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Recent advances in local anaesthetics for spinal anaesthesia

Milligan, K. R.

European Journal of Anaesthesiology: November 2004 - Volume 21 - Issue 11 - p 837-847
Review
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Although local anaesthesia is mentioned in historical manuscripts, it is only a hundred years since Bier first reported the intrathecal use of local anaesthetic agents. This has been followed by a rapid progression in the art and science of spinal anaesthesia. Isomerically pure agents with favorable clinical profiles, such as ropivacaine and levobupivacaine are now available. Spinal anaesthesia is commonly used in a variety of situations, including orthopaedic, abdominal, gynaecological surgery, Caesarean section and the relief of pain in childbirth. Hyperbaric solutions of local anaesthetics appear to produce more consistent results than plain solutions and the addition of other drugs, such as opioids and clonidine may improve analgesia. In addition to traditional spinal anaesthesia, local anaesthetics are now being evaluated in continuous spinal anaesthesia and combined epidural-spinal anaesthesia. This article reviews clinical experience with levobupivacaine and ropivacaine. Compared with levobupivacaine, ropivacaine generally produces a less intense motor block of shorter duration, which has advantages for earlier mobilization and discharge from hospital and may be particularly useful in obstetrics and ambulatory surgery.

Musgrave Park Hospital, Department of Anaesthesia, Belfast, Northern Ireland

Correspondence to: Kevin R. Milligan, Department of Anaesthesia, Musgrave Park Hospital, Stockman's Lane, Belfast BT9 7JB, Northern Ireland. E-mail: kevin.milligan@virgin.net; Tel: +44 2890902000/2007

Accepted for publication October 2004 EJA 2073

It is now over one hundred years since Bier and von Esmarch first reported their experience with cocaine as an intrathecal anaesthetic agent [1]. Although Corning may have already produced spinal anaesthesia with this drug [2], Bier was the first to attempt to use it in a practical setting, the clinical trial consisting of six patients undergoing orthopaedic surgery.

However, Bier decided to curtail his trials because 'so many complaints' arose in association with this anaesthetic technique including leg and back pain, vomiting and prolonged headache. He concluded that the problems that he was experiencing were as bad as those seen with general anaesthesia. Following further experimentation on himself and his assistant, Bier eventually concluded that better local anaesthetic agents were needed before spinal anaesthesia could be recommended. Despite these reservations his work attracted widespread interest. Within a decade technical improvements meant that an anaesthetic technique had evolved that would be instantly recognizable to the modern anaesthetist, most of the differences merely being refinements of earlier innovations [3].

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Indications for spinal anaesthesia

Spinal anaesthesia has been used in most types of surgery including orthopaedic [4-7], abdominal, gynaecological [8] and Caesarean section [9-11]. Indications for spinal anaesthesia in pain management include childbirth [12-14] and cancer pain [15,16]. More recently, it has been attracting attention for use in ambulatory surgery [5,17].

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Spinal anaesthetic agents

Efficacy, potency and safety of the local anaesthetic agent, baricity and adjuvants are issues in spinal anaesthesia. The ideal spinal anaesthetic for day-case surgery should provide rapid, adequate surgical anaesthesia together with early ambulation and ability to urinate, allowing early discharge from hospital [17].

The range of local anaesthetic agents available for intrathecal use is fairly limited and of these, bupivacaine, available in both hyperbaric and isobaric formulations, is the most commonly used. Lignocaine (lidocaine), previously widely used for spinal anaesthesia, especially in mainland Europe, has largely been withdrawn because of fears of radicular irritation. Bupivacaine, while a satisfactory spinal anaesthetic, is relatively long acting making it unsuitable for short procedures. With the demise of lidocaine attention is, therefore, focusing on ropivacaine and levobupivacaine, two relatively new aminoamides offering some potential advantages over bupivacaine both of which have now been successfully used as spinal anaesthetic agents (Table 1).

Table 1

Table 1

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The clinical relevance of isomeric purity

The two new amide local anaesthetics, ropivacaine and levobupivacaine are both less toxic to the central nervous and cardiovascular systems than bupivacaine, the standard long-acting local anaesthetic [18].

