Karolinska Institute, Stockholm, Sweden

This is an excerpt from the publication: Suresh S, Ecoffey C, Bosenberg A, Lonnqvist PA, de Oliveira GS Jr, de Leon Casasola O, de Andrés J, Ivani G. The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine Recommendations on Local Anesthetics and Adjuvants Dosage in Pediatric Regional Anesthesia. Reg Anesth Pain Med. 2018 Feb;43(2):211–216. doi: 10.1097/AAP.0000000000000702. PMID: 29319604.

Adjuvants in Pediatric regional Anesthesia

Per-Arne Lönnqvist

Initial word of caution/Disclaimer With the exception of clonidine and preservative free morphine none of the other adjuvant agents mentioned in this practice advisory guideline are registered for spinal/epidural administration. None of the agents are registered for injection close to peripheral nerve structures. Thus, the decision to use the drugs mentioned below as adjuvants to pediatric regional anesthesia will be governed by the individual practitioner´s decision, departmental policy and the existing medicolegal situation.

Rational for using adjuvants

Even long-acting local anesthetics (racemic bupivacaine, levo-bupivacaine and ropivacaine) have a limited duration of action (typically 4–12 h of duration) balanced against the time period of more intense postoperative pain associated with moderate or major surgery (24–72 h). Prolongation of the block effect in order to better match pain duration can be accomplished by the use of catheter techniques that will allow repeated bolus administration or continuous infusion of local anesthetics.¹ However, the majority of pediatric surgical interventions do not merit the use of these more complicated and resource demanding options for postoperative analgesia. Thus, a popular alternative to achieve prolongation of a single injection nerve block is to use adjuvant drugs that are mixed with the local anesthetics and thereby increase the duration of the nerve block.^2,3

Some of the advantages associated with the use of adjuvants drugs:

a. Will increase block duration in such a way that it may be possible to perform the surgical procedure before the block starts to wear off (e.g. neonatal spinal anesthesia)

b. Reduced general anesthetic requirement

c. Prolongation of the analgesic duration of the block

d. Allow for a smooth emergence from anesthesia and a calm recover room stay

e. Reduce the incidence of emergence delirium and shivering

f. In the context of ambulatory surgery provide a comfortable early postoperative period that will allow early discharge from the hospital and a pain free transfer back home

Fundamental requirements of adjuvant drugs Not only does there need to be published evidence for an enhanced effect compared to control (plain local anesthetics), a candidate adjuvant has to fulfill some further important requirements:

a. Preferably meta-analysis data should verify the beneficial effect of the adjuvant in order to recommend routine use outside clinical trials

b. There should be sufficient insight into the mechanism of action of the adjuvant

c. The side effect profile should be tolerable in comparison with the use of plain local anesthetics

d. The adjuvant must be available as a preservative-free preparation

e. Overall safety issues must be acceptable

List of published adjuvants used in association with neuraxial blocks in children include:

a. Preservative-free morphine

b. Synthetic opioids (fentanyl, sufentanil, buprenorphine, diamorphine)

c. Alpha-2 adrenoceptor agonists (clonidine, dexmedetomidine)

d. Racemic ketamine and S-ketamine

e. Corticosteroids (dexamethasone)

f. Midazolam

g. Neostigminie

h. Magnesium

Some of these adjuvants (midazolam, neostigmine, buprenorphine) have been tested, mostly off label and without proper pre-clinical trials, and their side effects outweigh the benefits limiting clinical use.⁴ Others (dexamethasone, fentanyl) have little or no added benefit over intravenously administered route of the same agent.

