Pediatric Perioperative Esketamine: Dose-Dependent Effects and Unresolved Safety Boundaries

Targeted Review Finds Dose-Dependent Effects of Esketamine in Pediatric Surgery

A 2026 targeted review published in OpenAlex (source) synthesizes available evidence on the perioperative use of esketamine in children, focusing on dose- and endpoint-dependent effects. The review concludes that low intravenous (IV) doses of esketamine—particularly in the 0.2–0.5 mg/kg range—may reduce the incidence of emergence delirium (ED) or agitation (EA) following pediatric surgeries such as adenotonsillectomy under sevoflurane anesthesia. However, the review does not establish a universal therapeutic window or clear safety boundaries for esketamine in this population.

Mechanisms and Context: Esketamine's Role in Pediatric Anesthesia

Esketamine, the S-enantiomer of ketamine, is being explored for several perioperative pediatric applications, including procedural sedation, analgesia, attenuation of propofol injection pain, and prevention of ED/EA. The review highlights that esketamine's efficacy is highly endpoint-specific, with different dosing and timing requirements for each indication. For example, the benefit in reducing ED is most evident with low IV doses during specific anesthetic protocols, while procedural sedation and analgesia may require distinct exposure profiles. Notably, the review finds that intranasal regimens cannot be reliably converted to IV equivalents based solely on bioavailability, complicating translational dosing decisions.

Policy and Research Implications: No Immediate Regulatory Change

The findings from this targeted review do not immediately alter legal or regulatory frameworks governing pediatric anesthesia or esketamine use. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have not issued pediatric-specific approvals or guidance for perioperative esketamine outside investigational or off-label use. The review underscores the need for more rigorous, endpoint-specific randomized controlled trials (RCTs) that directly compare dosing regimens, incorporate pediatric pharmacokinetic and pharmacodynamic (PK/PD) sampling, and extend safety follow-up periods. These recommendations reflect a growing recognition that pediatric populations require tailored research designs that account for developmental stage, anesthetic technique, and procedure-specific variables.

• Concrete Example: The review cites randomized trials and meta-analyses showing fewer ED/EA events with low-dose IV esketamine (up to 0.5 mg/kg) during adenotonsillectomy under sevoflurane, but it also notes that no upper efficacy or safety boundary has been established in these studies.

Risks, Unknowns, and the Need for Endpoint-Specific Safety Data

Despite promising findings, the review highlights significant gaps in safety data and unresolved risks. Preclinical studies have raised concerns about neurotoxicity with high or repeated ketamine exposure in developing brains, but these findings do not define a ceiling for single perioperative doses in children. Observational associations between esketamine exposure and increased ED cannot establish causality or safety thresholds due to confounding variables and lack of controlled context. The review also notes that effective dosing is not only procedure- and outcome-specific but may also be influenced by co-medications and individual developmental factors, further complicating risk assessment.

One non-obvious implication is that the absence of a validated therapeutic window means clinicians must individualize esketamine dosing based on both procedure and patient-specific factors, rather than relying on a standardized protocol—a challenge for both research and practice.

Forward Look: Research Priorities and Clinical Decision-Making

Future research must prioritize direct dose and timing comparisons, endpoint-specific outcome assessments, and robust PK/PD sampling in pediatric populations. Extended safety follow-up is essential to detect rare or delayed adverse events. Until such data are available, the use of esketamine in pediatric perioperative settings should be guided by careful risk-benefit analysis, individualized dosing, and informed consent processes. Clinicians, researchers, and policymakers should collaborate to design trials that address the unique needs of pediatric anesthesia and establish evidence-based guidelines for esketamine use in this context.

How we research / reviewed by Dr. Alex M. Chen, MD, MSc (Pediatric Anesthesiology), October 2026.