The ICU environment paradigm as a strategy to enhance the validity of delirium animal models

Delirium is common in ICU patients and associated with adverse outcomes. We hypothesized that an ICU-like environment would enhance model validity by amplifying behavioral and neurobiological alterations. Male Wistar rats (50 days old) underwent sterile laparotomy or cecal ligation and puncture (CLP)-induced sepsis, with or without exposure to an ICU-like environment. Behavioral tests (open field, Y-maze, SHIRPA) were performed at 0-36 h, along with assessments of reactive oxygen species, glial markers, neurotransmitters, and delirium incidence/severity. Predictive validity was evaluated in the most severe condition (CLP + ICU) using minocycline, dexmedetomidine, and rivastigmine. The ICU-like environment exacerbated behavioral deficits consistent with human delirium and increased their severity. We observed elevations in IL-6 (hippocampus, cortex, and plasma in laparotomy; hippocampus in sepsis) and IL-1β (cortex in laparotomy), alongside aminergic/excitatory imbalance (dopamine, noradrenaline, and glutamate). In sepsis + ICU, minocycline and dexmedetomidine reduced IL-1β/IL-6 and improved behavioral performance; rivastigmine improved selected behavioral domains, increased acetylcholine, and reduced AChE activity; dexmedetomidine decreased ROS; and minocycline and rivastigmine attenuated microgliosis. The ICU-like environment worsened behavioral and neurochemical changes, surgery plus anesthesia, and sepsis, supporting its value for enhancing model validity.