Definition of clinically relevant prolongation of analgesic effect

No consensus currently exists regarding the definition of what may be considered a clinically relevant prolongation of postoperative analgesia achieved by the use of adjuvant drugs in the context of pediatric regional anesthesia. However, it has been suggested that the postoperative duration of the analgesic effect of the block should be increased more than 20–50 % compared to control (plain local anesthetics)² and that the absolute time increase should be at least two hours compared to control to be considered of value for the pediatric patient.²

Toxicity aspects Potential risks of nerve root and spinal cord neurotoxicity is of paramount importance in the context of neuraxial blocks in children. Laboratory in vitro studies do point to potential neurotoxicity associated with certain adjuncts but clinical toxicity has to date not been reported in the literature (but, under-reporting is likely). However, in parallel with the potential risks of cerebral neurotoxicity following early exposure to general anesthetics, the more frequently used adjuvants used in pediatric regional anesthesia have undergone animal testing to investigate whether spinal administrations of these drugs may cause apoptosis of spinal cord neurons.^5–8 These reports show that local anesthetics (levo-bupivacaine), preservative-free morphine and clonidine do not increase apoptosis in neonatal mice^5,7,8 whereas ketamine was found to cause increased apoptosis in this setting.⁶ As a result of these studies Walker & Yaksh have strongly suggested that new adjunct alternatives should undergo similar testing before being applied in the clinical setting, especially in neonates and small infants.⁹ Against this background only clonidine and preservative-free morphine may currently be advocated for use in neonates and infants.¹⁰

Dexmedetomidine has recently been shown to have positive effects as an adjuvant both for caudal and peripheral nerve blocks in children.^11,12 This drug does also seem to be associated with acceptable safety features¹³ and may, thus, be a new interesting alternative in this setting.

Data regarding the use of adjuvants and peripheral nerve blocks in children are scarce but it may be reasonable to expect that drugs that are safe from a central nerve block perspective will also be safe to use when performing peripheral nerve blocks. Again it is important to note that any adjuvant that is used in association with peripheral nerve blockade must have a defined mechanism of action since peripheral nerves lack the expression of many of the receptors that are responsible for the adjunct’s effect in the central nerve block setting.¹⁴

Neuraxial blocks The issues regarding neuroaxial and the use of adjuvant drugs have recently been highlighted in a recent review.³

Intrathecal/Spinal blockade: Clonidine and the synthetic opioids fentanyl and sufentanil have been shown to prolong the duration of surgical blockade in babies.^15–17 Whether these agents will prolong postoperative analgesia in a clinically relevant way is still unknown. Intrathecal administration of morphine has mainly been performed in association with major spine surgery in older children (e.g. scoliosis surgery)¹⁸ but is associated with substantially more prolonged postoperative analgesia. However, in this context morphine is commonly injected as a single agent and not mixed with local anesthetics.

Caudal blockade: This represents the most frequently performed pediatric nerve block worldwide^19–21 and the vast majority of studies regarding adjuvants have been performed in this setting.

Racemic ketamine and S-ketamine Meta-analysis data show that ketamine does produce a useful adjuvant effect when co-delivered with LA ^22,23 and ketamine appears as more effective to prolong postoperative analgesia when compared to clonidine.²⁴ It must be emphasized that racemic ketamine can only be used if the preparation is preservative-free (preservatives are present is some commercially available ketamine formulations) and that ketamine is not recommended in neonates and infants due to the possible potential for enhanced neuronal apoptosis in the spinal cord. S-ketamine can also be used²⁵ and since this enantiomeric version of ketamine only exists as a preservative-free solution, this may be a preferred option if available.

Clonidine and dexmedetomidine Meta-analysis data clearly support a beneficial effect of clonidine as an adjuvant in the caudal block setting.^26–28 The analgesic effect of clonidine is comparable to that of preservative-free morphine but is associated with shorter effect duration.²⁹ A number of individual studies, including a recent meta-analysis (11), has shown dexmedetomidine to prolong postoperative analgesia when used as a caudal block adjunct. The effect size of dexmedetomidine appears very similar to that of clonidine despite the considerable difference in elimination half-life between these two alpha-2 adrenoceptor agonists.³⁰

