Department of Anaesthesia, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JN, UK
Corresponding author. E-mail: thomam@gosh.nhs.UK
Accepted for publication: July 29, 2002
Abstract
Br J Anaesth 2003; 90: 48798
Keywords: anaesthetic techniques, regional, caudal; anaesthetics i.v., ketamine; sympathetic nervous system, clonidine
Caudal epidural analgesia is one of the most popular and commonly performed regional blocks in paediatric anaesthesia. It is a reliable and safe technique that can be used with general anaesthesia for intra- and postoperative analgesia in patients undergoing abdominal and lower-limb surgery. Furthermore, it is easy to perform in younger children. In a retrospective study of 750 consecutive caudal blocks in children, Dalens and Hasnaoui20 noted a failure rate of only 1% in children less than 7 yr old, compared with a 14.5% failure rate in older children.
The main disadvantage of caudal anaesthesia is the short duration of action after a single injection of local anaesthetic solution. Even long-acting local anaesthetic drugs such as bupivacaine provide only 48 h of analgesia.60 The use of caudal catheters to administer repeated doses or infusions of local anaesthetic solution is not popular, partly because of concerns about infection. However, the merits of using a double-caudal technique, whereby the caudal is topped up at the end of the procedure, have recently been advocated.85 Prolongation of caudal analgesia using a single-shot technique has also been achieved by the addition of various adjuvants. This review summarizes the current knowledge regarding the ever-expanding field of caudal additives and balances the potential benefits against the perceived risks of these solutions in children.
Local anaesthetics
Bupivacaine
Bupivacaine has been in clinical use for more than 30 yr and is available commercially as a racemic mixture containing equal proportions of the S()- and R(+)-isomers. It is widely used for caudal epidural analgesia in children because of its long duration of action and beneficial ratio of sensory to motor block. Bupivacaine 0.1250.175% is the optimum concentration for this purpose, providing equivalent postoperative analgesia to bupivacaine 0.25% (48 h), but with a shorter duration of motor block.34 Despite this, the latter concentration is still frequently preferred. Whatever the concentration used, a safe maximal dose of bupivacaine (plain or with epinephrine) is 2.5 mg kg1 administered as a single injection.28 Bupivacaine is associated with a number of side-effects, including motor weakness, urinary retention and cardiovascular and central nervous system (CNS) toxicity. In particular, there have been reports of death attributable to bupivacaine-induced cardiotoxicity in adults after accidental i.v. injection.3 These cases and many unpublished anecdotal instances of bupivacaine toxicity have resulted in the continuing search for new and safer local anaesthetic agents.
Ropivacaine
Ropivacaine is a long-acting aminoamide local anaesthetic and was the first to be formulated as a pure S-enantiomer. It is reported to have a better safety profile than bupivacaine, with less risk for CNS and cardiac toxicity.51 The absence of any sequelae following the inadvertent i.v. injection of ropivacaine (approximately 1 mg kg1) in a 30-month-old child is testament to its minimal cardiotoxic potency.83 Ropivacaine also causes less motor block than bupivacaine, a characteristic that may benefit children presenting for day-case surgery. While pharmacokinetic studies have demonstrated the safety of caudal ropivacaine 0.2% (1 ml kg1) in children,61 other studies have shown it to be as effective as bupivacaine.19 41 52 63 In a double-blind multicentre study of 245 children aged 110 yr undergoing elective minor surgery, the mean onset time and mean time to first analgesia with caudal ropivacaine 0.2% (1 ml kg1) were similar to the values for bupivacaine 0.25% (1 ml kg1) [9.7 (SD 2.2) min vs 10.4 (2.3) min; 4.5 (2.0) h vs 3.9 (1.3) h, respectively]. Furthermore, motor block was less extensive and shorter in duration with ropivacaine than with bupivacaine.41
Ropivacaine 0.5% (0.75 ml kg1) is, however, associated with a significantly prolonged median duration of analgesia when compared with ropivacaine 0.25% [24.0 (range 5.524.0) h vs 3.5 (2.95.6) h; P<0.0001),52 but at this concentration peak plasma levels are very close to levels associated with early signs of toxicity in adults. In addition, these higher concentrations of ropivacaine produce increased motor block in the initial postoperative period.52 Reducing the ropivacaine concentration would provide an additional margin of safety as well as reducing the incidence of unwanted motor block. Unfortunately, however, the use of plain ropivacaine 0.1% for paediatric caudal block has been reported to be significantly less effective, and of shorter median duration, than ropivacaine 0.2% [1.7 (0.26.0) h vs 4.5 (1.76.0) h; P<0.05].63 In a recent double-blind randomized study comparing the analgesic efficacy of different concentrations of ropivacaine, Bosenberg and colleagues6 found that ropivacaine 0.2% (1 ml kg1) provided satisfactory postoperative analgesia after elective inguinal surgery. In comparison, ropivacaine 0.1% was found to be less efficacious, while the use of ropivacaine 0.3% was associated with a higher incidence of motor block without any significant improvement in postoperative pain relief. On the basis of current evidence, ropivacaine 0.2% appears to be the optimal concentration for paediatric caudal block.
