To summarize the delirium treatment trial literature, identify the unique challenges in delirium treatment trials, and formulate recommendations to address each in older adults.

A 39-member interprofessional and international expert working group of clinicians (physicians, nurses, and pharmacists) and nonclinicians (biostatisticians, epidemiologists, and trial methodologists) was convened. Four expert panels were assembled to explore key subtopics (pharmacological/nonpharmacologic treatment, methodological challenges, and novel research designs).

To provide background and context, a review of delirium treatment randomized controlled trials (RCTs) published between 2003 and 2023 was conducted and evidence gaps were identified. The four panels addressed the identified subtopics. For each subtopic, research challenges were identified and recommendations to address each were proposed through virtual discussion before a live, full-day, and in-person conference. General agreement was reached for each proposed recommendation across the entire working group via moderated conference discussion. Recommendations were synthesized across panels and iteratively discussed through rounds of virtual meetings and draft reviews.

We identified key evidence gaps through a systematic literature review, yielding 43 RCTs of delirium treatments. From this review, eight unique challenges for delirium treatment trials were identified, and recommendations to address each were made based on panel input. The recommendations start with design of interventions that consider the multifactorial nature of delirium, include both pharmacological and nonpharmacologic approaches, and target pathophysiologic pathways where possible. Selecting appropriate at-risk patients with moderate vulnerability to delirium may maximize effectiveness. Targeting patients with at least moderate delirium severity and duration will include those most likely to experience adverse outcomes. Delirium severity should be the primary outcome of choice; measurement of short- and long-term clinical outcomes will maximize clinical relevance. Finally, plans for handling informative censoring and missing data are key.

By addressing key delirium treatment challenges and research gaps, our recommendations may serve as a roadmap for advancing delirium treatment research in older adults.

To assess current evidence regarding guanfacine use in hospitalized patients with delirium.

Delirium is a common and important complication of critical illness. Central alpha-2 agonists are often used for symptomatic management. Guanfacine is an enteral central alpha-2 agonist approved for the treatment of attention deficit hyperactivity disorders. However, its use for delirium treatment has not been systematically assessed.

All studies of guanfacine to treat patients with delirium during hospitalization. We excluded reviews, letters, commentaries, correspondence, conference abstracts, expert opinions or editorials.

We performed a systematic search of the literature using: MEDLINE (Ovid), Embase (Ovid), CENTRAL and SCOPUS (Elsevier) from inception until 29 February, 2024. Two independent reviewers assessed the identified citations and abstracts. Data on study and patient characteristics, as well as efficacy and safety outcomes, were extracted. Efficacy was defined by guanfacine's ability to relieve delirium and improve clinical outcomes, including intensive care unit (ICU) length of stay (LOS), hospital LOS, and mortality. Safety was assessed for hemodynamic stability or other reported side effects.

We screened 908 articles and included two case reports, one case series, two retrospective descriptive cohorts, and one retrospective analytic cohort. Guanfacine therapy was associated with delirium attenuation and a reduction in the use of sedative agents. Median dosage was 1.5 mg daily, with a median time to delirium improvement of 3 days. However, guanfacine therapy was not associated with decreased ICU or hospital LOS. The most frequently reported adverse events were mild hypotension and bradycardia.

There is limited data on the efficacy of guanfacine for the treatment of delirium. However, given its pharmacologic properties and its available safety data, controlled investigations may be justified.