Preservative-free morphine Meta-analysis data for caudal morphine is lacking but a number of reports do attest to the efficacy of this adjunct in the setting of caudal blockade. Morphine does also have the advantage of a clearly defined dose-response, showing that increasing the dose to > 50 mcg kg-1 will not enhance the effect but only increases the risk for respiratory depression.³¹ Due to the hydrophilic nature of morphine this agent can successfully be used for surgery outside the area usually covered by a caudal block. Thus, caudal administration of morphine has been shown to produce prolonged analgesia even following sternotomy in pediatric cardiac surgery³² (please cf epidural blockade below). However, the use of caudal morphine is associated with an increase of side effects (e.g. pruritis, PONV, paralytic ileus).^33–35 Furthermore, caudal administration of morphine is associated with a risk of delayed respiratory depression that necessitates adequate postoperative monitoring for at least 12–24 hours following administration.³⁶

Synthetic opioids Although these agents are popular as adjuvants in the context of adult epidural analgesia there is currently a lack of evidence that synthetic opioids produce any relevant effect when used as adjuvants to caudal blocks in children.³³ Fentanyl does not potentiate the effect of either bupivacaine or ropivacaine in the context of caudal blockade.³⁷

Corticosteroids Only two studies so far has reported a beneficial effect of dexamethasone as a caudal adjuvant.^38,39 Despite the fact that caudal/epidural steroid injections in adults appear to be associated with reasonable safety there is a lack of toxicity data regarding the intraspinal deposition of corticosteroids in growing individuals. Furthermore, no mechanism has so far been identified that can explain how adjuvant use of corticosteroids in the context of central or peripheral nerve blocks is supposed to work. In addition, recent adult data show that intravenous administration of dexamethasone produces identical prolongation of block duration as deposition of dexamethasone together with local anesthetics close to the target nerve structures⁴⁰, which is also supported by pediatric data.^41,42 Thus, at this point adjuvant use of corticosteroids as adjuncts to local anesthetics in children cannot be recommended outside clinical trials.

Epidural blockade: Data relating to the effect of adjuvants in association with epidural analgesia in children is very sparse. As with caudal block, epidural co-administration of morphine will enhance the effect of epidural local anesthetics.³⁵ An advantage of epidural morphine is that it does not require administration at the spinal segments associated with the surgical intervention and, thus, may be an attractive alternative when the tip of the epidural catheter is not located at the optimal spinal level.³² Epidural morphine is rarely administered as a continuous infusion but instead as repeated bolus injections.³⁵

Regarding clonidine, dose-response data are available that show that the addition of clonidine to a low concentration of ropivacaine will enhance the effect of the local anesthetic infusion.⁴³ In contrast, the adjunct use of synthetic opioids as adjunct to pediatric epidural analgesia does not appear to be associated with any clinically significant effect.^44,45

Peripheral nerve blocks Alpha-2 adrenoceptor agonists. Peripheral nerves lack the expression of alpha-2 adrenoceptors but clonidine and dexmedetomidine act by interference with the repolarization process through interactions with the I _h current (14). Furthermore, adult meta-analyses have verified a beneficial effect of adjuvant use of alpha-2 adrenoceptors in the context of peripheral nerve blocks.^46,47

In the pediatric context a large single center study showed that adjuvant use of clonidine is associated with a prolongation of peripheral block duration in the order of 20–50 %.⁴⁸ Recently a meta-analysis with full access to all raw data of the included randomized controlled trials showed a definite advantage in favor of the use of adjuvant alpha-2 adrenoceptors,⁴⁹ a beneficial effect that remained even after the exclusion of the one RCT that investigated the use of dexmedetomidine.⁵⁰

Data for other adjuvants in the setting of peripheral nerve blockade is largely lacking.

Combinations of adjuncts At certain centers the combination of adjuvants is popular. The combined use of clonidine and opioids lead to a reduction of opioid induced side effects (e.g. pruritis and PONV) with no enhancement of postoperative analgesia.⁵¹ A prospective RCT using a combination of clonidine and fentanyl administered together with local anesthetics for paravertebral blockade in the setting of inguinal hernia repair produced significantly better postoperative analgesia compared to a ilioinguinal/iliohypogastric nerve block using plain local anesthetics⁵² or systemic multimodal analgesia.⁵³ Finally, Hager et al have shown that the caudal co-administration of S-ketamine and clonidine, without the administration of local anesthetics (!), results in approximately 24 hours of postoperative analgesia.⁵⁴

At this time point combinations of adjuvants lack supportive data and toxicology data are lacking. Thus, the combination of adjuvant drugs cannot be recommended outside clinical trials.

