Advanced age: Delirium is very common among hospitalized older adults; however, its etiology remains unclear[6]. With increase in age, organs deteriorate, and brain and cerebrovascular functions decline even in a non-diseased individual[8]. Neurons use glucose provided by the cerebral microvascular system to produce ATP via glycolysis as an energy uptake pathway[9]. The accumulation of neuronal and cerebral microvascular damage throughout life disrupts the energy uptake pathway, leading to inadequate energy uptake and decreased energy metabolism in the brain or specific areas of the brain. This can result in dysfunction in various ways and lead to delirium development in older individuals[10].

Cognitive decline or impairment: Dementia and neurodevelopmental delay are risk factors for delirium. Patients with Alzheimer's disease have a relatively high risk of delirium. Delirium occurred at a significantly higher rate in patients with faster cognitive decline than in those with slower cognitive decline[11]. The same higher prevalence of delirium exists for neurodevelopmental delays in childhood[12]. This evidence confirms that a low cognitive level is a risk factor for delirium.

History of delirium: The duration of delusions varies greatly among individuals, with most cases lasting a few days and some lasting several months. Persistent delirium is not uncommon, with 20% of patients still having some symptoms 6 mo after delirium onset[13]. In such cases, the likelihood of delirium recurrence is extremely high. Patients who have experienced delirium once are more likely to experience delirium again. Moreover, delirium maybe a predictor of cognitive decline and dementia[14]. History of delirium is common in patients with Alzheimer’s disease dementia and dementia with Lewy bodies[15].

History of emotional disturbance: Severe depressive symptoms in preoperative patients were significantly associated with higher delirium incidence[16]. A cohort study showed that depression and post-traumatic stress disorder severity were positively associated with delirium duration during a 3-mo follow-up[17].

History of alcohol abuse: During alcohol withdrawal, norepinephrinergic hyperexcitability causes symptoms such as increased blood pressure, tremors, and anxiety, which can be controlled with adrenergic agonist drugs[18]. Such drugs are also used to prevent delirium in elderly patients undergoing cardiac surgery or other procedures, including clonidine or dexmedetomidine treatment[19]. Opioids increase norepinephrine release, thereby increasing the risk of delirium development[20,21]. The use of benzodiazepines in the clinical management of alcohol withdrawal syndrome has been associated with disrupted sleep patterns and delirium[22].

Malnutrition: Nutritional deficiency is a risk factor for delirium development[23]. Preoperative malnutrition is correlated with postoperative delirium. Moreover, elevated nutrition levels may reduce the risk of postoperative delirium[24].

Visual and auditory impairment: Visual and hearing impairment increases risk of delirium; in general medical patients, the risk of delirium is 2.1-3.5 times higher in patients with visual impairment than in those without. In contrast, in surgical patients, the risk of delirium is 1.1 and 1.3 times higher in patients with visual and hearing impairment, respectively[1].

Other factors: Other factors include frailty, cardiovascular disease, cerebral atrophy, white matter disease, low education level, male sex, and comorbidities[10].

Brain function impairment: Delirium is affected by various factors of brain function, including cerebrovascular injury[25], altered metabolic levels in the brain[26], neurotransmitter imbalance[27], and damage to brain network connections[28,29]. Excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier dysfunction may be associated with delirium and severe cognitive impairment[30].

Acute somatic diseases: Acute somatic illnesses such as sepsis, hypoglycemia, and liver failure can increase the risk of delirium[31]. Septicaemia-related encephalopathy is a common neurological complication of sepsis that is poorly understood and is associated with increased morbidity and mortality. The clinical manifestations of the disease ranges from mild confusion and delusion to severe cognitive impairment and deep coma[30]. Recent popular theories such as the brain-gut axis, brain-kidney axis, and brain-spleen axis suggest that physical health can affect brain function to a certain extent[32,33].

Infection: Patients who develop delirium after infection show a significant increase in the presence of synaptic damage markers[34]. Patients with neocoronary pneumonia may also develop cerebral hypoxia and delirium[35].

Drug use: Drug use and withdrawal, including changes in medication use, are associated with delirium. Benzo-diazepines, dihydropyridines, L-type calcium channel blockers commonly used to treat hypertension, antihistamines, and opioids may pose a high risk of delirium[36].

Sleep rhythm disorders: Sleep rhythm disturbance and sleep deprivation are important factors in delirium development in ICU patients[37]. Sleep disorders and delirium share many symptoms, and their similarity has led to the belief that they are highly correlated[38].

Electrolyte imbalance: Electrolyte imbalance is a risk factor for delirium. Studies have reported that in 53 patients with delirium with serum electrolyte imbalance, correction led to a significantly shorter delirium duration in 18 patients than in 35 patients without electrolyte correction[39].

Environment: The probability of delirium increases by being in a 24-h light environment in the ICU ward or by changes in the senses, including vision and hearing, due to environmental changes[40].

Pain and surgical anesthesia: Both pain and anesthetic drug use for pain relief may trigger delirium; however, the interaction between the two and the extent of their contribution to delirium remains unclear[36]. A multicenter randomized clinical trial, among patients over 65 years old with fragile hip fractures, reported no significant difference in the incidence of delirium between general anesthesia and regional anesthesia within 7 d after surgery[41].

