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New caudal additives in children benefit vs. risk 2009

Acta Anaesthesiol Scand 2009; 53: 1097–1101 Printed in Singapore. All rights reserved

r 2009 The Authors Journal compilation r 2009 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA

Letters to the Editor
New caudal additives in children: bene?t vs. risk?
doi: 10.1111/j.1399-6576.2009.02013.x interesting that in the paper it was indicated that there was informed consent. How informed were the patients if the investigators themselves had no idea as to safety? Where is the institutional review board commentary regarding safety? As the requirements of local ethical review boards vary signi?cantly, some journals (e.g. Anesthesia and Analgesia15,16) have speci?c policies, which consider that off-label use of novel spinal agents must be preceded by competent pre-clinical studies or approval by a national agency (e.g. in the United States, the Food and Drug Administration). These journals are to be complimented on taking this stance, but have doubtless been criticized by those seeing this as an obstruction to development of clinical practice, rather than protection for the patient who has unwittingly engaged in clinical safety evaluation. Let us be clear, we enthusiastically encourage clinical research to improve the regulation of pain control in the young by interventions at the spinal level, but the way forward must be carried out with the appropriate steps taken to avoid an unexpected and untoward outcome. Where adequate alternatives already exist, every step must be taken to evaluate the risk bene?t ratio with the appropriate pre-clinical evaluations. In this matter, we agree in large part with the reasoned editorial provided by Lonnqvist17 on virtually the same topic. S. M. Walker T. L. Yaksh

Sir, We read with interest the report by Saadawy et al.1 on the use of dexmedetomidine as an additive to caudal anesthesia in 1–6-year-old children undergoing hernia repair. It has long been known that a2 receptors can regulate spinal nociceptive processing2 and that spinal dexmedetomidine has pre-clinical ef?cacy in neonatal animal models.3–5 We applaud the efforts to improve clinical care and the utility of a long-valued technique (e.g. caudal anesthesia). However, this enthusiasm does not make up for the risk potentially posed by the direct delivery of untested materials into the spinal canal of humans. Reading the paper indicates a well conducted, clearly presented, blinded study with appropriate measures and endpoints. However, we note that nowhere in the manuscript is there any indication of any measure that de?nes the safety of the use of spinally administered dexmedetomidine. As has been reviewed, there is every reason to expect that before spinal use in humans, particularly in children,6 there is a need to evaluate safety in the concentrations that equal or exceed those to be used clinically.7–9 We do not wish at this time to discuss the appropriate pre-clinical assessment models but would only emphasize that safety assessments cannot be based on simple behavioral studies that do not use any histological end point. Clearly persistent functional changes after spinal delivery are indicative of a drug effect, but behavior may be notoriously insensitive to moderate neurological insults that may only be observed with speci?c morphological assessments. With regard to the added variable of developmental age, evolving data suggest that during post-natal development, the pharmacodynamic response, side-effect pro?le and potential toxicity of anesthetic and analgesic agents may differ from that seen at older ages,10,11 and this difference may be presented at the spinal level.12 The relevance of this sensitivity remains a point of the current controversy in the pediatric literature, but emphasizes the importance of appropriate preclinical safety assessments in appropriate developmental models. Some would argue that a human drug exposure study should be an adequate support for the studies performed here, but we strenuously argue that there is a marked difference between asserting tolerability or ef?cacy (as human studies can readily do) and safety to assess the absence of morphological effects (which human studies cannot). Further, given the potential differences in sensitivity as a function of developmental age, the dose requirements and ‘‘safety’’ purportedly assessed in adult humans may have limited relevance to the young. We note that these comments are also directed to the editorial boards and referees who accept such studies using the off-label use of an agent for spinal delivery with no prior toxicology assessment. The use of a preservative-free preparation is not a panacea. Although many drugs used in pediatric anesthesia have not been speci?cally evaluated in children, thus necessitating ‘‘off-label’’ use,13 the potential risks and the bene?ts for individual patients must be considered.14 It is

1. Saadawy I, Boker A, Elshahawy MA, Almazrooa A, Melibary S, Abdellatif AA, A?? W. Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatrics. Acta Anaesthesiol Scand 2009; 53: 251–6. 2. Reddy SV, Maderdrut JL, Yaksh TL. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J Pharmacol Exp Ther 1980; 213: 525–33. 3. Walker SM, Howard RF, Keay KA, Fitzgerald M. Developmental age in?uences the effect of epidural dexmedetomidine on in?ammatory hyperalgesia in rat pups. Anesthesiology 2005; 102: 1226–34. 4. Walker SM, Fitzgerald M. Characterization of spinal alphaadrenergic modulation of nociceptive transmission and hyperalgesia throughout postnatal development in rats. Br J Pharmacol 2007; 151: 1334–42. 5. Yaksh TL. Neonates have a spinal alpha receptor too, as do adults. Br J Pharmacol 2007; 151: 1139–40. 6. Eisenach JC, Yaksh TL. Epidural ketamine in healthy children – what’s the point? Anesth Analg 2003; 96: 626–7. 7. Yaksh TL, Allen JW. Preclinical insights into the implementation of intrathecal midazolam: a cautionary tale. Anesth Analg 2004; 98: 1509–11. 8. Yaksh TL, Rathbun ML, Provencher JC. Preclinical safety evaluation for spinal drugs. In: Yaksh TL, ed. Spinal drug delivery. Amsterdam: Elsevier Science B.V., 1999:417–37. 9. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg 2004; 98: 1536–45. 10. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007; 104: 509–20.


