Ketamine Research in Perioperative Neurocognitive Disorders: Global Trends and Gaps

Global Surge in Ketamine Research for Perioperative Neurocognitive Disorders

Global research activity on ketamine’s effects in perioperative neurocognitive disorders (PNDs) has accelerated markedly since 2020, with China and the United States emerging as dominant contributors. According to a bibliometric analysis published on October 5, 2026 (OpenAlex W7220369688), 65.5% of all indexed publications in this domain appeared between 2021 and 2025, reflecting a rapid expansion of scientific attention. PNDs encompass a spectrum of postoperative cognitive complications, including postoperative delirium, delayed neurocognitive recovery, and longer-term neurocognitive disorder. The analysis included 432 unique publications and over 13,000 citations, with China producing the most papers (n=152) and the US leading in citation impact and international collaboration.

Despite the surge in research, the study cautions that publication volume should not be conflated with clinical efficacy. The increase in studies reflects research interest, not necessarily evidence supporting ketamine’s use in perioperative neurocognitive outcomes.

Mechanistic Focus and Evolving Research Themes

Recent ketamine research in PNDs increasingly emphasizes mechanistic questions, with a notable focus on esketamine—one of ketamine’s enantiomers—and its potential neurocognitive effects. The bibliometric analysis identified "intraoperative ketamine" as the strongest emerging keyword from 2021 to 2023, while terms like "mechanisms," "esketamine," and "delayed neurocognitive recovery" have surged through 2025. This thematic evolution reflects a shift from broad clinical questions to more granular investigations of pharmacological action, enantiomer specificity, and timing of administration.

One insight not widely discussed in the literature is the growing recognition that different ketamine formulations and enantiomers (such as esketamine versus racemic ketamine) may have distinct neurocognitive risk profiles and therapeutic windows. However, many published studies do not clearly distinguish between these formulations, complicating efforts to synthesize findings and guide clinical practice.

Policy, Research Implications, and Standardization Needs

Current research trends highlight the urgent need for standardized definitions and robust trial designs in the field of ketamine and perioperative neurocognitive disorders. The bibliometric analysis underscores that heterogeneity in outcome measures, diagnostic criteria, and study designs limits the interpretability and comparability of existing evidence. For instance, "postoperative delirium" and "postoperative cognitive dysfunction" are frequently used but inconsistently defined across studies, impeding meta-analysis and guideline development.

Regulatory agencies and research funders may increasingly require multicenter, adequately powered randomized controlled trials (RCTs) that distinguish between ketamine enantiomers and use harmonized perioperative neurocognitive outcome windows. The analysis suggests that without these methodological improvements, the field risks generating more data without resolving fundamental questions about efficacy and safety.

Risks, Unknowns, and Real-World Challenges

Despite the research boom, the clinical risks and unknowns surrounding ketamine use in perioperative contexts remain substantial. Adverse neurocognitive outcomes, including postoperative delirium and delayed recovery, are multifactorial and may be influenced by patient age, comorbidities, anesthesia protocols, and perioperative care standards. The evidence base for ketamine’s protective or deleterious effects on these outcomes is still inconclusive, with some studies suggesting benefit and others reporting neutral or even negative effects.

One real-world failure mode is the premature adoption of ketamine protocols based on promising but underpowered or methodologically inconsistent studies. Without standardized definitions and multicenter validation, there is a risk that clinical practice may outpace the evidence, potentially exposing patients to unanticipated harms or ineffective interventions.

Outlook: Toward Rigorous, Collaborative, and Standardized Research

The future of ketamine research in perioperative neurocognitive disorders will depend on the field’s ability to implement rigorous, collaborative, and standardized research protocols. International collaboration—already strong between China and the US—should be leveraged to design large-scale, harmonized trials that can clarify the therapeutic potential and safety profile of ketamine and its enantiomers in diverse surgical populations.

For researchers and policymakers, the key challenge is to move beyond bibliometric growth and focus on generating high-quality, actionable evidence. The next phase will likely see increased regulatory scrutiny, greater emphasis on trial reproducibility, and the development of consensus guidelines to inform both clinical practice and future research priorities.

Byline: Dr. Alex Lin, MD, PhD. Reviewed by Dr. Priya Natarajan, MD, October 2026. Research based on OpenAlex W7220369688 and primary bibliometric sources.