Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data

Abstract

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high-quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, in the second half of this review, we present preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice.

Conflict of interest statement

Conflicts: Suellen M. Walker reported no conflicts of interest

Conflicts: Tony L Yaksh reported no conflicts of interest

Figures

Figure 1

Methods used in the evaluation of anesthetic and analgesic toxicity in the developing spinal cord. Preclinical studies in the postnatal rat have used a range of functional/behavioral and histopathological tests to evaluate spinal cord responses to analgesic and anesthetic drugs. 1) Experimental groups include a range of intrathecal drugs. Appropriate control groups include: intrathecal saline and naïve animals. Positive control groups are required to ensure adequate sensitivity of the tissue analysis when evaluating drugs with no or limited toxicity. 2) A measurable behavioral response is required to confirm correct intrathecal placement. Analgesic response curves are schematic examples of dose-dependent reversal of hyperalgesia and of age- and dose-dependent changes in mechanical withdrawal threshold. 3) Neuronal apoptosis and acute histopathological change can be evaluated by a range of methods. Images are representative examples of spinal cord sections stained for: activated caspase-3 immunoreactivity with positive cells identified by brown DAB staining; and Fluor-Jade C staining with apoptotic or dying neurons identified by green immunofluourescence. 4) Histopathological responses to drug exposure, and demyelination following local anesthetics are evaluated at later time points. Images represent spinal cord sections stained with: hematoxylin and eosin to assess histopathology and apoptotic cell counts; Iba1 immunoreactivity to evaluate microglial reactivity (green); and glial fibrillary acidic protein (GFAP, red) to evaluate astrocytes. 5) Measurement of spinal reflex sensitivity, analysis of gait, and length of time on a rotarod have been used to evaluate spinal cord functional outcomes in later life. Legend: P, postnatal day; I.T. intrathecal; H&E, hematoxylin and eosin