Surgery · Medical Literature
Effects of low-dose esketamine on early quality of recovery following minimally invasive esophagectomy: a multicenter, randomized controlled study.
Abstract
Patients undergoing minimally invasive esophagectomy (MIE) frequently experience moderate-to-severe postoperative pain and anxiety-depressive symptoms, compromising postoperative quality of recovery (QoR). Esketamine is a promising adjunct for analgesia and anxiolysis; however, the effect of low-dose esketamine on patient-centered recovery outcomes in MIE remains unclear. In this double-blinded, multicenter randomized controlled trial, patients scheduled for elective McKeown esophagectomy were allocated to esketamine (0.25 mg/kg loading dose and 0.125 mg/kg/h continuous infusion during surgery) or placebo (equivalent volume and rate of saline). The primary outcome was the QoR-15 score on postoperative day (POD) 2. Secondary outcomes included QoR-15 scores on POD 1, 3, 7 and 30. Hospital Anxiety and Depression Scale - Anxiety Subscale (HADS-A) and Depression Subscale (HADS-D) scores, numeric rating scale (NRS) pain scores, and the Brief Pain Inventory (BPI) scores on POD 1 to 3, and safety evaluations. A total of 198 patients were analyzed (esketamine, n = 98; placebo, n = 100). Intraoperative esketamine significantly improved QoR-15 scores on POD 2 (116.9 ± 9.4 vs. 110.2 ± 9.8, p < 0.001) and POD 3 (123.6 ± 7.2 vs. 116.8 ± 8.4, p < 0.001) compared with placebo. HADS-A and HADS-D scores were lower in the esketamine group on POD 1 to 3 (all p < 0.001). Additionally, esketamine recipients reported significantly lower NRS scores at rest and during movement and BPI scores for pain severity and pain interference items (all p < 0.001). There were no significant between-group differences in safety outcomes. Intraoperative low-dose esketamine improved early, patient-reported recovery after MIE by enhancing analgesia and reducing postoperative anxiety and depression without increasing adverse events. Chinese Clinical Trial Register (identifier: ChiCTR2400088916).
Clinical relevance
Does intraoperative low-dose esketamine (0.25 mg/kg loading dose followed by 0.125 mg/kg/h continuous infusion) improve patient-reported quality of recovery on postoperative day 2 compared with placebo in adults undergoing elective McKeown minimally invasive esophagectomy? __SNAPSHOT__ {"studyDesign":"Double-blind, multicenter randomized controlled trial (superiority design)","setting":"Multicenter; China (Chinese Clinical Trial Register: ChiCTR2400088916); institutional type not specified in abstract","sampleSize":"n = 198 analyzed (esketamine: n = 98; placebo: n = 100)","population":"Adult patients scheduled for elective McKeown (three-stage) minimally invasive esophagectomy; detailed inclusion/exclusion criteria (ASA class, age range, comorbidity thresholds) not reported in the abstract","intervention":"Intraoperative IV esketamine: 0.25 mg/kg loading dose at induction followed by continuous infusion at 0.125 mg/kg/h throughout surgery","comparator":"Equivalent volume and rate of intravenous normal saline (placebo), administered identically to maintain blinding","primaryOutcome":"Quality of Recovery-15 (QoR-15) score on postoperative day (POD) 2; QoR-15 is a validated 15-item patient-reported scale (score range 0–150; higher = better recovery)","followUp":"30 days (QoR-15 assessed at POD 1, 2, 3, 7, and 30; pain and mood measures assessed POD 1–3)","fundingSource":"Not reported in the abstract"}
Key findings
Among 198 analyzed patients, intraoperative esketamine significantly improved the primary endpoint — QoR-15 score on POD 2 — compared with placebo (116.9 ± 9.4 vs. 110.2 ± 9.8; p < 0.001). The between-group mean difference on POD 2 was 6.7 points (calculated), which meets or marginally exceeds the commonly cited minimal clinically important difference (MCID) of approximately 6.0 points for the QoR-15 scale. QoR-15 scores were also significantly higher in the esketamine group on POD 3 (123.6 ± 7.2 vs. 116.8 ± 8.4; p < 0.001). QoR-15 results on POD 1, 7, and 30 are referenced as secondary outcomes but specific scores and p-values for those timepoints are not reported in the available abstract text. Esketamine recipients demonstrated significantly lower Hospital Anxiety and Depression Scale — Anxiety (HADS-A) and Depression (HADS-D) subscale scores across POD 1–3 (all p < 0.001). Numeric Rating Scale (NRS) pain scores both at rest and during movement, as well as Brief Pain Inventory (BPI) scores for pain severity and pain interference, were all significantly lower in the esketamine group across POD 1–3 (all p < 0.001). Absolute effect sizes, confidence intervals, and NNT/NNH for secondary outcomes were not reported in the abstract. Safety evaluations revealed no significant between-group differences in adverse events. Specific adverse event rates, types, and incidences are not reported in the abstract.
