Dose‐dependent relationship between intra‐operative ketamine administration and postoperative delirium: a retrospective cohort study

Summary Introduction Ketamine is used frequently as an adjunct for general anaesthesia, exerting analgesic and opioid‐sparing properties at lower doses and psychotomimetic effects at higher doses. All dose ranges may have effects on the incidence of postoperative delirium, but clinical trials have been equivocal. We hypothesised that intra‐operative low‐dose ketamine is associated with a lower risk of postoperative delirium. Methods A total of 106,982 adult patients undergoing general anaesthesia for non‐cardiac, non‐neurosurgical and non‐transplant procedures between 2008 and 2024 were included. Primary exposure was the intra‐operative cumulative ketamine dose (mg.kg ‐1 body weight) dichotomised into high vs. low‐dose, based on the median of the cohort. Primary outcome was postoperative delirium within 7 days, based on keyword‐based search strategy, manual chart review, Confusion Assessment Method recordings and International Classification of Diseases diagnostic codes. Multivariable logistic regression and fractional polynomial regression analyses to assess a potential nonlinear dose–response relationship were performed. Results Postoperative delirium occurred in 2837 (2.7%) patients. In total, 12,199 (11.4%) patients received ketamine, with a median (IQR [range]) intra‐operative dose of 0.35 (0.25–0.52 [0.01–3.86]) mg.kg ‐1 . Compared with patients not receiving ketamine, a low dose (≤ 0.35 mg.kg ‐1 , 6109 patients) was associated with lower risks of postoperative delirium (adjusted odds ratio 0.74 (95%CI 0.59–0.89), adjusted risk difference ‐0.7% (95%CI ‐1.0 to ‐0.3%); p = 0.003). Higher doses of ketamine (> 0.35 mg.kg ‐1 , 6090 patients) did not affect the risk of postoperative delirium (adjusted odds ratio 1.00 (95%CI 0.85–1.18); p = 0.96). Fractional polynomial regression analyses indicated a U‐shaped dose–response relationship, with a minimum postoperative delirium risk at a cumulative ketamine dose of 0.25–0.34 mg.kg ‐1 . Discussion Intra‐operative low‐dose ketamine was associated with a lower risk of postoperative delirium, while high doses did not influence the risk.