Levobupivacaine
Levobupivacaine, a new long-acting amide-type local anaesthetic, is the S()-isomer of the racemate bupivacaine.70 Like ropivacaine, it is less toxic to the CNS and is also less likely to cause myocardial depression and fatal arrhythmias than bupivacaine.37 Clinical studies in adults have shown that epidural levobupivacaine is well tolerated and produces a block clinically indistinguishable from that with bupivacaine. In patients undergoing elective lower-limb surgery there was no significant difference in the mean onset time or duration of sensory block between levobupivacaine 0.5% and bupivacaine 0.5% [mean onset time: 8 (SD 5) min vs 7 (4) min; mean duration: 6.3 (2.1) h vs 5.8 (1.8) h].17 In patients undergoing major lower-abdominal surgery, epidural levobupivacaine 0.75% resulted in a similar mean onset time of sensory and motor block to bupivacaine but a significantly longer duration of action [onset of action: 13.6 (5.6) min vs 14.0 (9.9) min; P=0.78; duration of action: 9.1 (1.4) h vs 8.4 (1.2) h; P=0.02].54
Levobupivacaine is currently only licensed for ilioinguinal and iliohypogastric nerve block in paediatric patients, and to date there are few published data regarding its caudal epidural use in children. In fact, only one study of caudal levobupivacaine in children has been performed. This was a two-centre open-label study of 49 children under 2 yr old undergoing circumcision, herniorrhaphy or orchidopexy repair, in which levobupivacaine 0.25% (2 mg kg1) was shown to provide satisfactory postoperative analgesia in almost 90% of children (mean time to request for analgesia 7.6 h).29
Epinephrine
Epinephrine 1:200 000 (5 µg ml1) has been used as a caudal adjuvant for many years. Its effect is less pronounced with bupivacaine and ropivacaine than with more hydrophilic drugs such as lidocaine. The reasons for this relate to the high lipid solubility of these agents, which causes them to be deposited in epidural fat and released slowly, combined with the relatively short duration of action of epinephrine. The effect of epinephrine on the duration of action of epidural bupivacaine also depends on the concentration of bupivacaine used. Little effect is seen when it is mixed with bupivacaine 0.5% or 0.75%, yet when mixed with 0.125% or 0.25% the effects of epinephrine are more marked.15 Although an increase in duration of postoperative analgesia has been demonstrated in a study of children undergoing penoscrotal surgery compared with plain bupivacaine,95 subsequent studies have failed to substantiate this. Work by Desparmet and colleagues24 suggests that the addition of epinephrine to caudal solutions may help early detection of inadvertent i.v. injection, and that the resultant ECG changes are more readily identified if the children have received atropine premedication.
Opioids
The administration of epidural opioids for the management of postoperative pain is well established in paediatric practice, although the optimal opioid is still a matter of some debate. Injection of opioids into the epidural space enables provision of analgesia without the sympathetic or motor block associated with local anaesthetics. This analgesic effect is attributable to a local action of the opioid at the spinal cord level rather than to an effect after systemic absorption, since plasma morphine levels after caudal injection are much less than the 12 ng ml1 considered necessary for systemic analgesia in children.64
Morphine
Since Jensen first described the use of caudal epidural morphine in 1981,44 several studies have provided evidence of prolonged analgesia following its use. A doseresponse study using caudal epidural morphine 0.033, 0.067 and 0.10 mg kg1 in children aged 18 yr undergoing major surgical procedures below the diaphragm showed that the mean duration of analgesia was significantly longer after 0.10 mg kg1 [13.3 (4.7) h] than after either 0.033 mg kg1 [10.0 (3.3) h] or 0.067 mg kg1 [10.4 (4.2) h].57 After hypospadias repair, caudal morphine 0.05 mg kg1 resulted in a median duration of analgesia of 20 (range 1036) h compared with 6 (4.08.5) h with bupivacaine 0.25% (0.5 ml kg1).44 Following lower-body surgery, the median duration of analgesia after caudal morphine 0.1 mg kg1 alone was 12.0 (4.024.0) h compared with 5.0 (3.824.0) h for bupivacaine 0.25% (1 ml kg1) with 1:200 000 epinephrine and 0.75 (0.324) h for i.v. morphine 0.1 mg kg1.55 The effectiveness of caudal morphine is further supported by the findings of a retrospective study in a large group of relatively young paediatric patients.93 In this report of 138 patients, a third of whom were under 6 months old, caudal morphine 0.07 mg kg1 provided effective postoperative analgesia in the majority of patients, with 75% of patients not requiring any supplemental analgesia for the first 10 h after administration of a single dose.
The synergistic effect of epidural opioid and local anaesthetic solutions on analgesia is well recognized, and the combination of these drugs is used more commonly than are opioids alone. In children, the addition of morphine 0.05 mg kg1 to caudal bupivacaine 0.125% (0.75 ml kg1) improves both the quality and duration of postoperative analgesia after orchidopexy.97 In this study none of the patients who received a combination of morphine and bupivacaine required postoperative opioids, whereas over 50% of those receiving bupivacaine alone needed additional opioid analgesia.
