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PEDIATRIC ANESTHESIA

Caudal Clonidine Prolongs Analgesia from Caudal S(+)-Ketamine in Children

Department of Anesthesia and Intensive Care Medicine, University of Vienna, Austria

Address correspondence and reprint requests to Peter Marhofer, MD, Department of Anesthesia and Intensive Care Medicine, University of Vienna, School of Medicine, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Address e-mail to peter.marhofer{at}univie.ac.at

	Abstract

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We performed a prospective randomized double-blinded study to test preservative-free S(+)-ketamine alone or in combination with clonidine for intra- and postoperative caudal blockade in pediatric surgery over a 24-h period. Fifty-three children (1–72 mo) scheduled for inguinal hernia repair were caudally injected with either S(+)-ketamine 1 mg/kg alone (Group K) or with additional clonidine (Group C1 = 1 µg/kg; Group C2 = 2 µg/kg) during sevoflurane anesthesia via a laryngeal mask. Intraoperative monitoring included heart rate, blood pressure, and pulse oximetry; postoperative monitoring included a pain discomfort scale and a sedation score. No additional analgesic drugs were required during surgery. The mean duration of postoperative analgesia was 13.3 ± 9.2 h in Group K, 22.7 ± 3.5 h in Group C1, and 21.8 ± 5.2 h in Group C2 (P < 0.0001, Group K versus other groups). Groups C1 and C2 received significantly fewer analgesics in the postoperative period than Group K (15% and 18% vs 63%; P < 0.01). The three groups had similar postoperative sedation scores. We conclude that the combination of S(+)-ketamine 1 mg/kg with clonidine 1 or 2 µg/kg for caudal blockade in children provides excellent analgesia without side effects over a 24-h period.

IMPLICATIONS: Caudally administered preservative-free S(+)-ketamine combined with 1 or 2 µg/kg clonidine provides excellent perioperative analgesia in children and has minimal side effects.

	Introduction

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Caudal blockade is a standard anesthetic technique to achieve an adequate level of perioperative analgesia in all subxiphoidal pediatric procedures (1). Our group previously demonstrated an equipotent analgesic effect of preservative-free S(+)-ketamine 1 mg/kg compared with bupivacaine 0.25% plus epinephrine 1:200,000 for caudal blockade in children over 360 min (2). We also demonstrated that the site of action seems to be a local one, at the level of the spinal cord (3). The analgesic effects of S(+)-ketamine are thought to be the result of N-methyl-D-aspartate (NMDA) receptor antagonism, opioid µ-receptor agonism, and voltage-sensitive sodium channel interactions (4–8).

The potential advantage of S(+)-ketamine over standard local anesthetics for caudal blockade is that inadvertent intravascular administration will not cause severe cardiovascular or central nervous system complications (1,9–12). This advantage may be important if intravascular injection cannot even be reliably detected by an epidural test dose containing epinephrine (13).

A large number of additives to analgetic substances have been investigated to extend the duration of caudal blockade in children. Clonidine is an ₂-receptor agonist known to prolong postoperative pain relief and to reduce the need for additional pain treatment in children (14,15) without significant hemodynamic or respiratory effects (16,17). The analgesic action of epidurally administered clonidine is due to stimulation of descending noradrenergic medullospinal pathways inhibiting the release of nociceptive neurotransmitters in the dorsal horn of the spinal cord (18). Nishiyama et al. (19) investigated neuroaxial NMDA receptor antagonists in combination with clonidine by isobolographic analysis and demonstrated a synergistic effect of AP-5, an experimental NMDA receptor antagonist, and clonidine in Sprague-Dawley rats. We therefore hypothesized that the duration of caudal blockade by S(+)-ketamine would be extended in combination with clonidine.

	Methods

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After we obtained approval from the local ethics committee and informed parental consent, 53 patients (ASA physical status I–II, age 1–72 mo) scheduled for inguinal hernia repair were randomly allocated to three study groups. The random assignments were prepared outside the study center and delivered in sealed, opaque, sequentially numbered envelopes. According to the randomization, patients were caudally administered preservative-free S(+)-ketamine 1 mg/kg (KetanestS^TM; Gödecke AG, Berlin, Germany) (16 children), or they were additionally injected with clonidine 1 µg/kg (20 children) or 2 µg/kg (17 children) (Catapresan^TM; Boehringer Ingelheim Pharma AG, Ingelheim, Germany). These groups will be referred to as Groups K, C1, and C2, respectively. Drugs were diluted in 0.9% saline (0.75 mL/kg) and prepared by a staff anesthesiologist not otherwise involved in the study.

