British Journal of Anaesthesia 100 (5): 7016 (2008)

doi:10.1093/bja/aen048

Advance Access publication March 15, 2008

REGIONAL ANAESTHESIA Analgesic effectiveness of caudal levobupivacaine and ketamine

B. G. Locatelli1, G. Frawley2*, A. Spotti1, P. Ingelmo3 4, S. Kaplanian2, B. Rossi1, L. Monia1 and V. Sonzogni1
1

Department of Anaesthesia and Intensive Care, Ospedali Riuniti di Bergamo, Bergamo, Italy. 2Department of Paediatric Anaesthesia and Pain Management, Royal Childrens Hospital, Melbourne, Australia. 3 Department of Anaesthesia and Intensive Care, A.O San Gerardo, Monz, Italy. 4Dipartimento di medicina ` sperimentale ambientale e biotecnologie mediche, Universita degli Studi Milano Bicocca, Milan, Italy
*Corresponding author. E-mail: geoff.frawley@rch.org.au
Background. Ketamine is used increasingly in paediatric anaesthetic practice to prolong the action of a caudal block. This study was designed to determine if adding S()-ketamine 0.5 mg kg21 allows a lower concentration of levobupivacaine to be used for caudal anaesthesia without loss of clinical effectiveness. Methods. One hundred and sixty-four children (ASA I or II) aged 3 months 6 yr were randomly allocated to receive 1 ml kg21 of levobupivacaine 0.15% with 0.5 mg kg21 S()-ketamine (Group 1), levobupivacaine 0.175% with 0.5 mg kg21 S()-ketamine (Group 2), or levobupivacaine 0.2% (Group 3) by the caudal route. Pain, motor block, sedation, and requirement for postoperative analgesia were assessed up to 6 h after operation. Results. There was no signicant difference between the groups in effectiveness at rst surgical incision. Signicantly lower analgesic requirements were reported in Group 2 compared with Group 3 at wakeup, 180 and 360 min after operation. Time to rst rescue analgesia was longer in Group 2 compared with Group 1 or 3. Kaplan Meier survival analysis of analgesia free time demonstrated a signicant advantage of Group 2 over Groups 1 and 3 (log rank P0.05). The incidence of postoperative motor block was not signicantly different between the groups. No excess sedation or dysphoric reactions were observed in the ketamine groups. Conclusions. The addition of 0.5 mg kg21 S()-ketamine to levobupivacaine 0.175% for caudal analgesia for lower abdominal and urological surgery is signicantly more effective in providing postoperative analgesia than levobupivacaine 0.15% with 0.5 mg kg21 S()-ketamine or levobupivacaine 0.2%. Br J Anaesth 2008; 100: 7016 Keywords: anaesthetic techniques, regional, caudal; anaesthetics local, steriosomers; anaesthetics, pharmacology, ketamine; analgesia, postoperative Accepted for publication: January 28, 2008
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A survey of paediatric anaesthetists in 2002 reported that more than 50% of anaesthetists used an adjuvant drug when performing caudal analgesia with the most commonly used being ketamine, clonidine, fentanyl, and diamorphine.1 Ketamine has been shown to have a synergistic effect with caudal local anaesthetics.2 Ketamine local anaesthetics combinations have been demonstrated to speed the onset of analgesia, prolong the duration of caudal analgesia, and reduce the incidence of ineffective analgesia.3 5 Epidural ketamine has allowed lower concentrations of bupivacaine and ropivacaine to be used and as

a result, the incidence of postoperative motor block has been lower.3 S()-ketamine 0.5 mg kg21 added to 0.20 0.25% of bupivacaine or ropivacaine for caudal anaesthesia is highly effective in improving the quality and duration of the analgesia in children.4 5 Levobupivacaine has been demonstrated to be an extremely effective agent for caudal analgesia,6 8 but its use in combination with ketamine has not previously been reported. We conducted this doubleblind randomized controlled trial to determine if ketamine added to lower concentrations of levobupivacaine is as

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effective as levobupivacaine 0.2% alone for caudal anaesthesia in children.