It has become apparent that this is in part due to the fact that stereoisomers of a compound exert different effects. Stereoisomers are compounds with the same chemical structure but with different three-dimensional arrangements of their atoms (Fig. 1). The simplest example of this is when the two forms of the molecule appear as mirror images of each other, these being known as enantiomers. It is not possible to superimpose one form on the other; e.g. the right hand is a mirror image of the left and cannot be superimposed on it, a situation known as chirality; most organic molecules are chiral.

Figure 1

Figure 1

To differentiate between enantiomers a number of classifications exist, the commonest being the +/− or R (rectus)/S (sinister) systems. In the first, a beam of polarized light is passed through a solution of the molecules. Each form of the molecule will rotate the light by a specific amount and in a specific direction, i.e. it will either be rotated clockwise (+) or else anticlockwise (−). If the solution contains equal amounts of the two enantiomers, then the net effect will be zero and the light will not be deviated. The R/S method of classification is based on the absolute configuration of the groups or atoms around the chiral centre. If the order of increasing size is to the left it is the S form or if to the right it is the R form of the molecule [19,20].

Levobupivacaine is the S(−) enantiomer of bupivacaine. The clinical relevance of this is that in a three-dimensional biological system the different forms of the molecule will exert different effects and there will also be differences in their distribution and metabolism. It has become clear that for local anaesthetics the S(−) forms are significantly less toxic than the R(+) forms.

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Baricity

The baricity of a local anaesthetic is the density of the solution relative to the density of the cerebrospinal fluid. A baricity of <0.9990 is defined as hypobaric, 0.9990-1.0015 is isobaric and >1.0015 is hyperbaric [21]. Hyperbaric and hypobaric solutions spread under the influence of gravity and this, together with other factors including the posture of the patient at the time of injection, site of injection, drug dose and drug volume can affect the maximum level of sensory block [22]. The clinical implications of the baricity of local anaesthetics will be discussed later in this review.

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Safety

Evidence for the relative safety of spinal local anaesthetics is provided by large-scale surveys of the complications. Concerns about the potential for neurotoxicity have been largely unfounded [17]. A number of terms are used in the literature to describe transient neurological symptoms including 'transient radicular irritation', 'transient lumbar pain' and 'transient neurological toxicity'. These transient neurological symptoms have been described after spinal anaesthesia, most commonly with lidocaine. To the author's knowledge there are no reports of transient neurological symptoms in association with spinal anaesthesia using ropivacaine or levobupivacaine.

The first successful report of spinal anaesthesia by Bier included a description of post-dural puncture headache, which was attributed to loss of cerebrospinal fluid [23]. Data on the incidence of post-dural puncture headache following the use of ropivacaine and levobupivacaine for spinal anaesthesia is sparse but studies to date indicate that it is not drug related and that technique is more important, the use of small-gauge pencil-point needles reducing its incidence [17].

Cauda equina syndrome describes the neurotoxic symptoms that have been reported following continuous spinal anaesthesia, particularly with 5% lidocaine [24] and may be the result of accumulation of hyperbaric spinal anaesthetic in the area of the cauda equina nerves, resulting in local nerve damage [25]. There are no reports to date of these symptoms in association with spinal use of ropivacaine or levobupivacaine.

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Clinical experience with levobupivacaine

Levobupivacaine, a long-acting amide local anaesthetic, is the isolated S-enantiomer of racemic bupivacaine and is now available commercially. On a milligram-per-milligram basis it is less toxic than bupivacaine because of decreased potency at the sodium channel [18].

Most studies comparing bupivacaine and levobupivacaine have concluded that the two drugs have similar clinical actions. However, these studies have concentrated on epidural anaesthesia/analgesia and peripheral nerve blockade, and do not necessarily predict the efficacy of levobupivacaine for spinal anaesthesia. For example levobupivacaine has some inherent vasoconstrictor properties and this may lead to a longer duration of action as demonstrated by Kopacz and colleagues in a study using epidural levobupivacaine 0.75% [26].

Studies on intrathecal levobupivacaine include the use of plain solutions [27,28] comparison of plain and hyperbaric levobupivacaine with bupivacaine [29] and the effects of the addition of sufentanil and epinephrine [30].

