BJA Advance Access originally published online on March 17, 2006
British Journal of Anaesthesia 2006 96(5):640-644; doi:10.1093/bja/ael066
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Comparison of ropivacaine 2 mg ml–1 and prilocaine 5 mg ml–1 for i.v. regional anaesthesia in outpatient surgery
1 Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital Helsinki, Finland.
2 Department of Clinical Pharmacology, University of Helsinki Helsinki, Finland
*Corresponding author: Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Helsinki, PO Box 340, FIN-00029 HUS, Finland. E-mail: tomi.niemi{at}hus.fi
Accepted for publication February 18, 2006.
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Abstract |
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Background. Ropivacaine 2 mg ml–1 (0.2%) provides longer-lasting analgesia after deflation of the tourniquet cuff, with fewer side-effects, than lidocaine 5 mg ml–1 (0.5%) after i.v. regional anaesthesia (IVRA). Whether ropivacaine 2 mg ml–1 also exerts this advantage over prilocaine 5 mg ml–1, the local anaesthetic of choice in IVRA in most European countries was investigated in this study.
Methods. Sixty outpatients scheduled for forearm or hand surgery received IVRA with 40 ml of ropivacaine 2 mg ml–1 (Ropi) or prilocaine 5 mg ml–1 (Prilo) in a randomized, double-blinded fashion. The development and recovery of pin-prick analgesia and motor power of the hand, as well as ropivacaine and prilocaine plasma concentrations (n=30), were assessed during and after operation.
Results. Anaesthesia for surgery was adequate in both groups. Pin-prick analgesia was achieved at a similar rate, except in the radial nerve distribution area where at 10 min 60% of Ropi and 90% of Prilo patients had analgesia (P=0.017). At 10 min 100 and 97% had motor block of the hand in the Ropi and Prilo groups, respectively. Recovery of the sensory block in all innervation areas was already observed 2 min after the tourniquet cuff release. At 10 min after releasing the tourniquet cuff 31% of the Ropi patients and none of the Prilo patients still had analgesia in the median nerve distribution (P=0.004). At 12 min, 42% in the Ropi group and none in the Prilo group had decreased grip strength. After the release of the tourniquet, mean plasma concentrations of ropivacaine were higher than those of prilocaine. The highest individual concentration of ropivacaine was 1.65 µg ml–1 and that of prilocaine 0.6 µg ml–1. None of the Ropi patients experienced any symptoms of local anaesthetic toxicity.
Conclusions. Compared with prilocaine 5 mg ml–1, analgesia in IVRA with ropivacaine 2 mg ml–1 developed slightly more slowly, while motor block developed at a similar rate. After the release of the tourniquet, sensation recovered quickly and at a similar rate in the two groups, except for a slightly slower recovery after ropivacaine in the innervation area of the median nerve, but no surgically useful extended analgesia after the cuff deflation was observed. Despite a 60% lower milligram-dose, ropivacaine plasma concentrations were markedly higher than those of prilocaine.
Keywords: anaesthetic techniques, i.v. regional; anaesthetics local, prilocaine; anaesthetics local, ropivacaine
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Introduction |
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I.V. regional anaesthesia (IVRA) is a technique suitable for hand and forearm surgery and it is safe when performed with care by expert practitioners. The most often used local anaesthetic for IVRA in Europe is prilocaine. It has a relatively short duration of action, similar to that of lidocaine1–3 and is the least toxic of the amino-amide local anaesthetics.4 Recently, ropivacaine has been tested in IVRA for its usefulness in providing prolonged sensory block after the release of the tourniquet.5 6 In comparison with lidocaine 5 mg ml–1, ropivacaine 2 mg ml–1 resulted in longer-lasting sensory blockade after the release of the tourniquet and a suggestion that this extension of the duration of the block by ropivacaine would provide the surgeon with an extra 15–30 min, when needed, to finish the operation.
With the similarity of lidocaine and prilocaine in mind, we hypothesized that a comparable post-deflation analgesic advantage of ropivacaine 2 mg ml–1 over prilocaine 5 mg ml–1 in IVRA could be demonstrable. In addition, symptoms of toxicity and plasma concentrations of the local anaesthetics were recorded.
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Patients and methods |
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The study protocol was approved by the Ethics Committee for Surgery in the Hospital District of Helsinki and Uusimaa, and by the National Agency of Medicines in Finland. Sixty ASA I–II patients, aged 18–65 scheduled for forearm or hand surgery, gave their written informed consent and were included in the study (Table 1). The patients were premedicated with diazepam 1 h before anaesthesia. Monitoring included ECG, pulse oximetry and non-invasive blood pressure measurement at 5 min intervals.
