Perioperative Esketamine Moves Into Focus as a Preventive Strategy for Postoperative Sleep Disturbance
Postoperative sleep disturbance remains one of the more stubborn complications after major surgery, with reported rates ranging from 15% to 72%. The problem is not cosmetic or trivial. Poor sleep after anesthesia can reverberate through recovery by worsening pain sensitivity, slowing cognitive restoration, and raising cardiovascular risk during a period when physiologic reserve is already strained.
This protocol in BMJ Open sets out to evaluate whether perioperative esketamine can prevent postoperative sleep disturbance rather than merely treating it after the fact. That shift matters because current pharmacologic management is largely reactive, and reactive treatment does little for the early postoperative window when sleep fragmentation, stress responses, and inflammatory activation are most likely to disrupt recovery.
Why Sleep Disturbance After Surgery Has Become a Perioperative Target
Sleep disruption after general anesthesia is increasingly treated as a recovery endpoint rather than an isolated complaint. Patients who sleep poorly after surgery may experience more pain, more delirium-like symptoms, and less stable hemodynamics, all of which can complicate standard postoperative care. The clinical concern is especially relevant in major surgery, where the body is already responding to tissue injury, anesthetic exposure, and a surge in neuroendocrine stress signaling.
The rationale for esketamine rests on pharmacologic plausibility. As an NMDA receptor antagonist, it may modulate central sensitization, dampen stress-related pain amplification, and influence the biologic pathways that disturb normal sleep architecture in the immediate postoperative period. In practical terms, a preventive strategy could spare patients from entering the familiar cycle of pain, arousal, shallow sleep, and delayed recovery.
The Planned Review Will Test Whether Prevention Outperforms Rescue Therapy
Investigators plan a systematic review and meta-analysis of randomized controlled trials examining perioperative esketamine for prevention of postoperative sleep disturbance. Two authors will independently search MEDLINE via Ovid, EMBASE via Ovid, the Cochrane Central Register of Controlled Trials via Ovid, PubMed, and Web of Science. The search strategy will combine indexed and free-text terms covering both esketamine and postoperative sleep disturbance, a design meant to reduce the chance of missing relevant trials in a field where terminology can vary across anesthesia, surgery, and pain medicine literature.
The primary outcome is the incidence of postoperative sleep disturbance on postoperative days 1, 3, and 7. Those time points are clinically meaningful because they capture both the immediate postoperative period and the early recovery phase, when sleep may either normalize or continue to deteriorate. In many surgical pathways, the first postoperative night is the most vulnerable, but the persistence of symptoms across several days is what often separates transient discomfort from a more consequential recovery problem.
A concise signal at day 1 can change perioperative practice.
Trial Selection, Bias Assessment, and Statistical Methods Are Built for Consistency
Study screening, data extraction, and risk of bias assessment will be handled independently by two authors using the Cochrane Collaboration’s tool. That approach should strengthen internal consistency and limit selection error, especially if the available randomized trials differ in anesthesia type, surgical population, esketamine dose, or timing of administration.
The planned statistical analysis will use RevMan V.5.4.1 and Stata V.17.0. Subgroup analysis, sensitivity analysis, and publication bias assessment are included to probe the robustness of any pooled estimate. Those steps are important because protocol-level reviews in perioperative medicine often confront heterogeneity that reflects real-world variation rather than simple methodological noise. A prophylactic agent may appear effective in one operative context and far less so in another if dosing, timing, or concurrent analgesic regimens differ materially between studies.
The evidence will also be graded with the Grading of Recommendations Assessment, Development and Evaluation approach. That matters because a favorable pooled effect is not enough on its own to justify practice change. Clinicians need to know whether the evidence base is consistent, direct, and precise enough to support routine perioperative use.
Safety, Feasibility, and the Real-World Question Behind the Meta-Analysis
This protocol is focused on prevention, but the bedside question extends beyond efficacy alone. If perioperative esketamine reduces sleep disturbance, clinicians will still need to weigh that benefit against the drug’s known psychotomimetic potential, hemodynamic effects, and the variability of response across surgical patients. Those issues are not theoretical when the intervention is given during anesthesia care, where even modest adverse effects can alter recovery trajectories, nursing workload, and discharge planning.
The review is also relevant because postoperative sleep disturbance is not typically managed with a single uniform strategy. Patients may receive opioids, non-opioid analgesics, antiemetics, sedatives, or regional techniques depending on procedure and risk profile. Esketamine sits within that broader perioperative environment, and its apparent benefit or lack of benefit will likely depend on how it interacts with analgesia intensity and anesthetic technique.
What This Protocol Can and Cannot Answer Yet
At this stage, the article is a protocol, not a results paper. No pooled effect, no efficacy estimate, and no safety conclusion can be drawn from it. What it does provide is a structured plan to resolve inconsistent findings from earlier studies and to determine whether perioperative esketamine offers a reproducible prophylactic effect on sleep after general anesthesia.
Ethical approval is not required for the planned review, and the findings are intended for presentation at national or international conferences before submission to a peer-reviewed journal. The protocol is registered in PROSPERO under CRD420251232636, which adds transparency to the review process and helps limit selective reporting.
The central question now is whether the randomized trial literature is strong enough to support a meaningful preventive role for esketamine in postoperative sleep disturbance, or whether the heterogeneity of dosing, timing, and surgical context will leave the evidence too uneven for routine use.