuality, the highest ED50 and widest 95% CI,14 which was very wide. The ED50 is useful in assessing the properties of drugs, and in comparing them, but in clinical practise, the ED95 or ED99 is of greater use. Unfortunately, all the methods used to extrapolate ED95 or ED99 from an ED50 obtained with the up-and-down technique, such as probit regression, are inaccurate.14 Furthermore, we did not assess the analgesic efficacy of the TAP blocks by directly testing the dermatomes involved, but we did record the ultrasonographic information. In all patients, the TAP and the spread of ropivacaine were visualised, providing indirect confirmation of a successful block. Moreover, we wanted to test the efficacy of the TAP block in providing successful analgesia, something that can also be expressed in terms of duration of analgesia. Another limitation is that the volume was not strictly fixed at 20 ml, but varied between 20 and 25 ml in order to administer the assigned dose. Finally, the relationship between total dose, injectate volume and concentration – and their effects on both efficacy and toxicity – require further study. Indeed, the resulting concentrations in our study varied from 5.2 to 10 mg ml−1. The potential toxicity of high concentrations of ropivacaine in TAP block, especially muscle toxicity, is not known and needs to be considered. A different approach is to use a fixed concentration (5 mg ml−1), bearing in mind that the resulting dose can be as high as 4.2 mg kg−1 and may be associated with a high plasma concentration.20 As Griffths et al.5 have already pointed out, there is a possibility that a dose of 3 mg kg−1 may be excessive in some patients.

Conclusion

We report an ED50 of ropivacaine in TAP blocks in reversal of ileostomy that is close to the toxic threshold. The risk of administering high doses of ropivacaine with a potential for subsequent clinical toxicity should be emphasised. Anaesthesiologists should always calculate the dose with regard to the weight of the patient.

Acknowledgements relating to this article

Assistance with the study: none

Financial support and sponsorship: This study was funded by a grant from the Research Committee of the Rennes teaching Hospital (CORECT) obtained in 2011.

Conflicts of interest: None.

Presentation: This study was presented as an abstract at the meeting of the French Society of Anesthesiology and Intensive Care, Paris, France, September 2013.

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