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A vein of the dorsum of the hand scheduled for surgery was cannulated. For blood sampling another cannula was inserted into a cubital vein of the contralateral arm. Exsanguination was achieved by using an elastic bandage with simultaneous elevation of the arm. The double-cuff brachial tourniquet was pressurized to 250–280 mm Hg. Patients were randomized in blocks of 10 (five in each group) to receive either 40 ml of ropivacaine 2 mg ml–1 (Naropin® 2 mg ml–1, Astra Zeneca) (Ropi group) or preservative-free prilocaine 5 mg ml–1 (Xylonest®, AstraZeneca) (Prilo group). The local anaesthetic was injected into the vein through the cannula at a rate of approximately 20 ml min–1. The investigator, the patients, and the medical personnel involved in the study observations, were blinded to the test drug injections.
Skin sensation to pin-prick was tested by using a 27-gauge needle before the block, and 2, 5, 10, 15 and 20 min after injection of the local anaesthetic. The tests were carried out in four areas: in the sensory distribution of the ulnar nerve (dorsum of distal phalanx of the little finger), the radial nerve (dorsum of proximal phalanx of the thumb), the median nerve (dorsum of distal phalanx of the middle finger) and the musculocutaneous nerve (lateral area of frontal forearm) nerves. Motor power of the hand was tested at the same intervals by grip strength. Degree of analgesia was graded as ‘sharp’, ‘blunt’, or ‘no sensation’ and motor power as ‘normal movement’, ‘decreased grip strength’ or ‘no movement’. The corresponding tests were performed at 2, 4, 8, 10, 12, 14, 16 and 18 min after deflation of the tourniquet cuff. The cuff was deflated at the end of surgery.
Times after cuff deflation to the first operative site sensation or pain and to the patients' first request for an analgesic were recorded. If there was no pain up to 1 h and no need for an analgesic up to 4 h, the periods were recorded as 60 and 240 min for statistical analysis. The first line analgesic was i.v. propacetamol (a prodrug of acetaminophen) or oral acetaminophen.
In the first 30 patients (15 in each group), 5 ml of blood were withdrawn from the cubital vein of the contralateral arm into heparinized tubes before application of the tourniquet, immediately after injection of prilocaine or ropivacaine, just before releasing the tourniquet, and 2, 5, 10, 15, 20, 25, 30, 45 and 60 min after cuff deflation. The blood samples were centrifuged and the plasma removed and stored at –20°C until the concentrations of ropivacaine and prilocaine were determined by liquid chromatography.7 The limits of quantification of ropivacaine and prilocaine in plasma were 6 and 7 ng ml–1, respectively. The day-to-day coefficients of variation were 1.6% for ropivacaine (n=6) and 3.6% for prilocaine (n=5) at 500 ng ml–1.
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Statistics |
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A mean (SD) recovery time for sensation in the arm of 7.6 (4.9) min after 200 mg of prilocaine for IVRA8 has been reported. A power calculation based on this report indicated that 26 patients per group would be needed to detect a 50% prolongation of sensory blockade after ropivacaine for IVRA with a power of 80% and an
-error of 5%. The statistical significance of differences between the groups was evaluated by two-way repeated measures ANOVA and t-test with Bonferroni correction. Otherwise the comparisons of skewed data were performed by Mann–Whitney Rank Sum Test. The frequencies of the patients with each skin sensation (i.e. sharp, blunt or no sensation) or motor power category (i.e. normal movement, decreased grip strength and no movement) were compared by 
2-test (SigmaStat for Windows Version 2.03, SPSS Inc., Chicago, IL, USA). The results are shown as means (SD), medians (25th/75th percentiles), exact numbers or proportions expressed as a percentage. |
Results |
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Data regarding patient characteristics are presented in Table 1. Most of the patients had carpal tunnel surgery (Table 1). The remaining procedures included tendovaginal dissections (six trigger fingers), neurolysis (five cubital tunnel syndrome), extirpations (six tumours) or other minor forearm or hand surgery. The mean (SD) tourniquet time was 39.9 (6.5) min in the Ropi group and 40.4 (9.3) min in the Prilo group (P=0.785, t-test).
