Effectiveness of ketamine/esketamine in alleviating postoperative fatigue: a systematic review

Postoperative fatigue (POF) is a clinically significant complication. Numerous studies have found that ketamine and esketamine show potential in alleviating POF. However, there is currently no systematic evidence to assess its exact effectiveness.

This study aimed to evaluate the effectiveness of perioperative ketamine/esketamine in alleviating POF in surgical patients.

A systematic review was reported following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The study protocol was prospectively registered in the PROSPERO Registry (CRD420251060988). We searched PubMed, Embase, Cochrane Library, and Web of Science from inception to May 31, 2025, using a combination of MeSH terms and free-text keywords related to "ketamine", "esketamine", "surgery", "anaesthesia" and "fatigue". Eligible studies were prospective or retrospective clinical studies comparing ketamine/esketamine with control in surgical patients, reporting fatigue-related outcomes. Two reviewers independently screened studies, another two reviewers independently extracted data and assessed risk of bias. A narrative synthesis was performed due to clinical and methodological heterogeneity.

In total, 556 studies were identified. Nine studies (n = 1606) were included in this review, among which seven were randomized controlled trials (RCTs) and two were observational studies. Four RCTs had low risk of bias, while the remaining three had some concerns. The two cohort studies were of moderate quality. The included studies encompassed various surgical procedures: colorectal cancer resection (n = 2), gastric surgery (n = 1), hysterectomy (n = 1), breast surgery (n = 2), orthopedic surgery (n = 1), and gastrointestinal endoscopy (n = 2). The outcomes varied according to the type of surgery. In studies of major abdominal surgeries, ketamine/esketamine has demonstrated certain potential in improving POF, but the certainty of evidence was graded as low. In contrast, no significant benefits were observed in breast or orthopedic surgeries. In the two studies on gastrointestinal endoscopy, the results were inconsistent.

Current evidence suggests that ketamine/esketamine may be effective in alleviating POF, particularly in major abdominal surgeries. These findings should be interpreted cautiously due to the heterogeneity in study designs, variations in fatigue assessment tools and time, and the limited sample sizes of the included studies. Future high-quality RCTs are needed to confirm these observations and establish the optimal dosing regimens.