Conclusions 1. Neuroaxial blocks

a. Caudal blocks: Meta-analysis data show that adjuvant use of clonidine is associated with improved postoperative analgesia compared to plain local anesthetics. Preservative-free ketamine is also effective in this setting but animal toxicity data suggest that ketamine should be avoided in newborns and infants due to a potential risk of increased neuronal apoptosis within the spinal cord. (Evidence A1).

b. Epidural blocks: Adjuvant use of preservative-free morphine and clonidine improve the quality of postoperative analgesia (Evidence A3)

c. Intrathecal blocks: Adjuvant use of preservative-free morphine, synthetic opioids and clonidine improve the quality and duration of intrathecal blocks (Evidence A3)

2. Peripheral nerve blocks

a. Meta-analysis data show that adjuvant use of preservative-free clonidine is associated with improved postoperative analgesia compare to plain local anesthetics (Evidence A3).

b. No other adjuvants have been shown to improve postoperative analgesia in the context of peripheral nerve blocks in children.

3. New potential adjuvant drugs should undergo proper toxicologic testing before being used in the human setting and new candidate drugs should first be properly investigated in clinical trials before being generally used in routine patient care.

References

1. Lönnqvist PA. Blocks for pain management in children undergoing ambulatory surgery. Curr Opin Anaesthesiol 2011 Dec;24(6):627–32.

2. Lönnqvist PA. Adjuncts should always be used in pediatric regional anesthesia. Paediatr Anaesth 2015 Jan;25(1):100–6.

3. Lundblad M, Lönnqvist PA. Adjunct analgesic drugs to local anaesthetics for neuroaxial blocks in children. Curr Opin Anaesthesiol 2016 Oct;29(5):626–31.

4. Lönnqvist PA. Adjuncts to caudal block in children--Quo vadis? Br J Anaesth 2005 Oct;95(4):431–3.

5. Westin BD, Walker SM, Deumens R, Grafe M, Yaksh TL. Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat. Anesthesiology 2010 Jul;113(1):183–99.

6. Walker SM, Westin BD, Deumens R, Grafe M, Yaksh TL. Effects of intrathecal ketamine in the neonatal rat: evaluation of apoptosis and long-term functional outcome. Anesthesiology 2010 Jul;113(1):147–59.

7. Walker SM, Grafe M, Yaksh TL. Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. Anesth Analg 2012 Aug;115(2):450–60.

8. Hamurtekin E, Fitzsimmons BL, Shubayev VI, et al. Evaluation of spinal toxicity and long-term spinal reflex function after intrathecal levobupivaciane in the neonatal rat. Anesthesiology 2013 Jul;119(1):142–55.

9. Walker SM, Yaksh TL. Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data. Anesth Analg 2012 Sep;115(3):638–62.

10. Lönnqvist PA, Walker SM. Ketamine as an adjunct to caudal block in neonates and infants: is it time to re-evaluate? Br J Anaesth 2012 Aug;109(2):138–40.

11. Tong Y, Ren H, Ding X, Jin S, Chen Z, Li Q. Analgesic effect and adverse events of dexmedetomidine as additive for pediatric caudalanesthesia: a meta-analysis. Paediatr Anaesth 2014 Dec;24(12):1224–30.

12. Lundblad M, Marhofer D, Eksborg S, Lönnqvist PA. Dexmedetomidine as adjunct to ilioinguinal/iliohypogastric nerve blocks for pediatric inguinal hernia repair: an exploratory randomized controlled trial. Paediatr Anaesth 2015 Sep;25(9):897–905.

13. Marhofer P, Brummett CM. Safety and efficiency of dexmedetomidine as adjuvant to local anesthetics. Curr Opin Anaesthesiol 2016 Oct;29(5):632–7.

14. Lönnqvist PA. Alpha-2 adrenoceptor agonists as adjuncts to Peripheral Nerve Blocks in Children--is there a mechanism of action and should we use them? Paediatr Anaesth 2012 May;22(5):421–4.