Forty millilitres of ropivacaine 0.2% (80 mg) or prilocaine 0.5% (200 mg) provided comparable anaesthesia for surgery. The time from the injection of the local anaesthetic to the onset of surgical anaesthesia (blunt or no sensation) at all test areas was comparable between the groups (P>0.05, Mann–Whitney Rank Sum Test). More patients had pin-prick analgesia (blunt or no sensation) in the radial nerve distribution at the 10 min after injection in the Prilo group (90%) compared with the Ropi group (60%) (P=0.017, 2-test). In the test areas of ulnar, median or musculocutaneous nerve innervation no significant differences were observed in the onset of IVRA. The development of motor block of the hand was comparable between the groups. Fentanyl was given during operation to 12 patients in the Ropi and 8 in the Prilo group (P=0.411).
Data representing the regression of sensory blockade were excluded in five patients (four in the Ropi group and one in the Prilo group), since the tourniquet cuff was deflated upon the surgeon's request before the wound closure, and lidocaine was infiltrated locally.
The regression of the sensory and motor block was comparable between the groups up to 4 min after the cuff deflation (Table 2). Thereafter, at 6, 8, 10 and 12 min, more patients in the Ropi group than in the Prilo group still had partial sensory blockade of the median nerve (blunt or no sensation): 39% vs 7% at 6 min (P=0.012), 31% vs 3% at 8 min (P=0.018), 31% vs 0% at 10 min (P=0.004) and 23% vs 0% at 12 min (P=0.021) (2-test). There were no statistically significant differences between the groups in the recovery of the sensory blockade of ulnar, radial and musculocutaneous nerves (Table 2). The motor blockade was longer-lasting in the Ropi group (Table 2). Fifty-seven percent in the Ropi group still had partial motor blockade of the hand at 12 min when all the Prilo group patients had complete motor recovery (P<0.001).
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The median (25th–75th percentiles) time to first operative site sensation or pain after cuff deflation was similar in both groups, that is 10.0 (8.0–15.8) min in the Ropi group and 9.0 (6.0–12.0) min in the Prilo group (P=0.364, Mann–Whitney Rank Sum Test). The time period to the patient's first request of an analgesic after cuff deflation was not statistically significant between the groups (P=0.102, Mann–Whitney Rank Sum Test), although, on average the time was over three times longer in the Ropi group, that is 82.0 (15.0–240.0) min vs 24.5 (14.0–115.0) min. When analysing only the patients undergoing carpal tunnel surgery (Ropi group n=17, Prilo group n=16), no differences were found in time to the first operative site sensation or pain, or intake of analgesic after the cuff deflation.
Plasma concentrations of ropivacaine were, on average, twice as high as those of prilocaine after cuff deflation (Fig. 1). The highest individual ropivacaine concentration was 1.65 µg ml–1 measured 2 min after the cuff deflation. The highest prilocaine concentration was 0.60 µg ml–1, seen 5 min after the cuff deflation. One patient in the Ropi group had a ropivacaine concentration of 0.077 µg ml–1 in plasma immediately after the injection. Six patients had low (0.077 µg ml–1 or less) concentrations of ropivacaine and four patients low (0.01 µg ml–1 or less) concentrations of prilocaine in plasma before the cuff deflation at the end of surgery. No symptoms indicating central nervous system (CNS) toxicity were observed during surgery. After cuff deflation, one patient in the Prilo group experienced mild CNS symptoms (dizziness and blurred vision for a few minutes). One patient in the Ropi group was dissatisfied about the IVRA whereas the rest of the Ropi patients were very satisfied (63%) or satisfied (33%). In the Prilo group 70% of the patients were very satisfied and 30% satisfied with their anaesthesia.
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Discussion |
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The results show that postoperative sensory analgesia after 40 ml ropivacaine 0.2% is short. Only in the innervation area of the median nerve, a 4–10-min prolongation in the duration of pin-prick analgesia could be demonstrated in comparison with the patients who had received prilocaine. The finding of statistical significance at consecutive time points between the groups, that is, at 6, 8, 10 and 12 min suggests that this difference in the median nerve territory is robust. In other test areas, that is ulnar, radial and musculocutaneous nerve dermatomes, no differences were detected between the two groups. The patients experienced postoperative pain equally soon in both study groups. The time to first intake of analgesic was on average longer in the Ropi group (82 min vs 24.5 min) but the difference did not reach statistical significance. Furthermore there was no difference between the groups when only the carpal tunnel patients were compared.