Fentanyl
The synergistic effect with local anaesthetics has also been demonstrated with other opioids. Fentanyl is commonly added to local anaesthetics, and in a meta-analysis of 18 studies conducted in adults this combination was found to provide safe and effective intraoperative pain relief.18 However, the analgesic efficacy of these caudal mixtures in children is less clear. No significant analgesic benefit was demonstrated when fentanyl 1 µg kg1 was added to caudally administered bupivacaine 0.125%,12 or lidocaine 2% with epinephrine 1:200 00046 in children undergoing urological surgery. In contrast, the addition of fentanyl 1 µg kg1 to a mixture of bupivacaine 0.25% with epinephrine 1:200 000 and lidocaine 1% in equal parts (1 ml kg1) significantly prolonged the mean duration of surgical analgesia in children undergoing bilateral correction of vesicoureteral reflux [4.1 (SD 1.7) h vs 2.7 (0.5) h, P=0.035 in the groups with and without fentanyl, respectively].14
It is difficult to compare results and come to a consensus regarding the usefulness of fentanyl and local anaesthetics in combination as the above studies differ in a number of important respects (nature of surgery, pre-medication used, and method of pain scoring).
Diamorphine/buprenorphine
Other opioids that have been investigated include diamorphine and buprenorphine. After hypospadias repair, diamorphine 0.03 mg kg1 combined with bupivacaine 0.25% (0.5 ml kg1) resulted in a median duration of analgesia of 11.0 (range 8.614.2) h compared with 8.5 (5.810.8) h for those receiving bupivacaine alone (P<0.05). Early pain scores were also significantly reduced in the combination group (P<0.05).49
Buprenorphine is a partial agonist with a very high affinity for the µ-opioid receptors in the spinal cord, and has a potency 2550 times that of morphine. Following orchidopexy or herniotomy, the mean duration of analgesia with caudal buprenorphine 4 µg kg1 was 5 h 40 min longer than with morphine 0.05 mg kg1 (19.9 h vs 25.6 h; P<0.01).32 Similarly, the combination of buprenorphine 2.5 µg kg1 and bupivacaine 0.5% (0.5 ml kg1) provided good analgesia for up to 24 h after lower-body surgery without any serious side-effects or the need for parenteral opioid drugs.47
Side-effects
Unfortunately, a number of potential side-effects are associated with the use of caudal epidural opioids. These include nausea and vomiting, pruritis, urinary retention and hypoventilation. Of these, the most serious is respiratory depression, resulting from rostral spread of opioid to the brainstem with subsequent depression of the medullary respiratory centres. While delayed respiratory depression is well described following epidural injection of morphine in adults (34 cases per 1000 administrations),35 the overall risk in children is unknown. In a retrospective review of 138 children given caudal morphine 0.07 mg kg1, there were 11 cases of clinically important hypoventilation (8%).93 Ten of these cases occurred in children less than 12 months old (eight less than 3 months) and seven had received i.v. opioids in addition to caudal morphine, a combination therapy that has been identified as a risk factor for respiratory depression in adults.35 In all cases, respiratory depression occurred within 12 h of caudal morphine administration, with a mean time of 3.8 h. The fact that most cases of hypoventilation occurred in infants less than 3 months old is not surprising since sensitivity to opioids in this particular age group is well known.60 Further to this, there have been reports of individual cases, including a 15-month-old child who developed respiratory depression 2 h after receiving a smaller dose of caudal epidural morphine (0.04 mg kg1).48 56 However, in a more recently published series of 500 children (including 23 neonates) given caudal morphine 0.030.04 mg kg1 there were no reported episodes of clinically significant respiratory depression.68 Rosen and Rosen84 reported on 16 children undergoing open-heart surgery who were given caudal morphine 0.075 mg kg1 as well as i.v. narcotic supplementation, with no respiratory depression.
With regard to the use of other opioids, no episodes of delayed respiratory depression have been reported following the use of epidural fentanyl,12 14 diamorphine,49 or buprenorphine,32 47 although in one study two transient decreases in arterial haemoglobin saturation to 92% were observed after fentanyl.14 This is not unexpected, however, since these highly lipophilic drugs are rapidly cleared from the water phase of the cerebrospinal fluid, thereby making rostral spread less likely.
Although most patients given caudal epidural morphine will not develop clinically important hypoventilation, ventilatory drive (as judged by airway occlusion pressure and response to breathing carbon dioxide) is depressed in the majority of patients for at least 6 h after administration.25 Furthermore, lumbar epidural morphine 0.05 mg kg1 in children resulted in a small reduction in the ventilatory response to carbon dioxide lasting for up to 24 h, although expired end-tidal carbon dioxide tension remained normal.4
Prevention of delayed respiratory depression, and identification of those children at increased risk, is vital, as is the detection of individuals once affected. Depression of respiratory rate is a late indicator of hypoventilation. This is because the reduction of minute ventilation induced by epidural morphine is largely the result of a decrease in tidal volume rather than a reduction in respiratory rate.13 This highlights the need for an effective non-invasive monitor of respiratory status in children who have received epidural opioids. Pulse oximetry is a sensitive but non-specific monitor of ventilation in patients breathing air and without significant cardiopulmonary disease.39 In children receiving systemic opioids, an SpO2 <94% is indicative of significant hypoventilation.26 Continuous monitoring of arterial oxygen saturation after surgery is therefore prudent for children who have received caudal opioids. The occurrence of hypoventilation with opioids is also associated with somnolence,48 56 and so the detection of oversedation can be useful in providing an early warning of impending respiratory failure.
If caudal opioids are used either alone or in combination with a local anaesthetic, the patient should be monitored after surgery in a high-dependency setting. As the period during which the patient is at risk of hypoventilation is unknown, pulse oximetry should be used for at least 24 h after administration, and the conscious level and sedation score assessed regularly. If possible, no other sedative or opioid drugs should be given.
