Preoperative Intranasal Oxytocin and Probable Acute Stress Disorder After Traumatic Fracture Surgery

Importance: Acute stress disorder (ASD) is a common and debilitating psychological sequela following traumatic fracture surgery, adversely affecting recovery and predicting chronic posttraumatic stress disorder. Effective pharmacological prevention strategies are currently lacking. Objective: To evaluate the efficacy and safety of a single preoperative dose of intranasal oxytocin for the prevention of screening-positive probable ASD in patients undergoing traumatic fracture surgery. Design, Setting, and Participants: This single-center, prospective, double-blind, placebo-controlled randomized clinical trial was conducted at the General Hospital of Western Theater Command in China. From April 2024 to April 2025, adult patients scheduled for traumatic fracture surgery were enrolled and randomized. Interventions: Participants were randomly assigned in a 1:1 ratio to either receive intranasal oxytocin, 40 IU, or an equivalent volume of intranasal saline placebo 10 minutes before the induction of anesthesia. Main Outcomes and Measures: The primary outcome was the cumulative incidence of a first screening-positive probable ASD within 3 days postoperatively, defined by a Stanford Acute Stress Reaction Questionnaire (SAS-RQ) score of 40 or higher. Key secondary outcomes included the Connor-Davidson Resilience Scale (CD-RISC), the Hospital Anxiety and Depression Scale (HADS), and salivary malondialdehyde, cortisol, and superoxide dismutase levels. Results: A total of 328 patients were randomized (164 to the saline group and 164 to the oxytocin group) and included in the intention-to-treat analysis. The median (IQR) age of all participants was 50 (34-57) years; 210 participants (64.0%) were male, and 118 participants (36.0%) were female. The 3-day cumulative incidence of screening-positive probable ASD was 26 of 164 (15.9%) in the oxytocin group vs 50 of 164 (30.5%) in the saline group (risk difference, -14.6 percentage points [pp]; 95% CI, -23.5 to -5.5 pp; risk ratio, 0.52; 95% CI, 0.34-0.79). In the prespecified Cox model, preoperative oxytocin was associated with a lower hazard of a positive screening result during follow-up (adjusted hazard ratio, 0.45; 95% CI, 0.27-0.75). Exploratory analyses suggested improved psychological outcomes and directionally consistent alterations in stress biomarker trajectories. No serious adverse events were observed. Conclusions and Relevance: In this randomized clinical trial, preoperative intranasal oxytocin is associated with a lower cumulative incidence of probable ASD after traumatic fracture surgery. These findings suggest that intranasal oxytocin may represent a feasible perioperative preventive strategy; however, these exploratory mechanistic insights and long-term safety profile warrant further investigation. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2400082612.