Burke and colleagues injected 3 mL of 0.5% plain (glucose free) levobupivacaine intrathecally into 20 patients undergoing lower-limb surgery [27]. The results were mixed in that, although satisfactory anaesthesia was achieved in most patients, the height of the block was very variable and in two cases was inadequate for surgery. Onset times were relatively slow, sensory block taking a mean of 25 min to achieve maximum cephalic spread and motor block taking 15 min. The duration of the sensory block was 388 min (range 295-478 min) and the motor block 266 min (170-415 min). The authors attributed the variation in effects to the plain solution being slightly hypobaric at body temperature. There were small decreases in heart rate (HR) and significant reductions in blood pressure (BP), as might be expected in patients undergoing spinal anaesthesia.

A more recent study by Glaser and colleagues also looked at the use of spinal levobupivacaine but for comparison included a bupivacaine group [28]. They administered 3.5 mL of either 0.5% levobupivacaine or else 0.5% racemic bupivacaine to 80 patients undergoing total hip replacement. In essence they were unable to demonstrate any clinical differences between the two drugs and concluded that they were equipotent in terms of onset time, duration, and degree of motor and sensory block. There were similar changes in haemodynamic parameters for both groups. They considered however that the spread of anaesthesia was predictable and found the onset times to be much shorter at 11 and 10 min for sensory and motor block, respectively.

Similar findings were reported by Alley and colleagues who completed a volunteer study comparing 4, 8 or 12 mg of intrathecal hyperbaric levobupivacaine with the same dose of bupivacaine in 18 subjects [29]. Each subject received two spinal anaesthetics, one with levobupivacaine and a second, at a later date, with the same dose of bupivacaine. Once again the drugs appeared to be very similar with no differences in the onset, duration or height of the blocks or in the incidence of side-effects. The authors considered that levobupivacaine was an alternative to bupivacaine and did not appear to offer any advantages.

Essentially similar results were obtained when sufentanil and epinephrine were added to levobupivacaine. Vercauteren and colleagues compared 2 mL of 0.125% levobupivacaine with 2 mL of 0.125% bupivacaine for analgesia during childbirth [30]. Both solutions had sufentanil 1.5 μg plus 2.5 μg of epinephrine added. Analgesia took between 4 and 5 min to develop and lasted 94-95 min. There were no clinical differences between the groups for any parameter measured apart from motor block. This was less dense in the levobupivacaine group but this was not marked and has not been reported in other studies. It is not clear what the likely role of levobupivacaine will be in spinal anaesthesia - it appears to be virtually identical to bupivacaine, so if the latter was to be removed from the shelves there is no reason why levobupivacaine could not be used as a substitute. Indeed, apart from cost there does not appear to be any particular reason why bupivacaine should continue to be used in clinical practice.

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Clinical experience with ropivacaine

Ropivacaine, the other relatively new aminoamide local anaesthetic, was the first local anaesthetic to be synthesized as a pure enantiomer. It is slightly less potent than bupivacaine, although to some extent this depends on the model used and whether or not its lower molecular weight is taken into account; i.e. 1 mg of ropivacaine will contain more molecules than 1 mg of bupivacaine. Early studies comparing ropivacaine with bupivacaine for epidural blockade assumed that the drugs were equipotent and compared 0.25% solutions of both. They demonstrated a tendency towards less motor block with ropivacaine, which was attributed to a greater differential block [31].

Polley and colleagues then addressed the potency issue and demonstrated that ropivacaine has a potency 0.6 times that of bupivacaine when administered by the epidural route [32].

Intrathecal ropivacaine was first administered in the early 1990s. These were essentially safety trials but demonstrated it to be a reliable and effective spinal agent [33]. Since its properties appear to be significantly different from those of bupivacaine, it is perhaps potentially a more interesting drug than levobupivacaine in terms of spinal anaesthesia.

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Plain (isobaric) ropivacaine

In common with the epidural route, intrathecal ropivacaine appears to be less potent than bupivacaine. Work by McDonald and colleagues suggested that for spinal anaesthesia ropivacaine is approximately 0.5 times as potent as bupivacaine [34]. The potency issue was also addressed by Malinovsky and colleagues, who used 15 mg of plain ropivacaine for endoscopic urological surgery, comparing it with 10 mg of bupivacaine [35]. There were no differences between the groups in terms of motor or cardiovascular effects but the median block heights were higher with bupivacaine - T4 vs. T6. There were no differences in the onset or offset times. Eight of the 50 patients receiving ropivacaine required intravenous (i.v.) alfentanil to supplement their anaesthesia. Therefore, the authors concluded that ropivacaine was not as effective as bupivacaine even at these doses.

