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. 2025 Jun;51(6):1011-1021.
doi: 10.1007/s00134-025-07926-w. Epub 2025 May 5.

Association of low-dose ketamine with hallucinations in critically ill patients: a target trial emulation

Ary Serpa Neto  1   2   3   4   5 , Marcus Young  6   7 , Jian Wen Chan  8   9 , Natasha E Holmes  6   10 , Kartik Kishore  6 , Dinesh Pandey  6   11 , Hossein Jahanabadi  6   11 , Andrew Casamento  8   7   12 , Rinaldo Bellomo  8   13   6   7
Affiliations

Association of low-dose ketamine with hallucinations in critically ill patients: a target trial emulation

Ary Serpa Neto et al. Intensive Care Med. 2025 Jun.

Abstract

Purpose: Ketamine use is a potentially modifiable risk factor for hallucinations. We aimed to use target trial emulation to investigate the association between low-dose ketamine and development of hallucinations in critically ill patients in the intensive care unit (ICU).

Methods: Retrospective study using data from a university affiliated ICU in Melbourne, Australia. Application of marginal structural models and parametric g-formulas to assess the impact of low-dose ketamine on the development of hallucinations.

Results: We studied 7514 patients from June 2016 to April 2021. Of these, 625 patients (8%) received low-dose ketamine, beginning at a median of 0 (0-1) days from ICU admission and at a mean daily dose of 0.11 (0.08-0.15) mg/kg/h. Low-dose ketamine treated patients had a higher rate of hallucinations within 30 days of ICU admission (26% vs. 7%; p < 0.001) and the first episode of hallucination occurred earlier than in unexposed patient (2 [1-3] vs. 3 [1-7] days from ICU admission; p < 0.001). After adjustment for baseline and time-dependent confounders, low-dose ketamine was associated with a higher risk of hallucinations within 30 days (OR, 6.46 [95% CI 5.17-8.07]; p < 0.001). These findings were confirmed with parametric g-formulas.

Conclusions: In ICU patients, low-dose ketamine was strongly associated with an increased risk of hallucinations. However, these findings should be interpreted with caution due to the observational nature of the study and the risk of residual confounding.

Keywords: Analgesia; Delirium; Hallucination; Ketamine; Sedation.

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Conflict of interest statement

Declarations. Conflicts of interest: All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Estimated risk of hallucinations within 30 days under different treatment strategies with varying initiation timing of treatment. Estimates from parametric g-formula. Reported estimates are for the ‘Always Received low dose ketamine’ group compared with ‘Natural course’. Shaded areas are 95% confidence interval. RD is risk difference and RR is risk ratio
Fig. 2
Fig. 2
Risk of hallucinations according to timing and duration of treatment with low-dose ketamine. Left panel, risk of hallucinations within 30 days and risk difference between natural course (black bars) and use of low-dose ketamine (blue bars) according to timing of initiation of ketamine. Right panel, risk of hallucinations within 30 days and risk difference between natural course (black bars) and use of low-dose ketamine (blue bars) according to duration of treatment with ketamine. The superimposed circles are the risk difference and bars are the 95% confidence interval of this difference. Risk difference calculated as the difference in risk between a strategy always using low dose ketamine and the natural course (usual care)
See this image and copyright information in PMC

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