15. Rochette A, Raux O, Troncin R, et al. Clonidine prolongs spinal anesthesia in newborns: a prospective dose-ranging study. Anesth Analg 2004; 98:56–59.

16. Kaabachi O, Zarghouni A, Ouezini R, et al. Clonidine 1 microg/kg is a safe and effective adjuvant to plain bupivacaine in spinal anesthesia in adolescents. Anesth Analg 2007; 105:516–519.

17. Gupta A, Saha U. Spinal anesthesia in children: a review. J Anaesthesiol Clin Pharmacol 2014; 30:10–18.

18. Gall O, Aubineau JV, Bernière J, Desjeux L, Murat I. Analgesic effect of low-dose intrathecal morphine after spinal fusion in children. Anesthesiology 2001 Mar;94(3):447–52.

19. Ecoffey C, Lacroix F, Giaufré E, Orliaguet G, Courrèges P; Association des Anesthésistes Réanimateurs Pédiatriques d’Expression Française (ADARPEF). Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth 2010 Dec;20(12):1061–9.

20. Polaner DM, Taenzer AH, Walker BJ, et al. Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth Analg 2012 Dec;115(6):1353–64.

21. Suresh S, Long J, Birmingham PK, De Oliveira GS Jr. Are caudal blocks for pain control safe in children? an analysis of 18,650 caudal blocks from the Pediatric Regional Anesthesia Network (PRAN) database. Anesth Analg 2015 Jan;120(1):151–6.

22. Schnabel A, Poepping DM, Kranke P, et al. Efficacy and adverse effects of ketamine as an additive for paediatric caudal anaesthesia: a quantitative systematic review of randomized controlled trials. Br J Anaesth 2011; 107:601–611.

23. Engelman E, Marsala C. Bayesian enhanced meta-analysis of post-operative analgesic efficacy of additives for caudal analgesia in children. Acta Anaesthesiol Scand 2012; 56:817–832.

24. De Negri P, Ivani G, Visconti C, De Vivo P. How to prolong postoperative analgesia after caudal anaesthesia with ropivacaine in children: S-ketamine versus clonidine. Paediatr Anaesth 2001; 11:679–683.

25. Marhofer P, Krenn CG, Plöchl W, et al. S(+)-ketamine for caudal block in paediatric anaesthesia. Br J Anaesth 2000; 84:341–345.

26. Ansermino M, Basu R, Vandebeek C, Montgomery C. Nonopioid additives to local anaesthetics for caudal blockade in children: a systematic review. Paediatr Anaesth 2003; 13:561–573.

27. Schnabel A, Poepping DM, Pogatzki-Zahn EM, Zahn PK. Efficacy and safety of clonidine as additive for caudal regional anesthesia: a quantitative systematic review of randomized controlled trials. Paediatr Anaesth 2011; 21:1219–1230.

28. Engelman E, Marsala C. Bayesian enhanced meta-analysis of post-operative analgesic efficacy of additives for caudalanalgesia in children. Acta Anaesthesiol Scand 2012 Aug;56(7):817–32.

29. Luz G, Innerhofer P, Oswald E, et al. Comparison of clonidine 1 microgram kg-1 with morphine 30 micrograms kg-1 for post-operative caudal analgesia in children. Eur J Anaesthesiol 1999 Jan;16(1):42–6.

30. El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM, et al. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. Br J Anaesth 2009; 103:268–274.

31. Krane EJ, Tyler DC, Jacobson LE. The dose response of caudal morphine in children. Anesthesiology 1989; 71:48–52.

32. Rosen KR, Rosen DA. Caudal epidural morphine for control of pain following open heart surgery in children. Anesthesiology 1989; 70:418–421.

33. Lönnqvist PA, Ivani G, Moriarty T. Use of caudal-epidural opioids in children: still state of the art or the beginning of the end? Paediatr Anaesth 2002; 12:747–749.

34. de Beer DA, Thomas ML. Caudal additives in children--solutions or problems? Br J Anaesth 2003 Apr;90(4):487–98.

