Dose-dependent relationship between intra-operative ketamine administration and postoperative delirium: a retrospective cohort study.
Lars Kaiser, Béla-Simon Paschold, Luca J Wachtendorf, Elena Ahrens, Theresa Tenge, Simone Redaelli, Max Hentges, Sebastian D Sahli, Guanqing Chen, Victor Novack, Matthias Eikermann, Haobo Ma, Maximilian S Schaefer
Anaesthesia July 6, 2025 DOI: 10.1111/anae.16681 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 106,982 |
| Population | Adult patients undergoing general anesthesia for non-cardiac, non-neurosurgical, and non-transplant procedures |
| Intervention | Ketamine |
| Dose | 0.35 mg.kg-1 (median; low-dose ≤0.35 mg.kg-1, high-dose >0.35 mg.kg-1) |
| Duration | Intra-operative period, with postoperative delirium assessed within 7 days |
| Topics | Ketamine Esketamine |
| Keywords | Multimodal anaesthesia Postoperative outcomes Postoperative delirium prevention Low-dose ketamine |
| Citations | 12 |
| Key findings | Intra-operative low-dose ketamine (≤0.35 mg/kg) was associated with a lower risk of postoperative delirium, while higher doses did not influence the risk. |
Abstract
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. 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. 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. Intra-operative low-dose ketamine was associated with a lower risk of postoperative delirium, while high doses did not influence the risk.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cites 3
- Effect of Esketamine on Postoperative Delirium in Patients Undergoing Cardiac Valve Replacement with Cardiopulmonary Bypass: A Randomized Controlled Trial. Anesthesia & Analgesia October 1, 2024
- Efficacy and Safety of Pharmacological Treatment in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis. Pharmaceuticals June 20, 2024
- Low-dose ketamine for acute pain: A narrative review. The American Journal of Emergency Medicine December 1, 2024