Background: Although guidelines recommend twice daily (BID) dosing of quetiapine for treatment of intensive care unit (ICU) delirium in most patients, once daily dosing at bedtime (HS) is commonly prescribed to reduce daytime somnolence. No studies have evaluated differences in outcomes. Objectives: To determine if twice daily vs bedtime dosing of quetiapine reduces the duration of ICU delirium. Methods: Retrospective analysis of ICU patients treated with twice daily vs bedtime dosing of quetiapine for ICU delirium. Health records were analyzed between January 1, 2017, and December 31, 2021. Exclusions included alcohol withdrawal, history of psychiatric conditions requiring medication, receipt of <24 hours of therapy, alternative dosing schedules, and death or transfer from the ICU <24 hours after beginning quetiapine. The primary outcome was recovery of delirium per Confusion Assessment Method (CAM-ICU). Secondary outcomes included lengths of stay, mechanical ventilation duration, in-hospital death, and QTc prolongation. Results: Baseline characteristics differed for sex (30.4% vs 61.1% female) and admission diagnosis (39% vs. 17% COVID-19, respectively). Time to delirium recovery was 3.5 days for BID vs 2.5 days for QHS dosing (P = .484). Secondary outcomes of ICU (16 vs. 19 days) and hospital (22 vs. 25 days) lengths of stay, duration of mechanical ventilation (10 vs. 14), delirium recovery (70% vs. 56%), in-hospital death (61% vs. 50%), and QTc prolongation did not differ significantly between groups. Conclusions: Twice daily vs bedtime dosing of quetiapine did not significantly alter delirium outcomes, suggesting similar efficacy. Larger sample sizes are needed to confirm these results.

Researchers often conduct small studies on testing a drug's efficacy in off-label indications. If positive results from these exploratory studies are not followed up by larger, randomized, double-blinded trials, physicians cannot be sure of a drug's clinical value. This may lead to off-label prescriptions of ineffective treatments. We aim to describe the way clinical studies fostered off-label prescription of the antipsychotic drug quetiapine (Seroquel).

In this systematic meta-epidemiological analysis, we searched EMBASE, MEDLINE, Cochrane CENTRAL and PsycINFO databases and included clinical studies testing quetiapine for unapproved indications between May 1995 and May 2022. We then assessed the frequency with which publications providing low-level evidence suggesting efficacy of quetiapine for off-label indications was not followed up by large, randomized and double-blinded trials within 5 years.

In total, 176 published studies were identified that reported potential efficacy of quetiapine in at least 26 indications. Between 2000 and 2007, publication of exploratory studies suggesting promise for off-label indications rapidly outpaced publication of confirmatory trials. In the 24 indications with a minimum of 5 years of follow-up from the first positive exploratory study, 19 (79%) were not followed up with large confirmatory trials within 5 years. At least nine clinical practice guidelines recommend the use of quetiapine for seven off-label indications in which published confirmatory evidence is lacking.

Many small, post-approval studies suggested the promise of quetiapine for numerous off-label indications. These findings generally went unconfirmed in large, blinded, randomized trials years after first being published. The imbalance of exploratory and confirmatory studies likely encourages ineffective off-label treatment.

Delirium is a neuropsychiatric syndrome common in critical illness. Worsening delirium severity is associated with poorer clinical outcomes, yet its assessment remains under-reported with most severity assessment tools not validated for critical care. The DRS-R98 is a widely applied and validated tool. The aim of this project is to report the validation and utility of the DRS-R98 in critical illness.

This prospective, cohort study was conducted in adults with delirium admitted to a critical care unit and predicted to stay for ≥ 24 h. We excluded patients with severe neurological or communication barriers that would have interfered with the DRS-R98 assessment. Patients were screened using a delirium detection algorithm and the Confusion Assessment Method for the Intensive Care Unit. Eligible patient informations were collected and reported to qualified assessor/s before visiting clinical areas, confirming delirium presence and undertaking DRS- R98 assessments. To assess the tool's construct validity, an intensivist completed the Clinical Global Impression-Scale (CGI-S). To calculate the inter-rater reliability (IRR) a subset of patients were simultaneously evaluated by two assessors.

We assessed 22 patients, 73% were male, with a median age of 65 years (IQR14). The DRS -R98 mean (SD) severity score was 24 (+/-7.7), total scale was 29 (+/18.0), and CGI-S 3.5 (+/11.5). Assessment duration was 90 min (+/-55) and 15 min (+/-5) for record data extraction and clinical assessment respectively. The CGI-S significantly correlated with DRS-R98 severity (r = 0.626) and total (r = 0.628) scales. The DRS-R98 Cronbach's alpha was 0.896 for severity scale and 0.886 for total scale. The inter-rater reliability (IRR) was assessed in six patients and reported an inter-correlation coefficient of 0.505 (p = 0.124) and 0.565 (p = 0.93) for the severity and total scale respectively.