35. Bosenberg A. Adjuvants in pediatric regional anesthesia. Pain Manag 2012 Sep;2(5):479–86.

36. Karl HW, Tyler DC, Krane EJ. Respiratory depression after low-dose caudal morphine. Can J Anaesth 1996; 43:1065–1067.

37. Kawaraguchi Y, Otomo T, Ota C, et al. A prospective, double-blind, randomized trial of caudal block using ropivacaine 0.2% with or without fentanyl 1 microg kg-1 in children. Br. J. Anaesth 2006; 97(6),858–861.

38. Kim EM, Lee JR, Koo BN, et al. Analgesic efficacy of caudal dexamethasone combined with ropivacaine in children undergoing orchiopexy. Br J Anaesth 2014; 112:885–891.

39. Choudhary S, Dogra N, Dogra J, et al. Evaluation of caudal dexamethasone with ropivacaine for post-operative analgesia in paediatric herniotomies: a randomised controlled study. Indian J Anaesth 2016; 60:30–33.

40. Desmet M, Braems H, Reynvoet M, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth 2013; 111:445–452.

41. Hong JY, Han SW, Kim WO, et al. Effect of dexamethasone in combination with caudal analgesia on postoperative pain control in day-case paediatric orchiopexy. Br J Anaesth 2010; 105:506–510.

42. Murni Sari Ahmad A, Azarinah I, Esa K, et al. Intravenous dexamethasone in combination with caudal block prolongs postoperative analgesia in pediatric daycare surgery. Middle East J Anaesthesiol 2015; 23:177–183.

43. De Negri P, Ivani G, Visconti C, et al. The dose-response relationship for clonidine added to a postoperative continuous epidural infusion of ropivacaine in children. Anesth Analg 2001; 93:71–76.

44. Lerman J, Nolan J, Eyres R, et al. Efficacy, safety, and pharmacokinetics of levobupivacaine with and without fentanyl after continuous epidural infusion in children: a multicenter trial. Anesthesiology 2003; 99:1166–1174.

45. Bailey PD, Rose JB, Keswani SG, et al. Does the use of fentanyl in epidural solutions for postthoracotomy pain management in neonates affect surgical outcome? J. Pediatr. Surg 2005;40(7),1118–1121.

46. McCartney CJ, Duggan E, Apatu E. Should we add clonidine to local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature. Reg Anesth Pain Med 2007; 32: 330–338.

47. Pöpping DM, Elia N, Marret E et al. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology 2009; 111: 406–415.

48. Cucchiaro G, Ganesh A. The effects of clonidine on postoperative analgesia after peripheral nerve blockade in children. Anesth Analg 2007; 104: 532–537.

49. Lundblad M, Trifa M, Kaabachi O, et al. Alpha-2 adrenoceptor agonists as adjuncts to peripheral nerve blocks in children: a meta-analysis. Paediatr Anaesth 2016 Mar;26(3):232–8.

50. Lundblad M, Marhofer D, Eksborg S, Lönnqvist PA. Dexmedetomidine as adjunct to ilioinguinal/iliohypogastric nerve blocks for pediatric inguinal hernia repair: an exploratory randomized controlled trial. Paediatr Anaesth 2015 Sep;25(9):897–905.

51. Cucchiaro G, Adzick SN, Rose JB, Maxwell L, Watcha M. A comparison of epidural bupivacaine-fentanyl and bupivacaine-clonidine in children undergoing the Nuss procedure. Anesth Analg 2006 Aug;103(2):322–7.

52. Naja ZM, Raf M, El Rajab M, et al. Nerve stimulator-guided paravertebral blockade combined with sevoflurane sedation versus general anesthesia with systemic analgesia for postherniorrhaphy pain relief in children: a prospective randomized trial. Anesthesiology 2005 Sep;103(3):600–5.

53. Naja ZM, Raf M, El-Rajab M, et al. A comparison of nerve stimulator guided paravertebral block and ilio-inguinal nerve block for analgesia after inguinal herniorrhaphy in children. Anaesthesia 2006 Nov;61(11):1064–8.

54. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth Analg 2002 May;94(5):1169–72.