Delirium-directed interventions show mixed long-term cognitive outcomes in ICU survivors with acute respiratory failure

BackgroundDelirium is a common manifestation of acute brain dysfunction during critical illness, strongly associated with persistent cognitive impairment among ICU survivors. Although delirium duration and severity have been linked to adverse neurocognitive outcomes, it remains uncertain whether delirium-directed interventions implemented during ICU admission or after discharge can meaningfully modify cognitive trajectories. We conducted a systematic review of randomized clinical trials to evaluate whether delirium-directed interventions improve long-term cognitive outcomes in adult ICU survivors.MethodsThis PRISMA-compliant systematic review was prospectively registered in PROSPERO (CRD420261295266). We included randomized clinical trials enrolling adults admitted to medical or surgical ICUs with acute respiratory failure requiring mechanical ventilation and/or shock. Eligible studies evaluated delirium-directed pharmacological or non-pharmacological interventions and reported validated cognitive outcomes assessed at least 3 months after discharge. Risk of bias was evaluated using the Cochrane RoB 2 tool. Due to substantial heterogeneity, findings were synthesized narratively rather than quantitatively.ResultsFour randomized clinical trials met all inclusion criteria; one additional trial (Schweickert et al., 2009) was reviewed as contextual evidence given absence of post-discharge neuropsychological outcomes. Two trials derived from the same parent cohort (MIND-USA 2018 and its 2024 long-term follow-up), yielding three effective independent randomized comparisons. Two trials evaluated pharmacological treatment of established ICU delirium using antipsychotic agents. Two trials evaluated non-pharmacological rehabilitation-based interventions with validated post-discharge cognitive outcomes. Rehabilitation-based interventions were feasible and associated with signals of improved executive function. Antipsychotic treatment did not improve global cognition, functional status, or quality of life at 3 or 12 months.ConclusionRehabilitation-based delirium-directed interventions demonstrate biological plausibility and preliminary signals of benefit for long-term cognitive outcomes after critical illness, whereas antipsychotic treatment of established ICU delirium does not confer sustained cognitive benefit. The evidence base comprises three distinct randomized comparisons, underscoring the need for larger, cognition-powered trials with harmonized survivorship endpoints.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261295266, CRD420261295266.