All children received 0.75 mg/kg rectal midazolam 20 min before anesthetic induction. General anesthesia was induced by administering sevoflurane via a face mask. After insertion of an IV access, the administration of glucose/saline solution 10 mL/kg, and maintenance of anesthesia with sevoflurane at 1 minimum alveolar anesthetic concentration and 70% nitrous oxide in oxygen via laryngeal mask, the caudal block was performed under aseptic conditions with a 22-gauge Quincke needle in a left lateral position. Immediately after the anesthetic was injected, the children were turned to a supine position.

Heart rate (HR), pulse oximetry (SpO₂), and systolic and diastolic blood pressure (BP) were obtained after the induction of general anesthesia, after caudal injection, and every 5 min thereafter, intraoperatively. In addition, end-tidal carbon dioxide concentration was monitored. The interval between caudal injection and skin incision was 15 min.

An intraoperative decrease in BP or HR of more than 30% from preoperative values was defined as hypotension or bradycardia, respectively, and was treated with rapid infusion of fluids or with atropine 0.01 mg/kg. Respiratory depression was defined as a decrease in SpO₂ to <93% requiring supplementary oxygen. An intraoperative increase in BP or HR by >10% was defined as insufficient analgesia and was treated with nalbuphine 0.2 mg/kg. At the beginning of skin closure, sevoflurane and nitrous oxide were discontinued. When the children were sufficiently awake, they were taken to the recovery room after the laryngeal mask was removed.

The efficacy of postoperative analgesia was documented by an observational pain/discomfort scale (OPS), by a sedation score, and by the duration of analgesia after caudal blockade. The OPS was based on objective behavioral variables (crying, facial expression, position of the torso, position of legs, motor restlessness) (20) that were assessed with three grades (1 = none; 2 = moderate; 3 = severe) to give a cumulative score of 5–15. If two consecutive assessments yielded an OPS score of >11, the child received rectal paracetamol 30 mg/kg. In that case, only the data collected before the administration of paracetamol entered the statistical analysis. The sedation score (1 = asleep and not arousable by verbal contact; 2 = asleep but arousable by verbal contact; 3 = awake and drowsy; 4 = awake and alert) was used both to quantify sedation and to help identify possible systemic effects of clonidine. A sedation score of 3 was defined as full recovery from narcosis. In addition, the first spontaneous voiding was recorded.

Six hours after caudal injection, the patients were discharged from the recovery room to the ward, where they were monitored for another 18 h. SpO₂, OPS, and sedation scores in the recovery room were recorded by an experienced nurse in 15-min intervals until 150 min after caudal injection and subsequently in 30-min intervals until the child was discharged to the ward. Once in the ward, only the OPS scores were documented (i.e., 420, 480, 540, 600, 900, 1200, and 1440 min after caudal injection).

All values are expressed as means ± SD. Data analysis was performed by factorial analysis of variance (ANOVA) with a Bonferroni-Dunn post hoc comparison to detect differences in demographics, time for surgery, voiding, time to reach a sedation score of 3, and duration of analgesia. ANOVA for repeated measurements was used to determine intergroup and intragroup differences in hemodynamics (StatView 4.51; Abacus Concepts, Berkley, CA). Results were considered to be statistically significant at P < 0.05. After data collection, power analysis was performed for the duration of the block by use of a commercially available program (Primer of Biostatistics 3.01; McGraw-Hill, San Francisco, CA).

	Results

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There were no significant differences among the three study groups with respect to age (mean, 26 ± 24 mo), weight (mean, 12 ± 6 kg), or duration of surgery (mean, 31 ± 16 min). Caudal administration of S(+)-ketamine 1 mg/kg in combination with clonidine either 1 or 2 µg/kg induced a longer duration of analgesia (P < 0.0001) compared with the administration of plain S(+)-ketamine 1 mg/kg (Table 1). None of the children required additional analgesics in the intraoperative period. However, within the 24-h postoperative study period, 16% of children in the C1 and C2 groups required additional analgesics, whereas 63% of the children in Group K required additional analgesics (data for each study group are presented in Table 1). We cannot, however, report the exact duration of analgesia in the various groups, because the observation period was confined to 24 h.