Methods
After approval from the Hospital Research Ethics Committee, informed written consent was obtained from the parents of 180 children. Patients undergoing elective lower abdominal or urological procedures of anticipated duration ,120 min who were between 3 months and 6 yr of age, with ASA score I III, and weighing ,20 kg were enrolled.

Anaesthetic technique
All children were fasted and received oral or rectal premedication with midazolam 0.5 mg kg21 30 45 min before surgery. I.V. anaesthesia was induced with propofol 2 4 mg kg21 and maintained by sevourane at ,1 MAC (age adjusted) in 50% oxygen air mixture administered by laryngeal mask airway or endotracheal tube without neuromuscular blocking agents. Ventilation was not controlled until after the rst skin incision and assessment of ventilatory response to the stimuli had been made. Ventilation was then controlled or assisted in order to obtain an end0 tidal carbon dioxide (ECO2) 45 mm Hg. After induction of anaesthesia, patients were placed in the lateral decubitus position and a consultant anaesthetist performed a caudal block using a 22 G i.v. cannula. The children were randomized in double-blind fashion into three separate groups. The rst group received 1 ml kg21 of levobupivacaine 0.15% (Chirocainaw, Abbott, Latina, Italy) and preservative-free S()-ketamine 0.05% (Ketanest Sw, Pzer, Germany). The second group received 1 ml kg21 of levobupivacaine 0.175% (1.75 mg kg21) and ketamine 0.05% (0.5 mg kg21). The third group received 1 ml kg21 of levobupivacaine 0.2% (2 mg kg21) without ketamine. The randomization sequence was computer generated and the drugs were prepared in a double-blinded manner. Non-invasive blood pressure (BP), heart rate (HR), respiratory rate (RR), oxygen saturation, and end-tidal CO2 were monitored continuously. Three minutes after local anaesthetic injection, a mechanical stimulus was applied at the surgical dermatome or at the immediate superior dermatome with a modied Allis clamp (m 30 132 15, Martinw; Tuttlingen, Germany) for the evaluation of block onset.9 Patients were stimulated every 3 min after the caudal block until block effectiveness or a maximum of 15 min after caudal injection (ve stimuli). Any related movement or signicant change in the HR or RR resulted in the discontinuation of the stimulus. Analgesic onset time was dened as the time in minutes between local anaesthetic injection and the absence of gross movement or signicant (.20%) change in HR, BP, or RR on application of the clamp. A physiological response or movement at 15 min was considered as prolonged local

anaesthetic onset. Data from patients who responded with movements or physiological changes to the fth stimulus but did not respond to rst surgical stimulus were assigned an onset time equivalent to the time between caudal block and surgical incision. Caudal block efcacy during surgery was dened as the absence of gross movements or signicant (.20%) change in BP, HR, or RR associated with surgical stimulation. In the event of gross movements or signicant physiological changes after incision or during surgery, children were treated with an i.v. bolus of fentanyl 2 mg kg21. The primary endpoint of the study was the quality of postoperative pain control. This was dened by the number of children requiring rescue analgesia because of a Children and Infants Postoperative Pain Scale (CHIPPS) Scale 4 during the rst 6 h after caudal block. Postoperative pain was evaluated using the CHIPPS10 (Table 1). In cases where the CHIPPS scale was four points, children received either rectal codeine 0.5 1 mg kg21 plus acetaminophen 10 15 mg kg21, i.v. morphine 0.05 0.1 mg kg21, or i.v. ketorolac 1 mg kg21. In the postoperative recovery ward, pain intensity, emergence agitation, and Aldrete scores were recorded every 10 min until an Aldrete score of 8 was achieved.11 The postoperative behaviour of the children was evaluated using a fourpoint scale. These were: (1) calm child: does not need any kind of intervention; (2) consolable child: requires only physical contact with the parents; (3) agitated child: a screaming and crying child; and (4) aggressive child: must be physically restrained in order to avoid harming himself. We dened postoperative agitation as a score of three or four points.12 We did not perform structured neurobehavioural testing and documentation of odd behaviour on awakening was recorded on an observational basis. The incidence of residual motor blockade was considered a secondary outcome measure and was evaluated using a modied Bromage scale. A score of 0 was
Table 1 Children and Infants Postoperative Pain Scale. In the postoperative period, scores between 0 and 3 indicate mild or no pain, scores 4 and above indicate analgesic requirements with increasing urgency as scores increase Item Crying Structure None Moaning Screaming Relaxed/smiling Wry mouth Grimace (mouth and eyes) Neutral Variable Rear up Neutral, relaxed Kicking about Tightened legs None Moderate Restless Points 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2