Somewhat different results were achieved by McNamee and colleagues, who evaluated the efficacy of plain solutions of ropivacaine for spinal anaesthesia in patients undergoing major orthopaedic surgery [36]. One hundred and four patients presenting for total hip replacement were randomly allocated to receive an intrathecal injection of glucose-free ropivacaine either 2.5 mL of a 7.5 mg mL−1 solution or 2.5 mL of a 10 mg mL−1 solution. The onset of motor and sensory block was rapid in both groups. The median time to achieve a block at the T10 dermatome was 2 min and the median height of block achieved was T4 for both groups. The median duration of the sensory block (at T10) was 3 h (range 0.5-4.2 h) for the 18.5 mg group and 3.4 h (range 1.1-5.9 h) for the 25 mg group. One patient complained of inadequate intraoperative analgesia and a general anaesthetic was administered. This patient was subsequently shown to have an adequate block postoperatively. The authors concluded that, in the doses used, ropivacaine provides effective and well-tolerated anaesthesia for major surgery.

In a more recent double-blind study, McNamee and colleagues compared intrathecal isobaric solutions of ropivacaine and bupivacaine in 66 patients undergoing total hip replacement [6]. Patients were randomly allocated to receive 17.5 mg of either ropivacaine or bupivacaine, and the intensity and duration of the motor and sensory blocks were studied. The onset of anaesthesia was rapid (median 2 min for both groups) and all patients had a block to T10 or above. The duration of this block (>T10) was 3 h in the ropivacaine group compared with 3.5 h for bupivacaine. Motor block was less pronounced in the ropivacaine group, the median duration of block (Bromage score >1) being 3.7 h for ropivacaine and 5 h for bupivacaine. At 4 h, 44% of the ropivacaine patients had a Bromage score >1 compared with 88% of the bupivacaine patients (see Fig. 2). Hypotension was reported for 34% of the ropivacaine patients and 38% of the bupivacaine patients. Postoperative morphine consumption from a patient controlled analgesia system was 54 and 44 mg in the ropivacaine and bupivacaine groups, respectively. There were no differences in adverse effects between the groups. The conclusion from this study was that ropivacaine is a good spinal anaesthetic agent but is shorter acting and produces less motor block than bupivacaine.

Figure 2

Figure 2

Ropivacaine has been compared with levobupivacaine in two studies. In the study by Delfino and colleagues [37], which compared ropivacaine 15 mg with levobupivacaine 15 mg, there were no significant differences in most variables observed; sensory block onset, maximum cranial spread time, maximum sensory block level, motor block onset and maximum motor block level. However, the time for onset of non-stimulated pain at the surgical site and the time for the reversal of total motor block were significantly longer in the levobupivacaine group (see Fig. 3). The authors concluded that both 15 mg ropivacaine and 15 mg levobupivacaine provide adequate analgesia and motor blockade for lower-limb surgery when given spinally. One further study by Breebaart and colleagues [7] compared levobupivacaine, ropivacaine and lidocaine with respect to urinary retention after spinal anaesthesia in day-case procedures (see later).

Figure 3

Figure 3

Ropivacaine has also been studied for use in obstetric anaesthesia. Khaw and colleagues randomized patients undergoing Caesarean section to receive 10, 15, 20 or 25 mg of intrathecal ropivacaine [9]. They reported that the duration of the sensory and motor block was positively related to dose (see Fig. 4) and that ropivacaine provided good anaesthesia for Caesarean section. These results have since been confirmed by another study which compared the use of isobaric ropivacaine 15 mg plus morphine 150 μg with bupivacaine 15 mg plus morphine 150 μg in patients undergoing Caesarean section [11]. All patients had adequate anaesthesia and there were few differences between the groups apart from a shorter duration of motor block in the ropivacaine group. There were no differences between the groups in terms of the sensory block or in the postoperative requirements for analgesia. This was probably due to the effect of the morphine masking any differences between the groups. The authors concluded that ropivacaine 15 mg plus morphine provided sufficient anaesthesia for Caesarean delivery [11].