In critical care, the Delirium Rating Scale R98 had good construct validity, excellent internal consistency, and moderate inter-rater reliability.

Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium.

Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared.

Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n = 45) for trazodone and 89.1% (n = 41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups ( P = 0.17 and P = 0.13, respectively).

Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

We conducted an updated, comprehensive, and contemporary systematic review to examine the efficacy of existing pharmacologic agents employed for management of delirium symptoms among hospitalized adults.

Searches of PubMed, Scopus, Embase, and Cochrane Library databases from inception to May 2021 were performed to identify studies investigating efficacy of pharmacologic agents for management of delirium.

Of 11,424 articles obtained from searches, a total of 33 articles (N = 3030 participants) of randomized or non-randomized trials, in which pharmacologic treatment was compared to active comparator, placebo, or no treatment, met all criteria and were included in this review. Medications used for management of delirium symptoms included antipsychotic medications (N = 27), alpha-2 agonists (N = 5), benzodiazepines (N = 2), antidepressants (n = 1), acetylcholinesterase inhibitors (N = 2), melatonin (N = 2), opioids (N = 1), and antiemetics (N = 2). Despite somewhat mixed findings and a relative lack of high-quality trials, it appears that antipsychotic medications (e.g., haloperidol, olanzapine, risperidone, or quetiapine) and dexmedetomidine have the potential to improve delirium outcomes.

Pharmacologic agents can reduce delirium symptoms (e.g., agitation) in some hospitalized patients. Additional double-blinded, randomized, placebo-controlled clinical trials are critically needed to investigate the efficacy of pharmacologic agents for diverse hospitalized populations (e.g., post-surgical patients, patients at the end-of-life, or in intensive care units).

Delirium is a syndrome characterised by an acute disturbance of attention and awareness which develops over a short time period and fluctuates in severity over the course of the day. It is commonly experienced during inpatient admission in the terminal phase of illness. It can cause symptoms such as agitation and hallucinations and is distressing for terminally ill people, their families and staff. Delirium may arise from any number of causes and treatment should aim to address these causes. When this is not possible, or treatment is unsuccessful, drug therapy to manage the symptoms may become necessary. This is the second update of the review first published in 2004.

To evaluate the effectiveness and safety of drug therapies to manage delirium symptoms in terminally ill adults.

We searched CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO from inception to July 2019, reference lists of retrieved papers, and online trial registries.

We included randomised controlled trials of drug therapies in any dose by any route, compared to another drug therapy, a non-pharmacological approach, placebo, standard care or wait-list control, for the management of delirium symptoms in terminally ill adults (18 years or older).

We independently screened citations, extracted data and assessed risk of bias. Primary outcomes were delirium symptoms; agitation score; adverse events. Secondary outcomes were: use of rescue medication; cognitive status; survival. We applied the GRADE approach to assess the overall quality of the evidence for each outcome and we include eight 'Summary of findings' tables.