Other factors: Other factors include poor feeding, drug combinations, lack of communication, and physical restraint (physical activity restriction).

The clinical manifestations of delirium are complex and vary, and they are described by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as altered attention, significantly different from the basal level and accompanied by changes in consciousness, cognitive decline, and sleep rhythm disturbances[56]. Delirium has a rapid onset and appearance of symptoms, duration of several hours or days, and a fluctuating nature. For ease of memory, the diagnostic criteria for delirium have been described more simply as A (attention and awareness), disturbances in attention and awareness; B (short period, hours or days), developing over a short period, usually hours or days; C (cognitive deficit), cognitive decline; D (disturbances in A and C), other cognitive deficits that interfere with A and C judgment, such as a complete coma state, are excluded; and E (exposure to medical conditions or drugs), exposure factors, such as surgery and medications.

The diagnostic process consisted of two basic steps. First, a bedside patient assessment was performed to determine the level of attention and arousal and the presence of other cognitive deficits, psychotic features, or mental status abnormalities. Second, the patient's baseline attention and consciousness status were determined by accompanying relatives or caregivers to obtain evidence of acute change.

After the initial diagnosis, the patient must be further evaluated to obtain more details, including features such as delusions, hallucinations, and mood changes. These details are very important and affect the patient’s subsequent treatment or management plan.

Neuropsychological scales: More than 50 assessment tool scales have been developed, with varying conditions of use, mainly including use when delirium first appears or is suspected, when monitoring delirium in hospitalized patients on a regular daily basis, during brief screening, during detailed symptom documentation and neuropsychological assessment, and when assessing delirium severity[57]. Table 2 shows the commonly used neuropsychological scale of delirium assessment.

Ancillary investigations: Delirium assessment should also consider its precipitating factors; therefore, detailed ancillary examinations such as blood, computed tomography (CT), magnetic resonance imaging (MRI), and electroencephalography (EEG) should be performed. In routine blood parameters, the mean red blood cell volume and aspartate aminotransferase can be delirium predictors in trauma patients[58]. Routine blood tests should corroborate the patient’s medical history and clinical features. In addition, some cases of delirium are caused by primary central nervous system disease. Specific brain tests, such as CT or MRI, EEG, lumbar puncture, and antibody testing for autoimmune encephalitis, are selectively performed in such cases. However, it is not reasonable to perform CT in all patients with delirium. A study that included 1653 patients showed that only 11% of patients had positive CT findings, with cerebral hemorrhage being the most common cause of delirium[59]. MRI showed that reduced cerebral blood flow, oxygenation, and abnormal glucose uptake might be associated with delirium, including a high white matter signal in the brain[60].

Although there are similarities in clinical manifestations between the delirium and dementia subtype, including fluctuating cognitive decline exhibited by dementia with Lewy body (DLB), visual hallucinations or delusions exhibited by DLB and Parkinson’s disease dementia, and attention deficit in severe Alzheimer’s disease (AD), all are similar to delirium presentation. However, there are also significant differences: in terms of the mode of onset, delirium is acute and dementia is slowly progressive; concerning duration, delirium usually lasts for a few hours or days, while dementia lasts for a long time; and there is decreased arousal in delirium and that in dementia remains relatively intact.

Previous studies have shown that symptoms such as dementia and depression sometimes appear in parallel with delirium, leading to poor prognosis and high in-hospital mortality and readmission rates. Identifying delirium superimposed dementia (DSD) is important for timely treatment. Patients with dementia who suddenly present with symptoms such as irritability, unexplained falls, resistance or reluctance to communicate with caregivers, drowsiness, and hallucinations need to be closely monitored for DSD and promptly treated symptomatically[61]. Delirium and depression are very common neuropsychiatric syndromes in the elderly, and accurate condition determination is necessary for providing the best treatment plan. However, the considerable clinical overlap of symptoms makes proper identification difficult, leading to adverse medical outcomes, such as clarifying whether the patient's mood disorder is a manifestation of delirium or depression or the comorbidity or primary stage before implementing therapeutic measures[62].

Non-pharmacological measures are recognized to be effective in dealing with delirium. The intervention protocols vary among studies and mainly include orientation, cognitive stimulation, early activity, non-pharmacological sleep improvement, sensory impairment correction, identification and intervention of potential controllable risk factors or postoperative complications, pain management, gastrointestinal function improvement, supplemental nutrition, and enhancing oxygen delivery.

The Hospital Elder Life Program (HELP) is a systematic non-pharmacological intervention program[63]. According to the British Institute for Health Care Excellence guidelines for preventing, diagnosing, and managing delirium, HELP added entries for coping with hypoxia, infection, pain, and constipation[64].

After delirium onset, non-pharmacological approaches are an indispensable way. Summarily, the main points are ABCDEF: A (assessing, preventing, and managing pain); B (both spontaneous awakening and spontaneous breathing trials), promoting spontaneous awakening and breathing; C (choice of analgesia and sedation), selection of a reasonable analgesic regimen; D (delirium assessment, management, and prevention), delirium pre-assessment, management, and prevention; E (early mobility), early activity; and F (family engagement), family involvement[65].