As is the case with respiratory depression, the incidence of other side-effects following the use of caudal epidural opioids tends to increase in parallel with the dose used. The reported incidence of nausea and vomiting with caudal morphine 0.05 mg kg1 is 3436%.97 The occurrence of pruritis is variable (057%),4 18 56 while urinary retention has been reported in 630% of patients after epidural morphine.57 The use of more lipophilic opioids such as fentanyl and diamorphine is associated with fewer side-effects.12 14 49
In view of the potentially serious side-effects associated with the use of caudal epidural opioids, their use has not become an established part of paediatric practice. Instead, attention has been focused on the use of other caudal additives such as ketamine and clonidine (see below), which do not seem to be associated with respiratory depression. In our opinion, these additives have largely superseded the use of caudal opioids. If opioids are to be used, consideration should be given to the use of a more lipophilic drug than morphine, limiting the technique to more major in-patient surgery, and ensuring that facilities are available for postoperative monitoring in a high-dependency setting.
Ketamine
Ketamine is an anaesthetic and analgesic agent with a wide range of applications in paediatric anaesthesia.30 Chemically related to phencyclidine, it exerts its effects by binding non-competitively to a subset of glutamate receptors stimulated by the excitatory amine N-methyl D-aspartate (NMDA), blockade of which leads to a decrease in the activation of dorsal horn neurones. These receptors are located throughout the CNS as well as in the substantia gelatinosa in the spinal cord and play an important role in central pain processing and in neural plasticity in the spinal cord.10 While NMDA receptor block appears to be the primary mechanism of action, ketamine also binds to opioid receptors, with a preference for the µ-receptor. However, the affinity of ketamine for these receptors is a tenth of that for the NMDA receptor, and the analgesic effect of ketamine in humans is not reversed by naloxone.38 Other neuronal systems may also be involved in the antinociceptive action of ketamine, as block of norepinephrine and serotonin receptors attenuates the analgesic action of ketamine in animals.80 Ketamine not only produces analgesia after systemic administration, but also exerts a profound analgesic effect at spinal cord level in animal preparations.10 It is this feature that has generated much interest in the epidural administration of ketamine to provide postoperative analgesia.
The efficacy of caudal epidural ketamine in children has been demonstrated in a number of studies (Table 1).16 45 58 74 87 In a double-blind study, Naguib and colleagues74 compared the analgesic effects of bupivacaine 0.25% (1 ml kg1) with and without ketamine 0.5 mg kg1 in children undergoing inguinal herniotomy. Although there was no significant difference in the quality of analgesia between the groups, only 7% of patients who received the ketamine/bupivacaine combination required any further analgesia in the first 24 h after surgery, compared with 20% and 50%, respectively, of children in the ketamine-only and bupivacaine-only groups. Similarly, Cook and colleagues16 demonstrated that the addition of ketamine 0.5 mg kg1 to bupivacaine 0.25% (1 ml kg1) provided a longer median duration of postoperative analgesia after orchidopexy (12.5 h) than either clonidine 2 µg kg1 (5.8 h, P<0.05) or epinephrine 5 µg ml1 (3.2 h, P<0.001).
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Although different doses of ketamine have been used in combination with local anaesthetics, the optimal dose is probably 0.5 mg kg1.87 In determining this dose, Semple and colleagues found that after orchidopexy, bupivacaine 0.25% (1 ml kg1) combined with ketamine 0.25 mg kg1, 0.50 mg kg1 or 1.0 mg kg1 produced a median duration of analgesia of 7.9 h, 11 h and 16.5 h, respectively. While there were no differences between the groups in terms of motor block, urinary retention or postoperative sedation, ketamine 1 mg kg1 was associated with significantly more behavioural side-effects such as odd behaviour and vacant stares.
Side-effects
The undesirable effects of ketamine are well described.36 However, there have been no reports of respiratory depression, cardiovascular changes or major psychotic or neurological problems following the use of epidural ketamine 0.5 mg kg1 in humans.16 45 58 87
Despite the apparent lack of significant side-effects, there is still some debate about possible neurotoxicity with ketamine. In this regard, no detrimental neurological symptoms have been reported in animal studies following the use of intrathecal ketamine, with or without preservative.7 11 However, in one animal study very high doses of intrathecal ketamine (1.6 mg kg1) resulted in three deaths (out of 33).2 Histological examination revealed vacuolation of neurones in the posterior root ganglia, a feature not present in surviving animals that were later destroyed. More recently, spinal neurotoxicity has been reported in a patient with chronic pain after the long-term infusion of intrathecal ketamine.91 In this case, the addition of ketamine with preservative (benzethonium chloride) to a mixture of bupivacaine, morphine and clonidine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges, without any clinical signs of neurological deficit. However, despite numerous studies, the causes of neurotoxicity remain controversial. While some investigators blame the preservative (benzethonium chloride or chlorbutanol),66 others claim that benzethonium chloride is not toxic in primates.11
Although the addition of ketamine to local anaesthetic solutions has been shown to significantly prolong the duration of caudal analgesia in children,16 45 58 74 87 the practice has not been adopted widely in the UK. This may be partly because of the difficulty in obtaining preservative-free ketamine (Ketamine Curamed®), which is not available in the UK. The commercially available preparation (Ketalar®) should not be administered epidurally because of the risk of neurotoxicity from the preservative agent (benzethonium chloride in the UK). The optimal dose of ketamine for caudal epidural block is probably 0.5 mg kg1. When combined with bupivacaine, ketamine significantly prolongs the median duration of postoperative analgesia (9.512.0 h) without any evidence of behavioural problems.