We included four studies (three new to this update), with 399 participants. Most participants had advanced cancer or advanced AIDS, and mild- to moderate-severity delirium. Meta-analysis was not possible because no two studies examined the same comparison. Each study was at high risk of bias for at least one criterion. Most evidence was low to very low quality, downgraded due to very serious study limitations, imprecision or because there were so few data. Most studies reported delirium symptoms; two reported agitation scores; three reported adverse events with data on extrapyramidal effects; and none reported serious adverse events. 1. Haloperidol versus placebo There may be little to no difference between placebo and haloperidol in delirium symptoms within 24 hours (mean difference (MD) 0.34, 95% confidence interval (CI) -0.07 to 0.75; 133 participants). Haloperidol may slightly worsen delirium symptoms compared with placebo at 48 hours (MD 0.49, 95% CI 0.10 to 0.88; 123 participants with mild- to moderate-severity delirium). Haloperidol may reduce agitation slightly compared with placebo between 24 and 48 hours (MD -0.14, 95% -0.28 to -0.00; 123 participants with mild- to moderate-severity delirium). Haloperidol probably increases extrapyramidal adverse effects compared with placebo (MD 0.79, 95% CI 0.17 to 1.41; 123 participants with mild- to moderate-severity delirium). 2. Haloperidol versus risperidone There may be little to no difference in delirium symptoms with haloperidol compared with risperidone within 24 hours (MD -0.42, 95% CI -0.90 to 0.06; 126 participants) or 48 hours (MD -0.36, 95% CI -0.92 to 0.20; 106 participants with mild- to moderate-severity delirium). Agitation scores and adverse events were not reported for this comparison. 3. Haloperidol versus olanzapine We are uncertain whether haloperidol reduces delirium symptoms compared with olanzapine within 24 hours (MD 2.36, 95% CI -0.75 to 5.47; 28 participants) or 48 hours (MD 1.90, 95% CI -1.50 to 5.30, 24 participants). Agitation scores and adverse events were not reported for this comparison. 4. Risperidone versus placebo Risperidone may slightly worsen delirium symptoms compared with placebo within 24 hours (MD 0.76, 95% CI 0.30 to 1.22; 129 participants); and at 48 hours (MD 0.85, 95% CI 0.32 to 1.38; 111 participants with mild- to moderate-severity delirium). There may be little to no difference in agitation with risperidone compared with placebo between 24 and 48 hours (MD -0.05, 95% CI -0.19 to 0.09; 111 participants with mild- to moderate-severity delirium). Risperidone may increase extrapyramidal adverse effects compared with placebo (MD 0.73 95% CI 0.09 to 1.37; 111 participants with mild- to moderate-severity delirium). 5. Lorazepam plus haloperidol versus placebo plus haloperidol We are uncertain whether lorazepam plus haloperidol compared with placebo plus haloperidol improves delirium symptoms within 24 hours (MD 2.10, 95% CI -1.00 to 5.20; 50 participants with moderate to severe delirium), reduces agitation within 24 hours (MD 1.90, 95% CI 0.90 to 2.80; 52 participants), or increases adverse events (RR 0.70, 95% CI -0.19 to 2.63; 31 participants with moderate to severe delirium). 6. Haloperidol versus chlorpromazine We are uncertain whether haloperidol reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 0.37, 95% CI -4.58 to 5.32; 24 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with chlorpromazine (MD 0.46, 95% CI -4.22 to 5.14; 24 participants). 7. Haloperidol versus lorazepam We are uncertain whether haloperidol reduces delirium symptoms compared with lorazepam at 48 hours (MD -4.88, 95% CI -9.70 to 0.06; 17 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with lorazepam (MD -6.66, 95% CI -14.85 to 1.53; 17 participants). 8. Lorazepam versus chlorpromazine We are uncertain whether lorazepam reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 5.25, 95% CI 0.38 to 10.12; 19 participants), or increases adverse events (MD 7.12, 95% CI 1.08 to 15.32; 18 participants). Agitation scores were not reported.

use of rescue medication, cognitive impairment, survival There were insufficient data to draw conclusions or assess GRADE.

We found no high-quality evidence to support or refute the use of drug therapy for delirium symptoms in terminally ill adults. We found low-quality evidence that risperidone or haloperidol may slightly worsen delirium symptoms of mild to moderate severity for terminally ill people compared with placebo. We found moderate- to low-quality evidence that haloperidol and risperidone may slightly increase extrapyramidal adverse events for people with mild- to moderate-severity delirium. Given the small number of studies and participants on which current evidence is based, further research is essential.

Delirium is reported in over 50% of critically ill ICU patients, and is associated with increased mortality and long-term cognitive consequences. Prevention and early management of delirium are essential components of ICU care. However, pharmacological interventions have not been effective in delirium prevention. This study investigated the effect of aripiprazole in the prevention of delirium in a neurosurgical intensive care unit.

