Esketamine and postoperative delirium: a real-looking signal at low certainty

Design

PRISMA 2020 systematic review and random-effects meta-analysis with GRADE certainty assessment, PROSPERO registered

Population

17 randomised trials, 2,914 surgical patients aged 60 and over; 11 trials in the primary analysis

Primary outcome

incidence of postoperative delirium

Effect

OR 0.57 (95% CI 0.40 to 0.82, I² 45.8%); nausea and vomiting OR 0.49 (0.32 to 0.75); psychiatric adverse events OR 1.41 (0.67 to 2.96)

A PROSPERO-registered meta-analysis pooled 17 randomised trials and 2,914 patients aged 60 and over undergoing surgery, with 11 trials contributing to the primary analysis of postoperative delirium.

Esketamine-containing regimens were associated with lower delirium incidence (OR 0.57, 95% CI 0.40 to 0.82, P = .002, I² 45.8 per cent). Four trials looking at postoperative cognitive dysfunction or delayed neurocognitive recovery suggested a larger effect (OR 0.39, 0.22 to 0.71, I² 0 per cent), but the authors rated that evidence very low certainty. Postoperative nausea and vomiting fell (OR 0.49, 0.32 to 0.75), and psychiatric adverse events did not rise (OR 1.41, 0.67 to 2.96). An exploratory analysis found no relationship between cumulative esketamine dose and delirium risk.

That last point is the one that should slow enthusiasm. If a drug prevents delirium through a pharmacological mechanism, more of it should generally do more — and here it did not. Combined with moderate heterogeneity in perioperative management across trials and the authors' own call for standardised confirmation, this is a signal worth a properly powered trial rather than a reason to change the anaesthetic today.

• Do not add esketamine to perioperative regimens for delirium prevention on this evidence
• Note the reduction in nausea and vomiting, which is a real and separately useful finding
• The absence of a dose-response relationship argues against a direct pharmacological effect
• Keep the interventions with better evidence: orientation, sleep, early mobilisation, medication review
• Watch for the standardised confirmatory trials the authors call for

Why it matters

Esketamine is already being added to perioperative regimens for this indication ahead of the evidence.

Don't overread it

Heterogeneous perioperative management across trials and limited GRADE certainty — the authors themselves ask for confirmation before practice changes.

The statistics, in plain English

An odds ratio of 0.57 with I² of 46 per cent is a moderate effect with moderate disagreement between trials. The very low certainty rating on the cognitive outcome — based on only four studies — means the estimate could change substantially with new evidence. The flat exposure-response curve is an argument against causality that a p-value cannot supply.

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