S-Ketamine
Recently, preservative-free S(+)-ketamine has become commercially available. While its pharmacokinetic properties are similar to those of the racemic mixture, S(+)-ketamine has approximately twice the analgesic potency of the racemate.96 S(+)-ketamine (Ketanest S®) is presented in two concentrations, 5 and 10 mg ml1. It is not available in the UK and must be imported.
In the first published study investigating the use of S(+)-ketamine for caudal block in children, Marhofer and colleagues67 showed that preservative-free S(+)-ketamine 1.0 mg kg1 provided intraoperative and postoperative analgesia equivalent to bupivacaine 0.25% 0.75 ml kg1 with epinephrine 1:200 000. In this study, the mean duration of analgesia was 5.0 (SD 1.6) h for bupivacaine 0.25% (0.75 ml kg1) with epinephrine 1:200 000, and 4.5 (2.0) h and 3.4 (2.1) h with S(+)-ketamine 1.0 mg kg1 and 0.5 mg kg1, respectively. However, in view of the fact that the patients were observed for only 6 h after surgery, no firm conclusions can be drawn as to the exact duration of action of caudally administered S(+)-ketamine. More impressive results were demonstrated in a study comparing the effects of caudal and i.m. S(+)-ketamine in children: caudal S(+)-ketamine 1 mg kg1 produced a median duration of analgesia of 8.8 (range 3.724.0) h compared with 1.8 h (1.024.0 h; P<0.001) for i.m. S(+)-ketamine 1 mg kg1 after inguinal hernia repair.53 Significant side-effects were not reported in either of these studies. More recently, de Negri and colleagues22 have shown that the addition of S(+)-ketamine 0.5 mg kg1 to caudal ropivacaine 0.2% (1 ml kg1) significantly prolongs the mean duration of postoperative analgesia following hernia repair or orchidopexy in children compared with ropivacaine plus clonidine 2 µg kg1 or plain ropivacaine [11.7 (SD 0.5) h vs 8.2 (0.3) h and 4.8 (0.5) h; P<0.05]. Although no significant side-effects were reported, one patient in the S(+)-ketamine group had nystagmus on awakening. In another study, the combination of caudal S(+)-ketamine 0.5 mg kg1 with ropivacaine 0.1% (1 ml kg1) significantly prolonged the mean duration of postoperative analgesia after subumbilical surgery compared with ropivacaine 0.1% alone [10.3 (SD 0.3) h vs 4.8 (0.4) h; P<0.05].23
Even though no adverse or toxic effects following the use of S(+)-ketamine have been reported, further randomized controlled trials need to be conducted before this new agent can be recommended as a safe adjuvant for use in paediatric caudal anaesthesia. Even so, cognisance should be taken of the fact that, as with racemic ketamine, S(+)-ketamine is not licensed for use in the epidural space.
Clonidine
Clonidine is an 2-adrenoceptor agonist, first introduced into adult clinical practice as an antihypertensive agent in the late 1960s, and into paediatric practice in 1973 as a treatment for migraine. Subsequently, its clinical role has expanded to include use as a sedative, premedicant and analgesic.69 77 Clonidine 150 µg in 1 ml (Catapres®) is available commercially as a preservative-free solution, but is not licensed for use in the epidural space.
The analgesic action of intrathecal or epidural clonidine results from direct stimulation of pre- and postsynaptic 2-adrenoceptors in the dorsal horn grey matter of the spinal cord, thereby inhibiting the release of nociceptive neurotransmitters.79 This effect correlates with the concentration of clonidine in the cerebrospinal fluid but not that in the plasma,27 and was first demonstrated clinically in 1984.92
The successful use of epidural clonidine in adults5 led to its evaluation in paediatric caudal epidural block. The resulting studies have consistently shown caudal clonidine to increase the duration of postoperative analgesia (Table 2).16 21 43 50 59 62 72 90 In a study of children aged 17 yr undergoing subumbilical general and urological surgery, Jamali and colleagues43 found that the mean duration of postoperative analgesia with caudal bupivacaine 0.25% (1 ml kg1) was significantly increased by the addition of clonidine 1 µg kg1 [16.5 (SD 9.5) h] compared with plain bupivacaine [7.6 (7.3) h], or bupivacaine plus epinephrine 5 µg ml1 [6.3 (5.7) h; P<0.01]. Furthermore, almost half of the children who received clonidine did not require postoperative analgesia during the first 24 h, compared with 13% of children who received plain bupivacaine and 6% who received bupivacaine plus epinephrine (P<0.05).
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Cook and colleagues16 confirmed the superiority of caudal clonidine 2 µg kg1 over epinephrine 5 µg ml1 added to bupivacaine 0.25% (1 ml kg1) in a double-blind study of boys aged 110 yr undergoing orchidopexy. The median time to first analgesia was significantly longer in the clonidine group compared with those receiving epinephrine (5.8 h vs 3.2 h, P<0.05). This result is less striking than that seen in previous studies,43 59 where sedative and analgesic pre-medication might have had a synergistic effect with caudal clonidine, apparently prolonging the duration of postoperative analgesia.
