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

Abstract

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.

Plain language summary: Ketamine is a medicine often used during surgery to help with pain. Small amounts can help reduce pain and the need for strong painkillers. Large amounts can cause strange thoughts or feelings. Doctors aren't sure if ketamine changes the chance of patients feeling confused after surgery, which is called delirium. This study looked at whether giving a low dose of ketamine during surgery makes delirium less likely. The study looked at 106,982 adults who had surgery (not heart, brain or transplant surgery) between 2008 and 2024. It compared patients who got high or low doses of ketamine during surgery. The researchers checked if the patients had delirium in the week after surgery using hospital records, doctor notes and special tests. Out of all the patients, 2.7% had delirium after surgery. About 11% of patients received ketamine. The middle dose given was about 0.35 mg for each kilogram of body weight. Patients who got a low dose (0.35 mg per kg or less) had a lower chance of delirium. Patients who got a higher dose (more than 0.35 mg per kg) had no change in their chance of getting delirium. The safest dose seemed to be between 0.25 mg per kg and 0.34 mg per kg. Giving a small amount of ketamine during surgery may help lower the chance of confusion afterwards. Higher doses didn't make a difference.

Keywords: delirium; ketamine; multimodal anaesthesia; postoperative outcomes.