Figure 4

Figure 4

Hyperbaric solutions. Khaw and colleagues have also investigated the use of hyperbaric ropivacaine solutions for Caesarean section [39]. After administering 25 mg of ropivacaine as either plain or hyperbaric solutions, they looked at the height of sensory block, its onset and its duration. Somewhat surprisingly, they claimed a 25% (5 of 20) failure rate in patients receiving plain ropivacaine. There were no failures in the hyperbaric group. Mean onset times were 7.7 vs. 16.4 min and recovery times to L1 were 189 and 216 min for the hyperbaric and plain solutions, respectively. The median height of block achieved was T1 for the hyperbaric group and T3 for the plain solution. Their conclusion was that hyperbaric solutions of ropivacaine produce a denser block with a more rapid onset and a shorter duration of action.

These results were broadly similar to those of Whiteside and colleagues, who studied general surgical patients receiving 15 mg of ropivacaine in glucose 10 mg mL−1 or 50 mg mL−1[40]. The time to achieve a block height to T10 was significantly faster in the 50 mg mL−1 solution than in the 10 mg mL−1 group (median 5 min, range 2-20 min vs. median 10 min, range 2-25 min). Maximum block heights were very similar (median T6, range T3-T10) as were the times to regression to S2 (median 210 min, range 150-330) for both groups. Virtually all patients had complete motor block and a block adequate for surgery was achieved in all cases.

The same group subsequently compared hyperbaric solutions (3 mL of 0.5% solution) of ropivacaine and bupivacaine in 40 patients undergoing spinal anaesthesia [41]. Adequate blocks for surgery were achieved in all cases but the duration of the blocks were significantly different. Duration of sensory block at T10 was 118 min for the bupivacaine group but only 57 min for the ropivacaine group. Complete regression of motor block took 180 min for the ropivacaine group but 255 min for the bupivacaine group; 14 of 20 bupivacaine patients required treatment for hypotension compared with 3 of 20 who received ropivacaine. They concluded that hyperbaric ropivacaine provides good anaesthesia but with a shorter duration of action than an equivalent dose of bupivacaine, the patients mobilizing and micturating faster when they received ropivacaine. Therefore, ropivacaine was felt to have a more useful profile for day-case surgery.

Chung and colleagues compared 18 mg (5 mg mL−1) of hyperbaric ropivacaine with 12 mg (5 mg mL−1) of hyperbaric bupivacaine in obstetric patients [10]. The peak level of analgesia was similar in both groups (T3) and both groups achieved complete motor block of the lower extremities. Compared with bupivacaine, ropivacaine produced significantly later onset of sensory block, shorter duration of sensory block, and shorter duration of motor block. The intraoperative quality of anaesthesia was excellent in both groups and there was no difference in side-effects.

These results were confirmed by Lopez-Soriano and colleagues [42]. The authors compared hyperbaric solutions of 0.5% ropivacaine and 0.5% bupivacaine (12.5 mg of each) in patients receiving spinal anaesthesia prior to lower-abdominal surgery. The duration of block in the ropivacaine group was much shorter and there were significantly fewer episodes of hypotension in this group. The sensory block lasted 127 ± 24.3 min as opposed to 175 ± 25.5 min in the bupivacaine group. Their conclusion was that hyperbaric ropivacaine was an effective drug for spinal anaesthesia and that, with its shorter duration of action and less motor block, it demonstrated advantages over bupivacaine when a quicker recovery is desired.

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Outpatient spinal anaesthesia

It is noteworthy that despite the widespread adoption of day-case surgery, spinal anaesthesia is used very infrequently in these patients. A Canadian study has reported that this technique was used in <3% of outpatients [43]. A recent study has compared outpatient spinal anaesthesia (10 mg hyperbaric bupivacaine) with total i.v. anaesthesia using propofol and remifentanil [44]. The authors found that the preparation times for the two techniques were similar (11 and 7 min, respectively) and that the incidence of intraoperative hypotension and bradycardia was the same for both groups. The times to hospital discharge were significantly longer in the spinal group 296 (195-720)min compared with 156 (101-345)min in the group who had received general anaesthesia. Patients expressed more satisfaction with the general anaesthetic (100%) compared to the spinal technique (75% satisfied). This suggested that spinal anaesthesia was less efficient but the results were in contrast to two other Canadian studies, which concluded that operating theatre efficiency is not reduced by the use of a regional technique [45,46].

