Anesthesia and analgesia have been found to reduce morbidity and mortality in newborns after surgery.1,2 Although general anesthetics have been linked to “developmentally regulated increases in perinatal apoptosis and long term deleterious behavioral changes,” neuraxial anesthetics and analgesics are associated with fewer systemic adverse effects, according to a review published in Anesthesia & Analgesia.3,4
Despite findings that support the tolerability and efficacy of such agents, there is a dearth of evidence demonstrating improved clinical outcomes in neonates and infants, and there have been few assessments of their safety in terms of spinal toxicity in the early developmental period.
In neonates, epidural or intrathecal delivery of neuraxial agents, most commonly opioids, as well as clonidine, dexmedetomidine, ketamine, midazolam, and neostigmine, may be used to supplement and limit the use of general anesthesia for perioperative analgesia, or as a sole anesthetic for surgery of the abdomen or lower limb. A 2006 survey showed an increase in the number of central blocks performed on neonates (5.6% vs 3.4% from the previous 1994 survey) and infants <6 months (30% vs 16.5%).5 In another study, spinal anesthetics in neonates accounted for 30% of the total procedures performed at 1 center in France.6
Although the available evidence precludes firm conclusions because of insufficient data and variability in study design, reported benefits of neuraxial delivery in infants and neonates include reduced respiratory complications such as postoperative apnea, reductions in circulating stress hormones, maintenance of cardiovascular stability, reduced hospital stay, and improved surgical outcomes.7-11
While the incidence of severe complications caused by pediatric neuraxial analgesia is low, it is elevated in neonates and infants, with 0.4% vs 0.1% for neuraxial blocks in general, and 1.1% vs 0.49% for epidural blocks specifically.5,12 Another potential disadvantage of this approach is the risk for infection and neurological injury, although evidence indicating substantial rates of such events is not available.
In the 2012 review, the authors point to findings from their rodent studies in this area to illustrate that, for further advances, systematic preclinical assessments are needed regarding the comparative safety of various agents, with particular attention on “the therapeutic ratio of the neuraxially delivered agent, the developmental time of exposure to the agent, and assessment of neuropathology (apoptosis, myelination, gliosis and dendritic morphology) and long term functional outcomes.” In addition, because there is no exact match between developmental phases of rodent and human neonates, preclinical models evaluating the safety of neuraxial agents should include a variety of developmental ages.
In clinical practice, when “considering the choice of spinal analgesic adjuvants, many provide similar analgesia but not all have undergone systematic evaluations of spinal toxicity, and changing practice to include only agents with the widest demonstrable safety margin can be achieved without compromising clinical care,” the authors concluded.
Clinical Pain Advisor followed up with 1 of the authors of the review, Tony L. Yaksh, PhD, a professor in the Department of Anesthesiology and the Department of Pharmacology at the University of California, San Diego, to gain additional insights into this topic.
Clinical Pain Advisor: What prompted you and your coauthor to write this review?
Dr Yaksh: Newborn humans often require surgical interventions, such as for cardiac problems. There was a time in the early 1970s when it was thought that babies did not have the appropriate neural substrate for perceiving pain. Early work found that was not true and that babies, similar to adults, survived better with appropriate surgical anesthesia. So, through the early 1980s, there was an increasing utilization of general anesthesia; for example, gaseous anesthetics, injectable systemic anesthetics. In the early 1990s, there was a growing appreciation of the possibility that general anesthetics might have adverse effects on neonatal brain development. Although this effect is controversial, it has given many in neonatal anesthesiology pause for thought.
My coauthor, Suellen M. Walker, MBBS, PhD, is a pediatric anesthesiologist [at University College London] who is interested in neonatal pain and anesthesia; specifically, the role of spinal drug delivery in medicating such patients. [This] is readily achieved with a high degree of safety and has value only in that the drug effects are limited to the spinal cord. Further, the density of anesthesia and analgesia achievable by the spinal delivery of drugs is typically superior to that which can be achieved by a systemically administered drug. This all argues strongly for an increased utilization of neuraxial anesthesia.