Further evidence of the effectiveness of caudal clonidine in potentiating postoperative analgesia comes from a study by Klimscha and colleagues.50 They demonstrated that in small children (mean age 3 yr) undergoing day-case hernia repair, the addition of clonidine 1 or 2 µg kg1 to bupivacaine 0.25% (0.75 ml kg1) significantly prolonged the median duration of analgesia and reduced the postoperative analgesic requirements within the first 24 h compared with bupivacaine alone or bupivacaine plus epinephrine 5 µg ml1 (P<0.05). The analgesic effects were similar for the two doses of clonidine, although the relatively low level of pain caused by inguinal herniotomy may have made it difficult to separate the analgesic efficacy of the two doses. Furthermore, the limited time of postoperative assessment (6 h) and reliance thereafter on parental assessment of pain may have also contributed to the difficulty in distinguishing the two doses. In another study, Luz and colleagues62 showed that the mean duration of analgesia achieved in children undergoing orchidopexy, hernia repair or circumcision was comparable whether caudal clonidine 1 µg kg1 or morphine 30 µg kg1 were added to bupivacaine 0.18%, 1.5 ml: 6.3 h (SD 3.3) h vs 7.1 (3.4) h (P=0.43) for the clonidine and morphine groups, respectively. However, the recovery time was significantly longer in the clonidine group [16.6 (8.8) min] than in the morphine group [11.5 (4.7) min; P<0.05], although one might question the practical significance of this finding.
More recently, the addition of clonidine 1 µg kg1 90 or 2 µg kg1 21 to low-volume (0.5 ml kg1) bupivacaine caudals provided no additional clinical benefit over bupivacaine alone in children undergoing hypospadias repair and circumcision, respectively. A possible explanation offered by the authors is that the small volume of local anaesthetic may have been insufficient to deliver the clonidine to its site of action.
The use of higher doses of caudal clonidine has also been investigated. Motsch and colleagues72 found that clonidine 5 µg kg1 significantly prolonged caudal block with bupivacaine 0.175% (1 ml kg1) in children aged 48 yr undergoing minor surgery. The mean duration of postoperative analgesia was 20.9 (SD 7.4) h with clonidine and 14.4 (10.9) h without clonidine (P<0.05). Furthermore, fewer children required postoperative analgesia within the first 24 h (3 vs 12; P<0.05), and the total amount of tramadol administered was significantly less in the clonidine group (20.5 mg vs 72.8 mg; P<0.05). The marked prolongation of caudal analgesia reported in this study might be explained by the fact that a higher dose of clonidine was used in patients undergoing relatively minor surgery.
The duration of analgesia achieved by the addition of clonidine to bupivacaine varies widely (5.816.5 h) in these studies. This may be the result of a number of factors, some of which have been alluded to earlier: dose of clonidine used; differences in premedication and volatile anaesthetic used; type of surgery; indications for rescue analgesia; assessment of pain; and statistical analysis.
What of the use of clonidine with other local anaesthetics? The addition of caudal clonidine 2 µg kg1 to mepivacaine 1% (7 mg kg1) significantly prolonged the duration of postoperative analgesia in children aged 110 yr undergoing general subumbilical surgery (mean time to supplementary analgesia was 3.6 h with mepivacaine 1% plus clonidine vs 2.4 h with mepivacaine 1% alone; P<0.05).40 In a study of 40 children aged 17 yr undergoing elective subumbilical surgery, a combination of clonidine 2 µg kg1 and ropivacaine 0.1% (1 ml kg1) was associated with improved quality of postoperative analgesia compared with ropivacaine 0.2% (1 ml kg1) alone [median duration 3.7 (range 3.04.4) h vs 2.0 (1.19.7) h].42 The majority (90%) of patients in the combination group did not require any supplementary analgesia within the first 24 h after surgery, compared with 55% of children in the ropivacaine-only group (P=0.034). The improved analgesia was achieved without causing any significant degree of postoperative sedation. More recently, de Negri and colleagues22 demonstrated an increase of almost 100% in mean duration of analgesic effect when a combination of clonidine 2 µg kg1 and ropivacaine 0.2% (1 ml kg1) was used in caudal blockade compared with ropivacaine 0.2% alone in children undergoing hernia repair or orchidopexy [8.2 (SD 0.3) h vs 4.8 (0.5) h, respectively; P<0.05].
The optimal dose of caudal clonidine when combined with ropivacaine is not known. We are therefore currently conducting a prospective randomized double-blind trial in children 17 yr old undergoing elective hypospadias repair to compare the duration of analgesia when caudal block is performed using ropivacaine 0.2% with either clonidine 1 or 2 µg kg1.