Time to first spontaneous voiding after caudal injection was equal in all study groups (Table 1). The times to a sedation score of 3 for Groups K, C1, and C2 were 164 ± 79 min, 179 ± 101 min, and 199 ± 130 min, respectively. These differences were not statistically significant (P = 0.64). In addition, we observed no adverse central nervous system effects.

	Discussion

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The most important finding of our study was that caudal blocks with preservative-free S(+)-ketamine 1 mg/kg in combination with clonidine either 1 or 2 µg/kg showed equally effective perioperative analgesic qualities compared with plain S(+)-ketamine. Thus, the combination of S(+)-ketamine with clonidine is a safe and effective alternative to common local anesthetics for caudal blocks in pediatric anesthesia.

Our experience with clonidine/S(+)-ketamine for caudal blockade in pediatric patients is consistent with the results obtained by Klimscha et al. (15) with clonidine/bupivacaine. On the basis of a six-hour observation period, those authors reported a significantly longer duration of analgesia with bupivacaine 0.25% combined with either clonidine 1 µg/kg (median, 360 minutes) or clonidine 2 µg/kg (360 minutes) than by bupivacaine with or without epinephrine 1:200,000 (300 or 346 minutes, respectively). Also, the clonidine groups in that study required significantly less supplementary analgesia within the first 24 hours (25% and 8% of cases for bupivacaine 0.25% plus clonidine 1 or 2 µg/kg, respectively, versus 66% for bupivacaine 0.25% with or without epinephrine 1:200,000). A placebo group in the study by Klimscha et al. showed a duration of analgesia of only 77 minutes (range, 45–190 minutes).

Koinig et al. (21), who used ropivacaine for caudal blockade, reported that 52% of children maintained a sufficient level of analgesia for 24 hours when a concentration of 0.5% was used, albeit at the cost of 362 ± 42 minutes of motor blockade. Reducing the dose to 0.25% decreased the duration of motor blockade to 248 ± 30 minutes, but, as a tradeoff, all of these children needed supplementary analgesics within 24 hours of caudal injection.

Ivani et al. (22) reported that the duration of analgesia offered by plain ropivacaine 0.2% could be extended by using ropivacaine 0.1% plus clonidine 2 µg/kg. Supplementary analgesics were required in only 10% of those children, compared with 45% of the former, which is a surprisingly small percentage to start with, when compared with the 100% reported by Koinig et al. (3) for ropivacaine 0.25%. One reason for these low rates of supplemental analgesia might be in the different indications for supplemental postoperative analgesia used by Ivani et al. (22) compared with other studies, including this one. Nevertheless, the data reported by that group for small-dose ropivacaine do suggest that by the addition of clonidine it might be possible to reduce the concentrations of caudally injected local anesthetics and still achieve sufficient levels of postoperative analgesia. Although we did not investigate varying doses of S(+)-ketamine combined with clonidine, one might speculate that clonidine combined with <1 mg/kg S(+)-ketamine could also have yielded sufficient postoperative levels of analgesia.

Although our study design did not include a motor score, all children were spontaneously moving their legs throughout the postoperative period. The sedation scores obtained in our three study groups were virtually identical, indicating that the caudally administered clonidine did not result in additional sedation. Caudal blocks with bupivacaine or bupivacaine/clonidine carry the risk of hypotension (15). Hypotension was not a problem in any of our study patients.

In conclusion, caudally administered S(+)-ketamine combined with 1 or 2 µg/kg clonidine provides excellent perioperative analgesia with minimal side effects.

	Acknowledgments

 
The authors thank Mag. Renate Schwarz of Pfizer Med. Inform Austria for providing patients’ medical insurance.

	Footnotes

 
Presented in part at the Fifth European Congress of Paediatric Anaesthesia, Helsinki, Finland, May 27–30, 2001.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999