Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a "cholinergic deficiency hypothesis" of delirium.Profound systemic inflammation occurring during sepsis is also known to cause delirium (often termed sepsis-associated encephalopathy). Animal models used to study the interactions between prior degenerative disease and overlying systemic inflammation have shown that even mild systemic inflammation causes acute and transient deficits in working memory among diseased animals. Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical delirium and "prior pathology" as defined by these new animal models may consist of synaptic loss, abnormal network connectivity, and "primed microglia" brain macrophages stimulated by prior neurodegenerative disease and aging to amplify subsequent inflammatory responses in the central nervous system (CNS). Cerebrospinal fluid
Studies of cerebrospinal fluid (CSF) in delirium are difficult to perform. Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging. However, a few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.A 2018 systematic review showed that, broadly, delirium may be associated with neurotransmitter imbalance (namely serotonin and dopamine signaling), reversible fall in somatostatin, and increased cortisol. The leading "neuroinflammatory hypothesis" (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described, but current evidence is still conflicting and fails to concretely support this hypothesis.
Predisposing factors
The most important predisposing factors are:
65 or more years of age
Male sex
Cognitive impairment/dementia
Physical comorbidity (biventricular failure, cancer, cerebrovascular disease)
Psychiatric comorbidity (e.g., depression)
Sensory impairment (vision, hearing)
Functional dependence (e.g., requiring assistance for self-care or mobility)
Dehydration/malnutrition
Drugs and drug-dependence
Alcohol dependence

Precipitating factors
Any acute factors that affect neurotransmitter, neuroendocrine, or neuroinflammatory pathways can precipitate an episode of delirium in a vulnerable brain. Clinical environments can also precipitate delirium. Some of the most common precipitating factors are listed below:
Prolonged sleep deprivation
Environmental, physical/psychological stress
Inadequately controlled pain
Admission to an intensive care unit
Immobilization, use of physical restraints
Urinary retention, use of bladder catheter,
Emotional stress
Severe constipation/fecal impaction
MedicationsSedatives (benzodiazepines, opioids), anticholinergics, dopaminergics, corticosteroids, polypharmacy
General anesthetic
Substance intoxication or withdrawal
Primary neurologic diseases
Severe drop in blood pressure, relative to the patients normal blood pressure (orthostatic hypotension) resulting in inadequate blood flow to the brain (cerebral hypoperfusion)
Stroke/Transient ischemic attack(TIA)
Intracranial bleeding
Meningitis, encephalitis
Concurrent illness
Infections – especially respiratory (e.g. pneumonia, COVID-19) and urinary tract infections
Iatrogenic complications
Hypoxia, hypercapnea, anemia
Poor nutritional status, dehydration, electrolyte imbalances, hypoglycemia
Shock, heart attacks, heart failure
Metabolic derangements (e.g. SIADH, Addisons disease, hyperthyroidism, )
Chronic/terminal illness (e.g. cancer)
Post-traumatic event (e.g. fall, fracture)
Mercury poisoning (e.g. Erethism)
Surgery
Cardiac, orthopedic, prolonged cardiopulmonary bypass, thoracic surgeries

Pathophysiology
The pathophysiology of delirium is still not well understood, despite extensive research. Animal models
The lack of animal models that are relevant to delirium has left many key questions in delirium pathophysiology unanswered. Earliest rodent models of delirium used atropine (a muscarinic acetylcholine receptor blocker) to induce cognitive and electroencephalography (EEG) changes similar to delirium, and other anticholinergic drugs, such as biperiden and hyoscine, have produced similar effects.