The primary treatment of delirium is still focused on identifying and managing potential triggers. In practice, the choice of clinical measures will vary according to patient-specific situations. It is crucial to summarize treatment strategies that minimize delirium severity and duration.

Antiepileptic drugs: Valproic acid is effective in both case reports and retrospective cohort studies for delirium treatment[66,67]. Valproic acid can be administered orally or intravenously and is effective in patients with delirium associated with alcohol withdrawal, a history of traumatic brain injury, or mood disorders. Valproic acid should be avoided in pregnant women and patients with significant hepatic or pancreatic dysfunction, active bleeding, or low platelet counts. Before starting valproic acid treatment, patients should have their blood counts and liver enzyme levels checked and monitored.

Alpha-2 agonists: Dexmedetomidine, an alpha-2 agonist, effectively reduces agitation associated with delirium, decreases CNS sympathetic activity, and indirectly reduces the risk of drug combinations by reducing the use of other delirium medications. A national study showed that dexmedetomidine effectively controlled delirium in postoperative patients other than those undergoing cardiac surgery[68].

Melatonin: The effects of melatonin on delirium have been described previously. Case and retrospective studies have shown that ramelteon helps treat delirium, especially active delirium[69,70]. Melatonin is well-tolerated and safe in the population. The role of melatonin and its receptor agonists in delirium treatment deserves to be studied in-depth. It can enhance sleep consolidation and maintain a good sleep-wake cycle in delirious patients.

Vitamin B1: Nutritional deficiencies, especially vitamin B deficiencies, are associated with delirium[71]. Vitamin B1 deficiency can lead to a range of changes in mental status, including Wernicke's encephalopathy (a triad of nystagmus, oculomotor paralysis, and altered mental status), Korsakoff's syndrome (irreversible memory impairment, usually the result of untreated Wernicke's encephalopathy), and delirium.

Although no medications have been approved by the United States Food and Drug Administration (FDA) specifically for treating delirium, antipsychotic medications are often used as first-line medications to respond to and manage patients when non-pharmacologic measures are insufficient to control or improve symptoms. However, antipsychotic use for delirium treatment remains controversial. Several studies have shown that the benefits of using antipsychotic medications outweigh the risks for patients, particularly in improving agitation and psychotic symptoms[72,73]. For the control of delirium incidence, duration, severity, length of hospital stay, and mortality, antipsychotic use does not achieve satisfactory results[54].

Obvious psychotic symptoms, such as hallucinations and delusions, can be controlled using antipsychotic drugs. Antipsychotic medications’ sedative effect can effectively resolve agitation in patients with delirium. For the core delirium symptoms, including decreased attention and cognition, there is no evidence that antipsychotic medications are effective. More importantly, patients should be carefully monitored for adverse reactions and side effects after antipsychotic medication use.

The choice of medication should be based on the actual clinical situation of the patient to choose the option that maximizes the benefit[74]. For patients with severe circadian rhythm and perceptual disturbances, sedative anti-psychotics, such as quetiapine, can be selected for nighttime use; for patients with overexcited delirium, haloperidol can be selected and administered intravenously or intramuscularly for those who cannot tolerate oral administration; for delirium in patients with PD or DLB, quetiapine is preferable because first-generation antipsychotics can aggravate motor symptoms in patients with PD; if these two groups of patients need parenteral medication, olanzapine or ziprasidone can be selected to be administered intramuscularly at minimal doses; olanzapine and risperidone can be selected for patients who cannot swallow; and olanzapine can be used to exert its antiemetic effect when delirium occurs in cancer patients.

Drug dosage was initially administered at the lowest dose and frequency, as assessed by symptom severity[74]. In addition, three major critical values need to be monitored: QTc prolongation (increased risk of sudden death from ventricular tachycardia), extrapyramidal symptoms, and all-cause death in patients with dementia. QTc prolongation is usually associated with antipsychotic use. An investigational study conducted by Pfizer for FDA comparing the QTc interval before and after the use of the maximum daily dose found QTc prolongation ranging from 4.7 ms (haloperidol) to 20.3 ms (ziprasidone)[75]. Patients with delirium should have an electrocardiogram before receiving antipsychotic medication and ensure no significant QTc prolongation interval during treatment. Patients with delirium receiving antipsychotics must also be monitored for extrapyramidal symptoms, such as inability to sit still, rigidity, and dystonia, which can exacerbate emotional disturbances and cause them to change their treatment plans.

This study comprehensively discussed the latest national and international research perspectives on delirium in terms of risk factors, preventive interventions, overlapping symptoms, and clinical and specific measures to clinically deal with delirium in real-world situations.

This paper reviews the whole delirium process and its latest research progress in risk factors, preventive interventions, identification of superimposed symptoms, and clinical measures to provide a comprehensive and systematic account of delirium and present the latest medical information. This article helps readers improve understanding of delirium and helps clinicians quickly identify and take timely therapeutic measures to address the various delirium subtypes that occur in the clinic setting. This is to ensure that patients can be treated as aggressively as possible.