Part of the problem may be in identifying suitable drugs for spinal anaesthesia on an outpatient basis. The anaesthetist requires a local anaesthetic agent which, when administered intrathecally, will produce acceptable surgical anaesthesia of appropriate duration followed by a rapid regression of the sensory and motor block with minimal residual effects. Lidocaine has been shown to be a useful local anaesthetic in this situation but as indicated above concerns have arisen concerning possible radicular irritation following its administration [47]. A recent meta-analysis by Eberhart and colleagues has suggested that the incidence of radicular irritation was 16.9% after intrathecal lidocaine, 19.1% after mepivacaine but only 1.1% after bupivacaine and 1.7% after prilocaine [48]. They considered that there was insufficient information to comment on ropivacaine, tetracaine or procaine. Since this analysis a Japanese group, investigating the mechanism of neural damage, has reported that in rabbits lidocaine and tetracaine were equally damaging and worse than bupivacaine, ropivacaine being the least toxic [49].

Bupivacaine is generally considered to be free of this problem but to be too long acting to be of much practical value in outpatients. However, there has been some interest in the use of low doses of bupivacaine for outpatient anaesthesia. This is because it appears that the total dose of the local anaesthetic administered is the principal factor determining the duration of the sensory block [50]. An alternative strategy is to use hyperbaric bupivacaine, which has been investigated as a possible alternative to plain bupivacaine. Volunteer studies by Liu and colleagues suggested that 7.5 mg of this drug would provide approximately 60 min of anaesthesia [51].

These results were confirmed in a clinical study by Ben-David and colleagues, where it was shown that 7.5 mg of hyperbaric bupivacaine, administered intrathecally, was a practical anaesthetic for patients undergoing day-case arthroscopy of the knee with a time to discharge of 202 ± 14 min [52]. Reducing the dose to 5 mg shortened the discharge time but unfortunately resulted in 4 of 15 patients complaining of pain making it unacceptable to most anaesthetists.

In contrast, a Finnish study, using a similar model, suggested that low-dose (4 mg in 0.8 mL) hyperbaric bupivacaine produced satisfactory analgesia with a rapid recovery and discharge [53].

There have been a few studies that have compared the properties of intrathecal anaesthetics in patients undergoing outpatient surgery. Buckenmaier and colleagues randomized patients undergoing outpatient anorectal surgery to receive either hyperbaric lidocaine 25 mg with fentanyl 20 μg or hyperbaric ropivacaine 4 mg with fentanyl 20 μg. They were unable to demonstrate any significant differences between the two groups and concluded that ropivacaine was just as effective as the lidocaine [54].

These results were not replicated in a study which looked at the time until micturition and hospital discharge following intrathecal isobaric levobupivacaine 10 mg, ropivacaine 15 mg or lignocaine 60 mg. Lidocaine was associated with a faster recovery and shorter time to discharge than the other two groups, the mean difference being 40 min but three patients reported symptoms compatible with a diagnosis of transient neurological symptoms. The authors did not consider the difference between the drugs to be of great significance since the overall time to discharge was 4-5 h. This was not altogether surprising considering the relatively large doses of drug used for outpatient procedures [7].

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Adjuvants in spinal anaesthesia

In an effort to improve the reliability of these drugs various adjuvants have been added to them. Epinephrine has been widely investigated but, while it increases the reliability of the injection, it will also prolong its duration and delay the time until the patient is able to void [55].

Opioids, such as fentanyl and sufentanil, have also been added to local anaesthetics with more success since they will prolong the duration of the sensory block but with little effect on the duration of the motor block or bladder function. The opioid interrupts pain transmission in the dorsal horn while the local anaesthetic blocks the conduction in motor and sensory nerves. There appears to be some evidence for a synergistic action [56] probably by a combined effect on the calcium, sodium and potassium channels.

Ben-David and colleagues have reported that 10 μg of fentanyl added to a low-dose bupivacaine spinal anaesthetic increased the success rate from 76% to 100% and did not prolong the time until patient discharge [57].

More recently Siddik-Sayyid and colleagues reported that 12.5 μg of fentanyl added to 12 mg of hyperbaric bupivacaine significantly improved the quality of spinal anaesthesia for Caesarean section, with the additional benefits of more prolonged postoperative pain relief and less nausea than when the same dose of fentanyl was given i.v. [58].