In this prospective, randomized placebo-controlled small clinical trial, 53 patients, 18 to 80 years old, were randomized to receive enteric aripiprazole (15 mg) or placebo for up to 7 days. Delirium, detected by the Confusion Assessment Method-ICU, ICU events, laboratory studies, aripiprazole safety, time to delirium onset, delirium-free days, delirium prevalence during follow-up and ICU length of stay were recorded.

Forty patients with similar baseline characteristics, including age, sex, neurosurgery types and APACHE II scores, completed the study. Delirium incidence and the mean days to its onset were 20% vs. 55% (p = 0.022) and 2.17 ± 0.41 vs. 2.09 ± 0.30 (p = 0.076) in the aripiprazole and placebo groups, respectively. The mean number of delirium-free days were: 5.6 (95%CI, 4.6-6.5) and 4.3 (95%CI, 3.2-5.4), in aripiprazole and placebo groups, respectively (p = 0.111). The prevalence of delirium during the follow-up was significantly lower in the aripiprazole group (p = 0.018). Serious aripiprazole adverse reactions were not observed.

Aripiprazole can reduce the incidence of delirium in the neurosurgical ICU. Studies with larger sample size in diverse ICU settings and longer follow-up are needed to confirm our findings.

Delirium is common in hospitalized patients and is associated with worse outcomes. Antipsychotics are commonly used; however, the associated benefits and harms are unclear.

To conduct a systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults.

PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception to July 2019 without language restrictions.

Randomized controlled trials (RCTs) of antipsychotic versus placebo or another antipsychotic, and prospective observational studies reporting harms.

One reviewer extracted data and assessed strength of evidence (SOE) for critical outcomes, with confirmation by another reviewer. Risk of bias was assessed independently by 2 reviewers.

Across 16 RCTs and 10 observational studies of hospitalized adults, there was no difference in sedation status (low and moderate SOE), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating delirium in adult inpatients, but potentially harmful cardiac effects tended to occur more frequently.

Heterogeneity was present in terms of dose and administration route of antipsychotics, outcomes, and measurement instruments. There was insufficient or no evidence regarding multiple clinically important outcomes.

Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients.

Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).

Although haloperidol is the most widely used drug in the treatment of delirium, evidence on the relevance of atypical antipsychotics (AAPs) is growing.

To review the literature on the efficacy and tolerability of AAPs in the treatment of delirium.

A systematic search of the literature published before April 2018 was performed on PubMed using the following search strings: "Delirium" and "Atypical antipsychotics", "Novel antipsychotics", "New antipsychotics", "Quetiapine", "Olanzapine", "Aripiprazole", "Risperidone", "Paliperidone", "Clozapine", "Asenapine", "Iloperidone", "Amisulpiride", "Ziprasidone", "Zotepine", "Sertindole", "Lurasidone" or "Perospirone".

Twelve randomized controlled trials (RCTs) and 22 open trials were considered. Despite an overall lack of large-scale RCTs, there is some evidence supporting the efficacy of olanzapine and quetiapine in placebo controlled trials. In a recent and large RCT in elderly patients, risperidone and/or haloperidol were associated with a significantly worse outcome than placebo. While preliminary, the current comparative studies suggest that haloperidol and the AAPs olanzapine, quetiapine and risperidone are similarly effective, although treatment with AAPs is associated with a reduced incidence of extrapyramidal symptoms. Ziprasidone was not shown to be effective. No RCTs are available for other AAPs.

Although the current evidence of the efficacy and tolerability of AAPs in the treatment of delirium is limited and the heterogeneity of the data precluded a meta-analysis, olanzapine and quetiapine seem to be adequate alternatives to haloperidol, especially in patients who are vulnerable for extrapyramidal symptoms, who require sedation or who have a history of haloperidol intolerance. Evidently, larger-scale RCTs are urgently required.

Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence.

Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects.

We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature.

We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients.

We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes.

We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence).

There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.