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Facial expression

Posture of the trunk

Posture of the legs

Motor restlessness

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assigned if no motor block was present. A score of 1 indicated an inability to stand unassisted, 2 indicated ability to ex the ankle but not the knee, and 3 indicated complete motor block in a fully awake child. Signicant residual motor blockade was dened as a motor block score equal to or greater than 1 point after awakening and 180 min after the last dose of local anaesthetic. In the event of an asymmetric block, the highest numerical value was recorded. An anaesthetist not primarily responsible for the conduct of the anaesthetic carried out preoperative evaluation and data collection. This anaesthetist obtained informed consent, conrmed validity of the inclusion criteria, and allocated the patients using computer-generated random number sequence to the study groups. In the event of an emergency related or possibly related to the study or study drugs, the pharmacist was authorized to disclose the contents of the syringe to the consultant anaesthetist. The study blinding was broken before statistical analysis.

Results
One hundred and eighty children were included in the study, 164 were analysed as per protocol and 16 children were excluded. Fourteen patients did not receive the drug under study (seven in Group 2, four in Group 1, and three in Group 3). One child in Group 3 underwent local and peripheral block because of technical difculties with the epidural block. One patient in Group 2 was lost to follow-up. The clinical characteristics of the children are shown in Table 2. There were no signicant differences in age, weight, gender, type of surgery, surgery time, end-tidal sevourane concentration during surgery, time to awakening, or postoperative agitation. Analgesic onset time measured with a mechanical stimulus was not signicantly different between the three groups. Median analgesic onset was 6 (IQR 6 9) min in Groups 1 and 2, and 9 (IQR 6 9) min in Group 3. Analgesic onset exceeding 15 min (manifesting as movements or physiological changes to the fth mechanical stimulus) was present in seven children in Group 2 compared with two children in each of the other groups (x2 P0.06). There were no signicant haemodynamic changes after caudal boluses and during surgery for any agent. There were no signicant differences between the groups in the proportion of children with effective epidural block at the rst surgical incision (x2 P0.13). Adequate analgesia on rst incision was demonstrated in 56 patients (95% CI 85 99%) in Groups 1 and 3 and 50 children (95% CI 87 99%) in Group 2. Two children (95% CI 0 13) in Group 2 received an extra dose of i.v. fentanyl after incision (x2 P0.73). CHIPPS scores at wakeup were signicantly different between Group 2 and Group 3 at wakeup (Wilcoxon rank sum P0.05) but at no other time up to 360 min (Fig. 1). There were no signicant differences between Group 1 and Group 3 (P0.38) or Group 1 and Group 2 (P0.44) at any time. The contribution of sedation induced by systemic absorption of caudal ketamine to lower CHIPPS