Side-effects
The main side-effects of epidurally administered clonidine are hypotension, bradycardia and sedation. The antihypertensive effect results from stimulation of 2 inhibitory neurones in the medullary vasomotor centre (nucleus reticularis lateralis) of the brainstem, which leads to a reduction in norepinephrine turnover and sympathetic nerve outflow from the CNS to the peripheral tissues. Epidurally administered clonidine also decreases the electrical activity of preganglionic sympathetic nerves. Bradycardia is caused by an increase in vagal tone resulting from central stimulation of parasympathetic outflow, as well as reduced sympathetic drive.1
Although the effect of clonidine on arterial pressure in animals is small,31 there is a risk of hypotension in humans. In adult studies, epidural clonidine has been associated with a reduction in heart rate and arterial pressure.5 This typically occurs within 1530 min of administration and persists for 3 h. Sedation after epidural clonidine results from activation of 2-adrenoceptors in the locus coeruleus, an important modulator of vigilance. This suppresses the spontaneous firing rate of the nucleus, thereby resulting in increased activity of inhibitory interneurones such as gamma aminobutyric acid (GABA)-ergic pathways, to produce CNS depression.29 Sedation appears to be dose dependent and, as is the case with haemodynamic effects, is probably the result of systemic absorption and vascular redistribution of clonidine to higher centres, rather than a consequence of cephalad migration in the cerebrospinal fluid. Few studies have investigated the ventilatory effects of clonidine. Penon and colleagues81 reported a slight decrease in the slope of the carbon dioxide response curve following the epidural administration of clonidine 300 µg in healthy adult volunteers. In a study of the ventilatory effects of epidural clonidine after Caesarean section, no significant respiratory depression was reported with clonidine 150 µg. How ever, clonidine 300 µg was frequently associated with marked sedation, obstructive apnoea and arterial oxygen desaturation.76
In children, clonidine 15 µg kg1 has been used with out clinically important respiratory or haemodynamic effects.16 40 50 59 72 Jamali and colleagues reported the lowest systolic pressure values 12 h after caudal injection (mean maximum decrease of 6.5%), which corresponds with the time of maximum decrease of mean arterial pressure at 1.2 h in another study.43 59 Although haemodynamic side-effects appear to be less pronounced in children than in adults, they may be dose dependent, as reported by Motsch and colleagues.72 They found that although heart rate and systolic pressure did not differ between groups during surgery, children receiving high-dose clonidine (5 µg kg1) had lower systolic pressures and heart rates during the first 3 h after surgery compared with the control group (P<0.05). However, apart from one of 20 children who received atropine to treat a heart rate <70 beats min1, no additional measures were necessary with this relatively high dose of clonidine.
Caudal clonidine does appear to have a dose-dependent sedative effect in children. Lee and Rubin59 demonstrated a longer duration of postoperative sedation following caudal bupivacaine with clonidine 2 µg kg1 than with bupivacaine alone (mean 9.1 h vs 5.8 h). These times corresponded closely to the duration of analgesia (9.8 h and 5.2 h, respectively), and the authors concluded that the increased duration of sedation was not only the result of the sedative effect of clonidine, but more importantly reflected superior analgesia. In this study, all patients were premedicated with trimeprazine, morphine and atropine. A number of other studies have also demonstrated increased sedation when caudal clonidine is used as part of the anaesthetic technique, although there were no episodes of respiratory depression.40 50 59 72 However, life-threatening apnoea following inguinal herniorrhaphy and orchidopexy in a 2-week-old term neonate has been reported.9 Caudal administration of ropivacaine 0.2% (1 ml kg1) plus clonidine 2.2 µg kg1 resulted in 15 long apnoeic episodes with bradycardia and decreases in oxygen saturation below 80% within the first hour after surgery. Another case report warns of the risk of postoperative apnoea in a preterm neonate who had clonidine 1.25 µg kg1 added to the caudal injection for hernia repair.8 Clonidine may be unsafe in neonates and preterm infants, and until further studies have evaluated the association of dose and side-effects, its use in this group of patients cannot be recommended. It is the authors practice not to use caudal clonidine in children <1 yr old or in patients weighing <10 kg.
Other additives
In addition to the more commonly used additives cited above, a number of other agents have been used in an attempt to prolong the duration of postoperative analgesia following a single-shot caudal epidural. However, they have not gained widespread acceptance and their use remains controversial.
Midazolam
Epidural midazolam exerts its analgesic effect through the GABAbenzodiazepine system in the spinal cord. Benzodiazepine binding sites have been demonstrated in the spinal cord, particularly within lamina II of the dorsal horn, and appear to be linked to the GABAA receptor complex. Furthermore, endogenous benzodiazepine-like substances have been isolated from human cerebrospinal fluid.71
Dose-dependent analgesia without respiratory depression following the intrathecal or epidural administration of midazolam has been demonstrated in both animal and adult human studies.89 The antinociceptive effects are antagonized by flumazenil and possibly also by naloxone, thereby implying that the mechanism of analgesia may involve activation of opioid receptors.88
The intrathecal or epidural administration of midazolam in animal studies has not been associated with any adverse neurological effects. Even after a constant subarachnoid infusion of midazolam 50 µg day1 for 15 days, no signs of spinal cord or meningeal toxicity were found in the rat.86 Only after administration of very large doses of midazolam 0.1% (0.3 ml) intracisternally in rabbits (equivalent to 111 µg kg1) were changes in the bloodbrain barrier observed.65
Clinical studies in adults have shown that epidural midazolam provides significant postoperative analgesia. A dose of 50 µg kg1 appears to be optimum in patients undergoing upper abdominal surgery, higher doses (75100 µg kg1) being associated with prolonged sedation.78
In children undergoing inguinal or urogenital surgery, bupivacaine 0.125% (0.75 ml kg1) combined with midazolam 50 µg kg1 produced a mean duration of analgesia of 21.1 (SD 1.2) h compared with 14.5 (1.6) h for bupivacaine 0.125% (0.75 ml kg1) combined with morphine 50 µg kg1 (P<0.01), and 8.1 (1.3) h for plain bupivacaine (P<0.001).33 Although sedation scores were higher in the bupivacaine/midazolam and bupivacaine/morphine groups than in the bupivacaine group at 812 h after surgery (P<0.01), there were no other significant side-effects. In another study, Naguib and colleagues75 showed that caudal administration of midazolam 50 µg kg1 produced equivalent analgesia to bupivacaine 0.25% (1 ml kg1) in children undergoing unilateral inguinal herniotomy. However, the combination of caudal midazolam 50 µg kg1 and bupivacaine 0.25% (1 ml kg1) significantly increased the duration of analgesia compared with that achieved with either midazolam or bupivacaine alone (P<0.001). Furthermore, only 13.3% of patients in the bupivacaine/midazolam group required analgesia during the first 24 h after surgery, compared with 53.3% of those in the bupivacaine or midazolam groups (P<0.05). The administration of caudal midazolam alone was not associated with prolonged sedation, respiratory depression or motor block. Despite the results of these studies, the caudal administration of midazolam remains controversial.