Letters to the Editor
11. Fitzgerald M, Walker SM. Infant pain management: a developmental neurobiological approach. Nat Clin Pract Neurol 2009; 5: 35–50. 12. Sanders RD, Xu J, Shu Y, Fidalgo A, Ma D, Maze M. General anesthetics induce apoptotic neurodegeneration in the neonatal rat spinal cord. Anesth Analg 2008; 106: 1708–11. 13. Cote CJ. Unapproved uses of approved drugs. Paediatr Anaesth 1997; 7: 91–2. 14. Department of Health Department for Education and Skills. (2007) National service framework for children young people and maternity services: medicines for children and young people. Standard 10. Available at http://www.dh.gov.uk/ en/Publicationsandstatistics/Publications/PublicationsPoli cyAndGuidance/Browsable/DH_4117980 (accessed 7 March 2009) 15. Shafer SL. Anesthesia & Analgesia’s policy on off-label drug administration in clinical trials. Anesth Analg 2007; 105: 13–5. 16. 2006–2007 Editorial Board Anesthesia and Analgesia. Anesthesia & analgesia guide for authors. Anesth Analg 2007; 105: 187–99. 17. Lonnqvist PA. Adjuncts to caudal block in children – Quo vadis? Br J Anaesth 2005; 95: 431–3. non-invasive procedures in radiology.8 Furthermore, it showed a potential role as a part of anesthesia care to prevent the occurence of delirium and post-anesthesia shivering.9–11 Third, the correlation between direct application of anesthetic agents and histopathological changes is not very well delineated in the literature. Despite their wide clinical use, local anesthetics were shown to induce morphological changes in nerve structures and have the potential to induce neuroapoptosis in the spinal cord. These ?ndings were demonstrated in vitro12 and were also suggested to be a plausible occurrence in vivo.13 On the other hand, there is growing evidence supporting the use of DEX as a neuroprotective agent that possibly has antiapoptoic properties. These features show that DEX appears to have promising future applications in the area of neuroprotection.14–20 Sanders et al.13 suggested that if local anesthesia-induced toxicity is observed, routine addition of an a2 adrenoceptor agonist may not only extend analgesia but may also provide neuroprotection. Fourth, Brummett et al.21 demonstrated that perineural administration of DEX with bupivacaine enhanced sensory and motor blockade in a sciatic nerve block without inducing neurotoxicity in rats. They found a wider safety margin for both the concentration and the total dosing, and the histopathological evaluation showed that nerve axon and myelin were normal in both groups at 24 h and 14 days. In their study, high-dose DEX attenuated the acute bupivacaine-induced perineural in?ammation without causing nerve damage. They found that DEX can safely improve the duration of bupivacaine-induced antinociception and encouraged further studies in patients. Only one study found that demyelinization of the oligodendrocytes in the white matter of the spinal cord occurred when a higher dose of DEX (6.06 and 6.25 mg/kg) was injected into the epidural space in rabbits, which is six times the dose used by us.22 Finally, a2 agonists have great potential to be ideal pharmaceutical agents for management of patients during the postoperative period.23,24 The highly selective a2 adrenoceptor agonist, DEX, is antinociceptive at all ages tested from infant rats (7 days old) to adults.25 Walker et al.26 established the ef?cacy of neuroaxially administered DEX at early stages of rat development, supporting recommendations for the clinical use of a2 adrenoceptor agonists.27 Walker et al.26 found that epidural DEX can induce selective reversal of in?ammatory hyperalgesia at all ages through a spinally mediated effect. A major advantage of the decreased dose requirements with spinal administration is the potential for reduced side effects when compared with systemic administration as several studies have shown that the therapeutic window is narrow after systemic administration of a2 agonists, because sedative and motor side effects often occur within the same dose range as analgesia. As we have limited space to our response to the letter, we could not include important topics that could be relevant to this debate.28 In conclusion, we partially agree with Dr Walker and Dr Yaksh that using histological evidence might impose a signi?cant restriction on new developments and discoveries on the off-label uses of approved drugs particularly in pediatrics. However, we reaf?rm that due process was used to evaluate the best available evidence. DEX administered through the caudal route is a promising drug with many advantages in pediatrics. Future studies need to address many of the issues in this debate as well as establish its optimal dose. I. Saadawy A. Boker

Address: Suellen M. Walker Clinical Senior Lecturer in Paediatric Anaesthesia and Pain Medicine Portex Unit 6th Floor, Cardiac Wing UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK e-mail: suellen.walker@ich.ucl.ac.uk

doi: 10.1111/j.1399-6576.2009.02049.x Sir, We thank Dr Walker and Dr Yaksh for their interest in our study, and we extend our thanks to the editorial board for providing us with an additional opportunity to expand on this new interesting topic. First, in our study, Dexmedetomidine (DEX) has been used caudally and not delivered directly into the cerebro spinal ?uid as mentioned in the letter. The concentration we used (1 mg/kg) did not exceed that used clinically (2 mg/kg). In addition, neonates and infants were not included; our study included children aged between 1 and 6 years. Second, the issue of additives in neuroaxial medications in general is very controversial. Although it is not approved for neuroaxial use, there are many human trials on the use of DEX in adults either through the intrathecal route1,2 or as an epidural,3–6 and none of them reported any side effects regarding its neurotoxicity. Also, there is a growing interest in the use of DEX in pediatrics. It is being used off-label as an adjunctive agent for sedation and analgesia in pediatric critical care7 and for sedation during