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Statistical analysis
The initial sample size estimation was performed based on a number of assumptions from prior studies of caudal anaesthesia in children. Assuming an incidence pain after surgery of 0.5, a two-sided type I error of 0.05, a power of 0.80, and an effect size of 0.50, more than 55 in each group were required to nd a signicant difference in the number of children requiring rescue analgesia in the rst hours after surgery. Quantitative data are presented as mean, standard deviation or range, and qualitative data as frequency and 95% condence interval (95% CI). ANOVA or Kruskal Wallis test was used for analysis of differences in age, weight, analgesic onset time, surgical time; wakeup time, and postoperative analgesic time. Type of surgery, ASA physical status, sex, block effectiveness during operation, residual motor blockade, postoperative agitation, and number of patients requiring analgesics after operation were analysed with x2 or Fishers exact test. Pain and sedation scores (at various times) and frequency of rescue analgesia were compared using Mann Whitney U-tests. Signicance was dened as P0.05. All statistical comparisons were accomplished with Epi Info, version 2005 [EpiInfo 3.2.2, Center for Disease Control and Prevention (CDC), Atlanta, GA, USA]. The incidence and time to rst rescue analgesia were analysed using Kaplan Meier survival analysis with comparison between the groups using the log-rank test. Survival data were dened as time from caudal anaesthesia to the requirement of rst rescue analgesia. Patients who did not require rescue analgesia during the 6 h of observation were considered censored. The Mantel-Cox (log-rank) test was used to perform intergroup comparisons.

Table 2 Patients clinical characteristics. Data are mean (range), mean (SD), or number of children for sex and type of surgery Levobupivacaine Levobupivacaine Levobupivacaine 0.15%1Ketamine 0.175%1Ketamine 0.20% (n556) (n556) (n552) Age (yr) Weight (kg) Sex (F/M) Inguinal hernia Orchidopexy Hypospadias Surgery time (min) Wakeup time (min) 3 (0.25 5.7) 14 (3) 4/52 32 16 8 37 (23) 21 (10) 3 (0.8 5.0) 13 (2) 6/46 30 14 8 36 (20) 20 (10) 3 (0.5 4.6) 13 (3) 9/47 31 17 8 33 (21) 18 (8)

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Fig 1 Incidence of postoperative pain and distress with caudal solutions of levobupivacaine and ketamine. CHIPPS score of 3 described mild or no pain, 4 6 moderate, and 7 severe pain. A CHIPPS score of 4 at wakeup or up to 360 min after caudal block was treated with supplemental analgesia.

Fig 2 Results of Kaplan Meier survival analysis are displayed as survival curves for the three caudal solutions. Mantel-Cox (log-rank) test was used to compare the rate of requirement for additional analgesia in the study with the rate of expected requirements for additional analgesia if all groups had received equally effective caudal analgesia. Group 1 (0.15% levobupivacaine with 0.5 mg kg21 ketamine) was signicantly different (P0.05) to Group 2 (0.175% levobupivacaine with 0.5 mg kg21 ketamine) but not Group 3 (0.2% levobupivacaine) (P0.27). There was no signicant difference between Group 2 and Group 3 (P0.15).

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scores could not be determined, but sedation was not a feature in either of the caudal ketamine groups. Wakeup times were not signicantly different between the groups (21 min Group 1, 20 min Group 2, and 18 min Group 3). Hallucinations, nightmares, odd behaviour or unexplained distress, excessive agitation, or restlessness was not reported in any child. Ninety children (95% CI 47 63%) received rescue analgesia after surgery. In children with a CHIPPS score 4, the median time (inter-quartile range) to rst analgesic requirement was 145.5 (90 235) min for Group 1, 167.5 (87 214) min for Group 2, and 94.5 (68 180) min for Group 3. There was no difference in median analgesic times between Group 1 and Group 2 (Kruskal Wallis P0.66), Group 1 and Group 3 (Kruskal Wallis P0.12) nor Groups 2 and 3 (Kruskal Wallis P0.08). Twenty-two children in Group 2 received analgesia because of CHIPPS4 points compared with 38 children in Group 1 and 30 patients in Group 3 (P0.03 for x2). Differences in analgesic requirements were signicant at wakeup (x2 P0.05), 180 min (x2 P0.04), and 360 (x2 P0.03) min after caudal block. Mantel-Cox (log-rank) analysis (Fig. 2) to compare the rate of requirement for postoperative analgesia demonstrated that Group 1 (levoketamine 0.15%) was signicantly different (P0.05) to Group 2 (levoketamine 0.175%) but not Group 3 (levo 0.2%) (P0.24). There was no signicant difference between Group 2 and Group 3 (P0.15). No additional analgesia in the 6 h postoperative observation period was