Our finding of only a very short extension of the duration of post-deflation analgesia in just one of the main innervation areas of the hand after ropivacaine IVRA contradicts with the results of two previous studies.5 6 Hartmannsgruber and colleagues5 administered 40 ml of ropivacaine 2 mg ml–1 for IVRA in healthy volunteers and reported to have observed analgesia for up to 30 min after releasing the tourniquet. However, the prolonged residual effect of ropivacaine was significant only for sensation in the distribution of the lateral antebrachial cutaneous nerve (i.e. forearm branch of musculocutaneous nerve) and motor power of the hand at 3, 10 and 30 min post-deflation tests. The authors did not report any difference between ropivacaine and lidocaine5 in the sensory distributions of median cutaneous, ulnar, median and radial nerves. In the study of Atanassoff and colleagues,6 of patients undergoing outpatient surgery, the first evidence for return of sensation in the distribution of the five peripheral nerves tested occurred later in their ropivacaine group patients than in those who received lidocaine. However, they could not demonstrate any clinical advantage of the slight prolongation of analgesia in terms of lower postoperative VAS values or need for analgesics. This is, in accordance with our study.
The possibility of performing thorough haemostasis in the operative area before closing the wound in hand surgery has been the suggested indication for the use of a long-acting local anaesthetic in IVRA.6 In our opinion, and as shown in the present study, this possibility appears to be very limited when using ropivacaine 2 mg ml–1. The additional pain free surgery time appears to be restricted to the median nerve innervation area, and in our study, had a duration of only a few minutes. An increase in the ropivacaine dose might provide additional prolongation of post-deflation sensory analgesia, but with an increased risk of systemic toxicity. This is obviously not to be recommended and therefore, prilocaine as a rapidly acting local anaesthetic with a low degree of toxicity, remains the local anaesthetic of choice in IVRA also in our department.
In the current study, some patients had low, but detectable plasma concentrations of ropivacaine or prilocaine in plasma before cuff deflation, and one patient even just after ropivacaine injection, indicating some degree of venous leakage under the pneumatic cuff or through the venous channels within the bone. The amounts of leaked local anaesthetic were so small that systemic toxicity symptoms were not detected during surgery. In spite of a tourniquet cuff inflated to 100 mm Hg or more above the systolic arterial blood pressure, the venous pressure at the time of injection of the local anaesthetic may rise to a level causing a stream of local anaesthetic to pass into the systemic circulation under the inflated cuff.9 This acute passage of drug under the cuff may be considered an additional, and real risk when using potent local anaesthetics, like ropivacaine. On the other hand, low local anaesthetic concentrations in systemic circulation before releasing the tourniquet cuff, indicating leakage under the cuff during the period of inflation, have been observed in some patients in several studies.2 10–12 In the present study, in spite of the relatively high plasma concentrations of ropivacaine, none of the Ropi group patients had CNS toxicity and, in fact, the only one of our patients who experienced CNS symptoms had received prilocaine.
Peak total plasma concentrations of the local anaesthetic after tourniquet cuff release are known to correlate poorly with CNS toxicity symptoms.11 13 14 Instead, it is the unbound concentration of the local anaesthetic, which relates to the pharmacological and toxic effects.15 Since only about 5% of ropivacaine in plasma is unbound,16 that is active, it can be extrapolated that the unbound concentrations of ropivacaine in our patients were at a level of 0.08 µg ml–1, or less. Toxicity is not expected to result from such low concentrations of unbound ropivacaine. In a volunteer i.v. infusion study, unbound concentrations of higher than 0.6 µg ml–1 were needed to evoke CNS toxicity.17 The free fraction of prilocaine in plasma is about 55%.18 Thus, in the present study unbound concentrations of prilocaine after cuff deflation were at the 0.1–0.3 µg ml–1 level.
In conclusion, in comparison with 40 ml of prilocaine 5 mg ml–1 we have demonstrated a delayed onset of adequate anaesthesia, and a slightly delayed return of sensation in a limited innervation area (median nerve) after 40 ml of ropivacaine 2 mg ml –1 in IVRA of the arm, and a lack of systemic toxicity. The extended sensory blockade was short and limited in distribution and may not allow the continuation of pain free surgery (e.g. wound closure) after tourniquet cuff deflation. Finally, we do not recommend ropivacaine for IVRA in routine clinical practice because of the relatively slow onset of analgesia and the lack of analgesic advantages compared with prilocaine.
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