Practice implications
This multicenter double-blind RCT provides evidence that intraoperative low-dose esketamine improves early patient-reported quality of recovery, reduces pain (rest and movement), and attenuates postoperative anxiety and depression following McKeown MIE — a procedure known for high rates of moderate-to-severe postoperative pain and psychological morbidity. The observed difference in QoR-15 at POD 2 (6.7 points, calculated) is at the threshold of the established MCID (~6.0), suggesting the benefit, while statistically significant, may be at the lower boundary of clinical meaningfulness; individual patient variation (SD ~9–10 points) means that a meaningful proportion of patients may not experience a perceptible benefit. Importantly, the study was restricted to elective McKeown MIE, and findings may not generalize to Ivor-Lewis MIE, open esophagectomy, emergency cases, or patients with significant psychiatric comorbidities, chronic opioid use, or dissociative disorder history. The absence of QoR-15 data and confidence intervals for POD 1, 7, and 30 in the abstract limits full assessment of durability of benefit. The lack of adverse event frequency data in the abstract prevents a complete benefit-risk characterization, though the authors report no statistically significant safety signals. Confirmation of whether POD 7 and 30 QoR-15 benefits were sustained is needed before recommending routine adoption. Only the abstract was available for this summary — full-text review is necessary to assess blinding fidelity, allocation concealment, baseline covariate balance, concomitant analgesic protocols, institutional ERAS adherence, and completeness of outcome reporting. __LIMITATIONS__ Only the abstract was available; full-text methodological details (randomization sequence, allocation concealment, CONSORT flow, covariate balance, analgesic co-interventions) could not be verified.,Sample size is modest (n = 198) for a complex, high-morbidity surgical procedure with heterogeneous patient populations; power calculation assumptions not reported in the abstract.,The absolute between-group QoR-15 difference on POD 2 (~6.7 points, calculated) meets the MCID threshold only marginally; given large within-group SDs (~9–10 points), clinical benefit at the individual patient level may be limited.,Confidence intervals for all outcomes are not reported in the abstract, preventing assessment of precision of effect estimates.,Secondary outcomes (QoR-15 at POD 1, 7, 30; individual HADS and BPI subscores) lack absolute values and CIs in the abstract, limiting full interpretation.,Specific adverse event rates, types, and absolute frequencies are not reported in the abstract; the safety conclusion rests solely on a 'no significant between-group differences' statement.,Generalizability is restricted to elective McKeown (three-stage, cervical anastomosis) MIE; findings should not be extrapolated to Ivor-Lewis MIE, open esophagectomy, or non-esophageal thoracic procedures.,Setting is exclusively Chinese multicenter; perioperative analgesic protocols, ERAS pathways, and baseline opioid use may differ substantially from Western practice, limiting external validity.,Blinding integrity (e.g., emergence phenomena, hemodynamic changes) was not assessed or reported in the abstract.,Funding source is not disclosed, precluding assessment of potential industry influence.,Long-term functional outcomes, oncologic recovery parameters, length of stay, opioid consumption, and cost-effectiveness were not reported. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In this multicenter double-blind RCT of 198 patients undergoing elective McKeown MIE, intraoperative low-dose esketamine (0.25 mg/kg bolus + 0.125 mg/kg/h infusion) significantly improved QoR-15 scores at POD 2 and 3, reduced postoperative pain scores, and attenuated anxiety and depression without apparent safety signal. The primary effect size (~6.7 points on QoR-15, calculated) meets the established MCID threshold only marginally, and full-text review is required to evaluate allocation concealment, concomitant analgesic regimens, and complete safety data before clinical implementation. This trial is potentially practice-informing for thoracic anesthesia teams managing McKeown MIE, but should be considered hypothesis-strengthening rather than immediately practice-changing pending replication in diverse surgical and geographic settings.