demonstrated in 32% of patients in Group 1, 57% of Group 2, and 46% of Group 3. The incidence of residual motor block on awakening was not statistically different between the groups (Fig. 3) on awakening (x2 P0.8) or 3 h after caudal block injection (x2 P0.6). Postoperative nausea and vomiting (PONV) occurred in ve patients, one each in Groups 2 and 3 and three in Group 1. Postoperative agitation was present in 10 patients in Group 1, 11 in Group 2, and 14 in Group 3.

Discussion
The key nding of this study is that the addition of 0.5 mg kg21 of preservative-free S()-ketamine to caudal levobupivacaine 0.175% signicantly decreases the need for rescue analgesia in the immediate postoperative period. When S()-ketamine 0.5 mg kg21 is added to 0.15% caudal levobupivacaine, the quality of postoperative analgesia is equivalent to that produced with caudal 0.2% levobupivacaine alone. This is consistent with previous reports of caudal ketamine in association with bupivacaine and ropivacaine for intra- and postoperative analgesia.13 14 Ketamine local anaesthetics combinations have been shown to speed the onset of analgesia, prolong the duration of caudal analgesia, and reduce the incidence of ineffective analgesia compared with local anaesthetics alone.4 5 Most studies use the duration of postoperative analgesia or the time to rst analgesic request to determine the effect of ketamine on local anaesthetic effectiveness. When racemic ketamine 0.25 mg kg21 is added to bupivacaine or ropivacaine for caudal anaesthesia, the duration of postoperative

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Fig 3 Incidence of residual motor block with caudal solutions of levobupivacaine or ketamine levobupivacaine. Residual motor block is dened as Bromage score of greater than one at wakeup or up to 180 min after caudal block.

analgesia is 8 12 h. Increasing the dose to racemic ketamine 0.5 mg kg21 does not substantially increase the duration of analgesia or reduce the proportion of patients requiring postoperative analgesia. Using S()-ketamine 0.5 mg kg21 with bupivacaine or ropivacaine appears to not confer any advantages over the racemic local anaesthetic mixtures, despite a four-fold increase in potency. Because our patients were observed for only 6 h after surgery, no rm conclusions on the exact duration of action of caudally administered S()-ketamine can be made and no direct comparison with ropivacaine or bupivacaine solutions is possible. Despite this restriction, 57% of patients in the 0.175% of levobupivacaine ketamine group did not require analgesia up to 6 h after operation. This is consistent with other studies reporting the proportion of patients requiring postoperative analgesia. The optimum dose of ketamine to add a local anaesthetic or other analgesic for neuraxial anaesthesia to improve or prolong postoperative analgesia, however, has not been determined. As there is an unacceptable incidence of behavioural side-effects with 1 mg kg21, our study used 0.5 mg kg21.15 When racemic ketamine 0.25 mg kg21 is combined with bupivacaine 0.25% only 7% of the ketamine/bupivacaine group required any analgesia in the 24 h post-surgery compared with 20% of ketamine only caudals and 50% of bupivacaine only caudals.16 The addition of ketamine 0.5 mg kg21 to bupivacaine 0.25% produces a longer median duration of analgesia after orchidopexy than either clonidine 2 mg ml21 or adrenaline 5 mg ml21.17 Similarly, racemic ketamine 0.25 mg kg21 with caudal ropivacaine 0.2% increases the median duration of analgesia from 3 to 12 h.18