Yet an important issue has been the question of how safe the spinal route is in the neonate. Until the work that Dr Walker and I have undertaken on neonatal safety in rats, there was no formal evaluation of spinal drug safety in the newborn. Accordingly, we had argued that proposing an increased utilization of spinal delivery in the newborn without such safety data might be an example of jumping from the frying pan into the fire. Accordingly, several years ago we initiated self-funded studies to develop the neonatal rat model.
Clinical Pain Advisor: What are the main treatment implications for pain clinicians?
Dr Yaksh: Our paper reviews the extensive work we have published in this area. Out of this, we found extensive evidence for an absence of toxicity after morphine, clonidine, and bupivacaine at doses that are multiples of the intrathecal therapeutic dose. In contrast, for the molecule ketamine, we found spinal apoptosis at doses that were comparable to those minimal doses required to have effects on pain processing.
Clinical Pain Advisor: What are the future directions for research in this area?
Dr Yaksh: Clearly other molecules should be examined for their relative safety. These include agents such as fentanyl, other alpha-2 agonists such as dexmedetomidine, and anesthetics such as ropivacaine or 2-chloroprocaine. Also of interest is the synergy that might be expected between anesthetics and an opiate or an opiate and an alpha-2. Such combinations require specific consideration as to their safety profile.
The effects of ketamine were disappointing, as the target of this drug, the spinal N-methyl D-aspartate (NMDA) receptor, is believed to play a major role in pain processing. There is a critical need to pursue the mechanisms of this apparent toxicity to determine whether it is mechanism- or molecule-dependent.
As noted, the extensive work we have done was not supported by extramural requests, despite diligent efforts targeted at several foundations and the National Institutes of Health. Additional work would benefit from such funding.
The development of spinal drugs for neonatal anesthesia and selective pain control has great promise. Yet, it should be emphasized that the development of such drugs must be proceeded by robust assessment of safety. In spite of the apparent safety of a drug after systemic delivery, such safety does not apply to the effects of the drug after neuraxial delivery. High concentrations and direct tissue exposure pose many issues for therapeutic safety.
- Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987;1(8524):62-66.
- Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J (Clin Res Ed). 1988;296(6623):668-672.
- 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;115(3):638-662.
- Stratmann G. Review article: neurotoxicity of anesthetic drugs in the developing brain. Anesth Analg. 2011; 113(5):1170–1179. doi:10.1213/ANE.0b013e318232066c
- Ecoffey C, Lacroix F, Giaufre E, Orliaguet G, Courreges P. 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;20(12):1061-1069.
- Rochette A, Dadure C, Raux O, Troncin R, Mailhee P, Capdevila X. A review of pediatric regional anesthesia practice during a 17-year period in a single institution. Paediatr Anaesth. 2007;17(9):874-880.
- Craven PD, Badawi N, Henderson-Smart DJ, O’Brien M. Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy. Cochrane Database Syst Rev. 2003;3:CD003669.
- Solak M, Ulusoy H, Sarihan H. Effects of caudal block on cortisol and prolactin responses to postoperative pain in children. Eur J Pediatr Surg. 2000;10(4):219-223.
- Somri M, Gaitini LA, Vaida SJ, et al. The effectiveness and safety of spinal anaesthesia in the pyloromyotomy procedure. Paediatr Anaesth. 2003;13(1):32-37.
- Lin YC, Sentivany-Collins SK, Peterson KL, Boltz MG, Krane EJ. Outcomes after single injection caudal epidural versus continuous infusion epidural via caudal approach for postoperative analgesia in infants and children undergoing patent ductus arteriosus ligation. Paediatr Anaesth. 1999;9(2):139-143.
- Kost-Byerly S, Jackson EV, Yaster M, Kozlowski LJ, Mathews RI, Gearhart JP. Perioperative anesthetic and analgesic management of newborn bladder exstrophy repair. J Pediatr Urol. 2008;4(4):280-285.
- Llewellyn N, Moriarty A. The national pediatric epidural audit. Paediatr Anaesth. 2007;17(6):520-533.