There appears to be little benefit in adding >40 μg of fentanyl or 12.5 μg of sufentanil and these doses can be expected to prolong bupivacaine analgesia by 30 and 60 min, respectively. It has also been reported that the addition of epinephrine to intrathecal injections of fentanyl does not prolong the duration of analgesia produced [59].

Postoperative respiratory depression following opioid administration does not appear to be a particular problem but pruritus, although usually described as mild, has been reported in up to 70% of patients.

An alternative that has aroused some interest is neostigmine. When administered intrathecally in doses of 25-100 μg together with bupivacaine, it significantly reduced the consumption of postoperative analgesics. Unfortunately its usefulness has been limited by the high incidence of nausea and vomiting that accompanies its use [60].

Another possibility is the use of excitatory amino acids. These are important for both sensory and motor function within the spinal cord. Following intrathecal injection, they have been reported to produce blockade of the sensory and motor nerve fibres in animal models without changes in BP, an effect that was more sustained than that produced by bupivacaine [61].

Given the differences emerging between ropivacaine and bupivacaine, the former might offer a better profile for use in day-case anaesthesia. Gautier and colleagues studied 150 patients, split into five groups, undergoing arthroscopy of the knee [62]. These patients received 8 mg of bupivacaine or 8, 10, 12 or 14 mg of ropivacaine. As might have been expected, the ropivacaine 8 and 10 mg groups produced a mean shorter duration of sensory block than bupivacaine (151 vs. 181 min). Unfortunately, this was accompanied by a decreased quality of intraoperative analgesia. There was virtually no difference between the bupivacaine and ropivacaine 12 mg groups. Therefore, the conclusion from this study was that at equipotent doses there is no advantage in using ropivacaine. Of interest in this study was the lack of any evidence of any postoperative back pain. This had been a concern following a small volunteer study by McDonald and colleagues, who reported a high incidence (28%) of back pain following intrathecal ropivacaine [34].

This has been investigated further by Malinovsky and colleagues, who studied rabbits into which lumbar intrathecal catheters were inserted [63]. A variety of doses of ropivacaine (0.2-2.0%) were administered through these, either as a single dose or else as repeated injections over a 2-week period. For comparison, a group receiving intrathecal saline was included as was a group receiving intrathecal 5.0% lidocaine. Histological examination within 7 days of the last administration of drug demonstrated no signs of neurotoxicity in the rabbits that had received ropivacaine but the rabbits that had received lidocaine demonstrated both clinical and histopathological changes.

Therefore, attention has switched to possible combinations of ropivacaine with other drugs to utilize the shorter duration of action while improving the analgesia. In a study into pain relief during labour, Levin and colleagues mixed sufentanil 10 μg with bupivacaine 2.5 mg, or ropivacaine 2 or 4 mg [4]. Analgesia lasted between 78 and 98 min with no differences between the groups in this or any other measures such as motor block or side-effects. Similar results were obtained by Hughes and colleagues, who added 25 μg of fentanyl to 2.5 mg of ropivacaine or 2.5 mg of bupivacaine and administered the solutions to patients requiring analgesia for labour [12]. The only detectable difference was a much lower incidence of motor block in the ropivacaine group (1 in 20 vs. 8 in 20 for the bupivacaine group) (Fig. 5). Therefore, they concluded that ropivacaine offered significant benefits over bupivacaine in this setting. Soni and colleagues reported on the use of low-dose spinal ropivacaine (3 mg) with or without the addition of sufentanil (10 μg) for labour pain analgesia in 36 term parturients [13]. All patients had satisfactory analgesia 5 min after block placement although the patient satisfaction pain scores were superior in the ropivacaine plus sufentanil group. The duration of analgesia was significantly longer in the ropivacaine plus sufentanil group compared to the ropivacaine group (mean 95 vs. 41 min). Again, no patients showed evidence of motor block. There were no differences in Apgar scores or birth weights of the neonates between the two study groups. All patients were satisfied with the analgesia provided during labour and no neurological complications, including headache, were observed in any of the patients. The authors concluded that low-dose spinal ropivacaine provides effective analgesia during labour, although when it is combined with sufentanil both the quality and duration of anaesthesia is increased. Thus spinal ropivacaine in these doses gives minimal, or no motor block, which should facilitate ambulation during labour.