Tramadol
Tramadol is a synthetic analogue of codeine that is only licensed for use in children over 12 yr old. It is a racemic mixture of two enantiomers: (+)-tramadol and ()-tramadol. The (+)-enantiomer has a moderate affinity for the opioid µ-receptor and also inhibits serotonin uptake, while the ()-enantiomer is a potent norepinephrine inhibitor. These complementary properties result in an opioid with an analgesic potency approximately equal to that of meperidine, but without any respiratory depressant effect.94
The analgesic efficacy of epidural tramadol remains controversial. With regard to its role in paediatric practice, Prosser and colleagues82 compared caudal tramadol 2 mg kg1, bupivacaine 2 mg kg1 and a combination of the two in 90 boys undergoing hypospadias repair. They found that epidural tramadol produced a mean duration of analgesia of 10.7 (SD 2.2) h compared with 10.5 (2.0) h and 9.3 (3.0) h for the combination and plain bupivacaine groups, respectively, without any significant side-effects. The interval between caudal injection and recovery from anaesthesia was <2 h, and the incidence of immediate pain requiring rescue analgesia was high (30%), thereby necessitating its use with bupivacaine to ensure good analgesia during recovery. This is because epidural tramadol has a slow onset of action, because of either slow absorption across the dura or slow uptake from the epidural space into the systemic circulation. A recently published pharmacokinetic study has confirmed that caudally administered tramadol is absorbed systemically, and that it is equally efficacious whether given by this or the parenteral route.73 On this basis, there appears to be no advantage in using caudal epidural tramadol and its use in this way cannot be recommended.
Summary
Caudal analgesia remains the most popular and commonly used regional block in paediatric anaesthesia. Bupivacaine is the most widely used local anaesthetic for this technique and provides postoperative analgesia lasting 48 h. More recently, ropivacaine has been shown to be suitable for caudal anaesthesia in children. Its duration of action is similar to that of bupivacaine (in equivalent doses), but the motor block is slower in onset, less intense and shorter in duration for a given level of sensory block. Furthermore, ropivacaine appears to cause less cardiac and CNS toxicity than bupivacaine. Levobupivacaine is a new aminoamide local anaesthetic with a similar duration of action to bupivacaine, but with less potential for cardiotoxicity. These newer agents need to be studied further but seem promising prospects, particularly when extending the use of caudal analgesia into day-case surgery.
It is clear that the extended duration of analgesia that can be achieved by using caudal additives is significant. What is not so clear is whether the perceived benefits justify the potential risks, and which is the ideal agent. Epinephrine prolongs the analgesic effects of lidocaine, but seems to have little effect on bupivacaine. The addition of opioids significantly prolongs the duration of caudal analgesia but carries with it a number of unpleasant side-effects, as well as the risk of late respiratory depression.
The use of caudal opioids seems to have been superseded by clonidine and ketamine. Clonidine 12 µg kg1 and ketamine 0.5 mg kg1 offer the potential to significantly prolong the duration of single-shot caudal injections with minimal risk of side-effects. The addition of clonidine 1 µg kg1 to plain bupivacaine 0.25% can extend the duration of postoperative analgesia by 4 h, with mild sedation as the only side-effect. A combination of ketamine 0.5 mg kg1 and bupivacaine is even more effective, providing analgesia for up to 12 h. At this dose, behavioural problems do not appear to be significant. However, further study and the introduction of ketamine into mainstream clinical practice is limited by the difficulties in obtaining preservative-free ketamine and ongoing concerns about potential neurotoxicity. The use of caudal additives for day-care anaesthesia is controversial and at present their routine use cannot be recommended.
It has become something of a holy grail in recent years to achieve longer and longer duration of analgesia from a single caudal injection. Perhaps it is time to reappraise what we hope to achieve by this, and whether the same or similar clinical effects can be achieved by the use of standard single-agent caudals in combination with regular systemic analgesics. However, in the absence of new longer acting local anaesthetic drugs, and until such time as alternative methods of prolonging caudal analgesia are validated, the use of caudal additives is likely to continue. The use of the caudal route has a long and impressive track record but, like any old friendship, it is important that we nurture and foster it appropriately. Rather than continually testing its limits, perhaps it is time to re-explore its strengths.
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