Delirium is the most common psychiatric syndrome found in the general hospital setting, with an incidence as high as 87% in the acute care setting. Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances. The development of delirium is associated with increased morbidity, mortality, cost of care, hospital-acquired complications, placement in specialized intermediate and long-term care facilities, slower rate of recovery, poor functional and cognitive recovery, decreased quality of life, and prolonged hospital stays. This article discusses the epidemiology, known etiological factors, presentation and characteristics, prevention, management, and impact of delirium.

We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007.

Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated.

We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol.

Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required.

The pharmacotherapy of psychiatric emergencies is essentially determined by the acuteness, the scene of the emergency, the diagnostic assessment and the special pharmacological profile of the drug used. As there are no specific drugs, syndromic treatment is carried out. For this, primarily antipsychotic drugs and benzodiazepines are available. This article gives an overview of the current state of treatment options for major psychiatric emergency syndromes, namely agitation, delirium, stupor and catatonia, anxiety and panic, as well as drug-induced emergencies.

Delirium occurs frequently in older patients in the emergency department (ED), is underrecognized, and has potentially serious consequences. Despite its seriousness, delirium is frequently missed by emergency providers, and patients with unrecognized delirium are often discharged from the ED. Even when it is appropriately recognized, managing delirium in older adults poses a significant challenge for ED providers. Geriatric delirium is typically caused by the interaction of multiple factors, including several that are commonly missed: pain, urinary retention, constipation, dehydration, and polypharmacy. Appropriate management includes nonpharmacological management with medication intervention reserved for emergencies. We have developed a new, comprehensive, evidence-based protocol for diagnosis/recognition, management, and disposition of geriatric delirium patients in the ED with a focus on identifying and treating commonly missed contributing causes.

Delirium is a complex but common disorder in palliative care with a prevalence between 13 and 88 % but a particular frequency at the end of life (terminal delirium). By reviewing the most relevant studies (MEDLINE, EMBASE, PsycLit, PsycInfo, Cochrane Library), a correct assessment to make the diagnosis (e.g., DSM-5, delirium assessment tools), the identification of the possible etiological factors, and the application of multicomponent and integrated interventions were reported as the correct steps to effectively manage delirium in palliative care. In terms of medications, both conventional (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine, risperidone, quetiapine, aripiprazole) were shown to be equally effective in the treatment of delirium. No recommendation was possible in palliative care regarding the use of other drugs (e.g., α-2 receptors agonists, psychostimulants, cholinesterase inhibitors, melatonergic drugs). Non-pharmacological interventions (e.g., behavioral and educational) were also shown to be important in the management of delirium. More research is necessary to clarify how to more thoroughly manage delirium in palliative care.

Delirium is a highly prevalent complication in patients in palliative care settings, especially in the end-of-life context.

To review the current evidence base for treating episodes of delirium in palliative care settings and propose a framework for future development.

We combined multidisciplinary input from delirium researchers and other purposely selected stakeholders at an international delirium study planning meeting. This was supplemented by a literature search of multiple databases and relevant reference lists to identify studies regarding therapeutic interventions for delirium.

The context of delirium management in palliative care is highly variable. The standard management of a delirium episode includes the investigation of precipitating and aggravating factors followed by symptomatic treatment with drug therapy. However, the intensity of this management depends on illness trajectory and goals of care in addition to the local availability of both investigative modalities and therapeutic interventions. Pharmacologically, haloperidol remains the practice standard by consensus for symptomatic control. Dosing schedules are derived from expert opinion and various clinical practice guidelines as evidence-based data from palliative care settings are limited. The commonly used pharmacologic interventions for delirium in this population warrant evaluation in clinical trials to examine dosing and titration regimens, different routes of administration, and safety and efficacy compared with placebo.

Delirium treatment is multidimensional and includes the identification of precipitating and aggravating factors. For symptomatic management, haloperidol remains the practice standard. Further high-quality collaborative research investigating the appropriate treatment of this complex syndrome is needed.

