Current controversies and future perspectives on treatment of intensive care unit delirium in adults

Table 1 Features and pharmacological management of delirium in intensive care unit

Delirium subtypes	Notes
Hypoactive (24.5%-43.5%)[6]: Apathy, decreased responsiveness, slowed motor function, withdrawn attitude, lethargy, and drowsiness	Poor response to antipsychotics
Hyperactive (1.6%-23%)[6]: Agitation, hallucinations, restlessness	May respond to antipsychotics
Mixed (52.5%)[6]: Fluctuation of hypoactive and hyperactive features	Requires a careful assessment over the time
Prevention (Drugs)
Haloperidol	Poor efficacy on ICU-D prevention and related clinical outcomes (e.g., mortality). Not recommended[15]
Atypical antipsychotics	Poor efficacy. Not recommended[15]
Dexmedetomidine	Although not recommended[15], low doses (e.g., 0.1 μg/kg per hour) may reduce ICU-D occurrence
Treatment (Drugs)
Haloperidol	Useful: 2-10 mg (IV every 6 h), but recommended for not routinely using (especially in hyperactive form)[15]
Atypical antipsychotics	Olanzapine (IM 5-10 mg; max: 30 mg/d), risperidone (0.5-8 mg), quetiapine (orally 50 mg; max 400 mg/d), and ziprasidone (IM 10 mg; max: 40 mg/d)1. Starting regimens may need to be higher than maintenance doses; Recommended for not routinely using[15]
Dexmedetomidine	Useful, but recommended (with low quality evidence) in adults under MV, especially when hyperactive manifestations preclude weaning[15]
Short-acting benzodiazepines	Useful in patient experiencing alcohol or sedative withdrawal, or for delirium resulting from seizures; Lorazepam: IM and IV forms; no active metabolites (preferred); Midazolam: IM and IV forms; has active metabolites
Drug side effects
Haloperidol	Insomnia, EPSs2 and agitation are the most common side effects. Dose dependent changes of EPSs. Cardiotoxicity occurs at doses > 2 mg IV
Atypical antipsychotics	EPSs at high doses. Olanzapine and quetiapine may lead to excessive sedation, ziprasidone is more associated with QTc prolongation
Dexmedetomidine	Bradycardia, and hypotension. Hypertension
Benzodiazepines	Delirogenic effect

¹Compared to haloperidol, their efficacy is similar, and with less extrapyramidal side effects;

²EPSs management: dose-escalation; anticholinergic; dopamine agonist; beta blockers or even benzodiazepines for akathisia. ICU-D: Intensive care unit delirium; IV: Intravenous; IM: Intramuscular; MV: Mechanical ventilation; EPSs: Extrapyramidal symptoms; QTc: Corrected QT interval.

Table 2 Selected evidence-based research on pharmacological management of delirium in intensive care unit

Ref.	Analysis	Findings
Burry et al[41]	Cochrane analysis	In non-ICU patients there is a poor evidence about the efficacy of typical, or SGAs, on the duration of delirium, discharge time, or HRQoL
Lonergan et al[42]	Cochrane analysis	Low dose haloperidol may be effective against POD, although with greater incidence of side effects when compared to the SGAs; Limitation: analysis based on small studies of limited scope
Serafim et al[43]	Systematic review	Prophylactic use of haloperidol, may be useful for reducing the prevalence of ICU-D
Herling et al[44]	Cochrane analysis	No difference proved between haloperidol and placebo for preventing ICU-D
Tao et al[53]	Meta-analysis	Administration of dexamethasone was associated with a reduction in delirium after on-pump cardiac surgery; Limitation: studies at a high risk of bias
Barbateskovic et al[45]	Systematic overview of reviews and meta-analyses	Pharmacological strategies for prevention or management of ICU-D is poor, or sparse
Chen et al[46]	Cochrane analysis	No evidence on the preventive and therapeutic role of dexmedetomidine against ICU-D and its outcome
Liu et al[47]	Meta-analysis	Dexmedetomidine may reduce delirium and duration of MV in patients after cardiac surgery when compared with propofol
Pasin et al[48]	Meta-analysis	Dexmedetomidine may reduce delirium also in patients undergoing non-invasive ventilation
Tampi et al[50]	Systematic review	Anticholinesterase inhibitors have no benefit against ICU-D prevention, or treatment
Lonergan et al[24]	Cochrane analysis	There is no evidence to support the use of BDZs in the treatment of non-alcohol withdrawal related delirium

ICU: Intensive care unit; SGAs: Second generation antipsychotics; LOS: Length of stay; HRQoL: Health-related quality of life; POD: Postoperative delirium; MV: Mechanical ventilation; BDZs: Benzodiazepines.