The anaesthetic potency of S()-ketamine is twice that of the racemic mixture due to a three-fold greater afnity for the N-methyl-D-aspartate (NMDA) receptor. This difference in afnity for the NMDA receptor does not appear to translate into differences in clinical effectiveness. The difference in afnity does not translate into a halving of the dose required to provide analgesia. Studies where racemic ketamine 0.25 mg ml21 is added to solutions of bupivacaine or ropivacaine for caudal anaesthesia produce the same duration of analgesia as studies using S()-ketamine 0.5 mg ml21, despite a four-fold potency difference. One conclusion is that there is a ceiling effect on the concentration of ketamine and another is that the concentration of local anaesthetic is much more critical to the effect than the ketamine dose. Other advantages of S()-ketamine include fewer psychomotor side-effects, less salivation, and shorter recovery time compared with the racemic mixture. A number of studies have examined the effect of a combination of caudal S()-ketamine and local anaesthetics on perioperative analgesia.19 21 Marhofer and colleagues19 reported that caudal S()-ketamine 1 mg kg21 provided equipotent intra- and postoperative analgesia compared with 0.75 ml kg21 of bupivacaine 0.25% with 1:200 000 adrenaline but 0.5 mg kg21 provided sufcient analgesia only during the intraoperative period. De Negri and colleagues5 found that the addition of S()-ketamine 0.5 mg kg21 to ropivacaine 0.2% for lower abdominal surgery resulted in an improvement in postoperative analgesia compared with ropivacaine alone. Using neuraxial analgesics other than local anaesthetics may confer distinct advantages such as avoiding motor blockade and the serious complications associated with inadvertent intravascular injection of the local anaesthetic solution. Inadvertent intravascular injection of ketamine will not result in signicant complications, as the caudal dose is lower than the i.v. dose. Ketamine, however, has a relatively short duration of action when used alone. A combination of caudal ketamine and clonidine22 23 or tramadol is effective but associated with unacceptable sedation or signicant PONV.24 25 In our study, caudal ketamine 0.5 mg kg21 did not increase the incidence of emergence agitation, PONV, or residual motor blockade. Side-effects of ketamine such as delirium, hallucinations, or nightmares can occur with caudal ketamine at doses of 0.5 1 mg kg21 16 but have not been reported at doses of 0.25 mg kg21.18 26 Toxic reactions after prolonged neuraxial exposure to racemic ketamine formulations with preservatives (benzethonium chloride or chlorbutanol) have been reported in animal species.27 28 Spinal neurotoxicity after continuous intrathecal racemic ketamine infused over 3 weeks for terminal cancer-related pain has been reported.29 Controversy exists about the riskbenet ratio of neuraxial ketamine. As a result, only preservative-free S()-ketamine should be used for neuraxial anaesthesia. The risk of spinal toxicity, however, is greatest in prolonged subdural administration

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for cancer pain. Physiological NMDA receptor activity is necessary for cell survival and cerebral function and prolonged NMDA receptor blockade by ketamine results in apoptosis of central neurons of immature rat brain.30 As yet, no permanent neurological injury has resulted from singleshot caudal ketamine use but caution is warranted. In conclusion, the addition of 0.5 mg kg21 of S()-ketamine to caudal levobupivacaine 0.175% signicantly decreases the need for rescue analgesia in children undergoing abdominal and urological surgery compared with levobupivacaine 0.2%. The effect of ketamine added to levobupivacaine 0.15% is as effective as levobupivacaine 0.2% alone. Preservative-free S()-ketamine may be used by the caudal route as a local anaesthetic sparing agent allowing lower concentrations of levobupivacaine to be used. To determine if the effect of ketamine is synergistic or purely additive would require isobolographic analysis.

Acknowledgements
The authors wish to thank the nursing and surgical staff of the Paediatric Surgery Service of the Ospedali Riuniti di Bergamo; Mrs Daniela Lodetti for protocol supervision and Mr Andrea Paravisi for logistical support.

References
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