Representation of hospitalized patients with pre-existing cognitive impairment in pharmaceutical delirium trials is important because these patients are at high risk for developing delirium. The aim of this systematic review is to investigate whether patients with cognitive impairment were included in studies on pharmacological prophylaxis or treatment of delirium and to explore the motivations for their exclusion (if they were excluded).

This study was a systematic review. A MEDLINE search was performed for publications dated from 1 January 1985 to 15 November 2012. Randomized and non-randomized controlled trials that investigated medication to prevent or treat delirium were included. The number of patients with cognitive impairment was counted, and if they were excluded, motivations were noted.

The search yielded 4293 hits, ultimately resulting in 31 studies that met the inclusion criteria. Of these, five studies explicitly mentioned the percentage of patients with cognitive impairment that were included. These patients comprised a total of 8% (n = 279 patients) of the 3476 patients included in all 31 studies. Ten studies might have included cognitively impaired patients but did not mention the exact percentage, and sixteen studies excluded all patients with cognitive impairment. The motivations for exclusion varied, but most were related to the influence of dementia on delirium.

The exclusion of patients with pre-existing cognitive impairment hampers the generalizability of the results of these trials and leaves clinicians with limited evidence about the pharmacological treatment of this group of vulnerable patients who have an increased risk of side effects.

Despite the significant burden of delirium among hospitalized adults, no pharmacologic intervention is approved for delirium treatment. Antipsychotic agents are the best studied but there are uncertainties as to how these agents can be optimally applied in everyday practice. We searched Medline and PubMed databases for publications from 1980 to April 2012 to identify studies of delirium treatment with antipsychotic agents. Studies of primary prevention using pharmacotherapy were not included. We identified 28 prospective studies that met our inclusion criteria, of which 15 were comparison studies (11 randomized), 2 of which were placebo-controlled. The quality of comparison studies was assessed using the Jadad scale. The DRS (N = 12) and DRS-R98 (N = 9) were the most commonly used instruments for measuring responsiveness. These studies suggest that around 75% of delirious patients who receive short-term treatment with low-dose antipsychotics experience clinical response. Response rates appear quite consistent across different patient groups and treatment settings. Studies do not suggest significant differences in efficacy for haloperidol versus atypical agents, but report higher rates of extrapyramidal side effects with haloperidol. Comorbid dementia may be associated with reduced response rates but this requires further study. The available evidence does not indicate major differences in response rates between clinical subtypes of delirium. The extent to which therapeutic effects can be explained by alleviation of specific symptoms (e.g. sleep or behavioral disturbances) versus a syndromal effect that encompasses both cognitive and noncognitive symptoms of delirium is not known. Future research needs to explore the relationship between therapeutic effects and changes in pathophysiological markers of delirium. Less than half of reports were rated as reasonable quality evidence on the Jadad scale, highlighting the need for future studies of better quality design, and in particular incorporating placebo-controlled work.

Most previous studies on the efficacy of antipsychotic medication for the treatment of delirium have reported that there is no significant difference between typical and atypical antipsychotic medications. It is known, however, that older age might be a predictor of poor response to antipsychotics in the treatment of delirium. The objective of this study was to compare the efficacy and safety of haloperidol versus three atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) for the treatment of delirium with consideration of patient age.

This study was a 6-day, prospective, comparative clinical observational study of haloperidol versus atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) in patients with delirium at a tertiary level hospital. The subjects were referred to the consultation-liaison psychiatric service for management of delirium and were screened before enrollment in this study. A total of 80 subjects were assigned to receive either haloperidol (N = 23), risperidone (N = 21), olanzapine (N = 18), or quetiapine (N = 18). The efficacy was evaluated using the Korean version of the Delirium Rating Scale-Revised-98 (DRS-K) and the Korean version of the Mini Mental Status Examination (K-MMSE). The safety was evaluated by the Udvalg Kliniske Undersogelser side effect rating scale.