Figure 5

Figure 5

More success was seen with clonidine. Again, using patients undergoing arthroscopy, De Kock and colleagues administered 8 mg of ropivacaine with 0, 15, 45 or 75 μg of clonidine [5]. The ropivacaine only group had a sensory block lasting a mean of 132 min and a lower quality of anaesthesia than the other groups. This was in agreement with the same group's earlier study [62]. The patients who received 75 μg of clonidine had sensory anaesthesia, which was significantly prolonged (195 min) and was associated with systemic effects, such as sedation and reduced arterial pressure. Ropivacaine plus clonidine 15 μg did not demonstrate any prolongation of the motor or sensory block, any systemic side-effects and was associated with high quality intra-operative analgesia. The addition of small doses of clonidine to ropivacaine would therefore appear to be a useful technique for improving the quality of ropivacaine anaesthesia while retaining its short duration of action.

These results are in keeping with what might be expected in that equivalent doses ropivacaine provides a shorter duration of anaesthesia than bupivacaine but is effective and well tolerated with the possible advantage of a much shorter duration of motor blockade [63,64].

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Continuous spinal anaesthesia

Continuous spinal anaesthesia is a technique for producing and maintaining spinal anaesthesia using small doses of local anaesthetics, which are injected into the subarachnoid space via an indwelling catheter.

The history and development of this technique, together with its complications and clinical applications has been reviewed by Denny and Selander [65]. The small, intermittent doses of anaesthetic used for continuous spinal anaesthesia minimize the risks of cardiovascular and respiratory disturbances. These are qualities that are particularly useful for lower-abdominal and lower-limb surgery in the elderly and high-risk patients.

The use of continuous spinal anaesthesia for postoperative analgesia has also been described in a number of studies using bupivacaine, morphine and diamorphine, although the results from studies using bupivacaine have been inconsistent in terms of motor block and hypotension [65]. For the provision of long-term analgesia for cancer patients, continuous spinal anaesthesia has been shown to be effective for several months when using dilute mixtures of bupivacaine and morphine, or bupivacaine and buprenorphine [66,67].

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Combined spinal-epidural anaesthesia

Combined spinal-epidural anaesthesia has become more popular with advantages including rapid onset, profound neuraxial block, potential to titrate block and lower drug usage [17]. There are some potential disadvantages including increased failure rate of the spinal anaesthetic. However technology has improved with the advent of combined spinal-epidural needles. An epidural needle with a 'black-eye' is available, reducing the risk of threading the epidural needle through the dural hole, which may produce a lower failure rate by providing a better 'feel' for dural puncture [17].

Combined spinal-epidural anaesthesia is popular with obstetric patients. Spinal opioids, such as fentanyl or sufentanil, provide rapid analgesia without motor block allowing ambulation and reducing the incidence of instrument assisted vaginal delivery [68]. Combined spinal-epidural anaesthesia provides rapid titratable block with good muscle relaxation in Caesarean section [38]. As rescue analgesia is possible via the epidural catheter, low doses of the spinal anaesthetic can be used, allowing rapid recovery [69]. A higher incidence of failure of the spinal anaesthetic has been reported for the combined technique compared with spinal anaesthesia alone. This has been discussed by Liu and McDonald and may be related to the gauge of needles and patient positioning [17].

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Conclusion

From their ancient origins to the first report of intrathecal anaesthesia by Bier over a hundred years ago to the present day, local anaesthetic agents have progressed a long way. Isomerically pure agents with favourable clinical profiles, such as ropivacaine and levobupivacaine, are now available. Levobupivacaine could provide a suitable alternative to bupivacaine while ropivacaine may be a good choice for short surgical procedures, e.g. obstetrics and ambulatory surgery, where rapid motor recovery is an advantage. The addition of small doses of clonidine to ropivacaine appears to be useful in improving the quality of anaesthesia, while retaining its short duration of action.

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Acknowledgements

The help given by Urban Gustafsson, PhD, and Lars Westman, MD, PhD, AstraZeneca R&D, Sodertalje, Sweden, in the preparation of this manuscript is gratefully acknowledged. KR Milligan has been an investigator in studies sponsored by Astra-Zeneca (ropivacaine) and Chiroscience Ltd (levobupivacaine).

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Keywords:

ANAESTHETIC TECHNIQUES, subarachnoid; ANAESTHETICS, local, ropivacaine, bupivacaine

© 2004 European Academy of Anaesthesiology