There were no significant differences in mean DRS-K severity or K-MMSE scores among the four groups at baseline. In all groups, the DRS-K severity score decreased and the K-MMSE score increased significantly over the study period. However, there were no significant differences in the improvement of DRS-K or K-MMSE scores among the four groups. Similarly, cognitive and non-cognitive subscale DRS-K scores decreased regardless of the treatment group. The treatment response rate was lower in patients over 75 years old than in patients under 75 years old. Particularly, the response rate to olanzapine was poorer in the older age group. Fifteen subjects experienced a few adverse events, but there were no significant differences in adverse event profiles among the four groups.

Haloperidol, risperidone, olanzapine, and quetiapine were equally efficacious and safe in the treatment of delirium. However, age is a factor that needs to be considered when making a choice of antipsychotic medication for the treatment of delirium.

Clinical Research Information Service, Republic of Korea, (http://cris.nih.go.kr/cris/en/search/basic_search.jsp, Registered Trial No. KCT0000632).

Atypical antipsychotic drugs may have low propensity to induce extrapyramidal side effects in delirious patients. This study aimed to compare the efficacy and tolerability between quetiapine and haloperidol in controlling delirious behavior.

A 7-day prospective, double-blind, randomized controlled trial was conducted from June 2009 to April 2011 in medically ill patients with delirium. Measures used for daily assessment included the Delirium Rating Scale-revised-98 (DRS-R-98) and total sleep time. The Clinical Global Impression, Improvement (CGI-I) and the Modified (nine-item) Simpson- Angus Scale were applied daily. The primary outcome was the DRS-R-98 severity scores. The data were analyzed on an intention-to-treat basis.

Fifty-two subjects (35 males and 17 females) were randomized to receive 25-100 mg/day of quetiapine (n = 24) or 0.5-2.0 mg/day of haloperidol (n = 28). Mean (standard deviation) doses of quetiapine and haloperidol were 67.6 (9.7) and 0.8 (0.3) mg/day, respectively. Over the trial period, means (standard deviation) of the DRS-R-98 severity scores were not significantly different between the quetiapine and haloperidol groups (-22.9 [6.9] versus -21.7 [6.7]; P = 0.59). The DRS-R-98 noncognitive and cognitive subscale scores were not significantly different. At end point, the response and remission rates, the total sleep time, and the Modified (nine-item) Simpson-Angus scores were also not significantly different between groups. Hypersomnia was common in the quetiapine-treated patients (33.3%), but not significantly higher than that in the haloperidol-treated group (21.4%).

Patients were excluded if they were not able to take oral medications, and the sample size was small.

Low-dose quetiapine and haloperidol may be equally effective and safe for controlling delirium symptoms.

clinicaltrials.gov NCT00954603.

The aim of this study was to review the efficacy and safety of atypical antipsychotics, comparing within class, placebo, or compared to another active treatment for delirium. A literature search was conducted using PubMed, EMBASE, and the Cochrane database (1 January 1990-5 November 2012). Selection criteria for review were prospective, controlled studies (comparison studies), using validated delirium rating scales as outcome measures. A total of six prospective, randomized controlled studies were included in the review. It was found that atypical antipsychotics are effective and safe in treating delirium, even though there seemed to be no difference between each agent. In particular, comparison studies with haloperidol showed that the efficacy of atypical antipsychotics was similar to that of low-dose haloperidol. It was concluded that atypical antipsychotics appear to be effective and tolerable in the management of delirium, even though the evidence is limited.

Delirium is associated with high rates of morbidity and mortality in hospitalized medically ill patients. Haloperidol has historically been the agent of choice for the treatment of delirium, but recent studies have explored the efficacy of second-generation antipsychotics such as quetiapine. The unique pharmacology of quetiapine may allow it to treat delirium and provide sedation without causing significant extrapyramidal side effects.

To evaluate the efficacy of quetiapine for the treatment of delirium.

A search was conducted in MEDLINE and Embase (January 1960-December 2012) using keywords "quetiapine," "second-generation antipsychotic," "atypical antipsychotic," "delirium," and "agitation."

The search was limited to English-language articles and trials with treatment of delirium as the primary end point. Eight trials met this inclusion criterion.

Two randomized controlled trials, 5 open-label studies, and 1 retrospective cohort study evaluating quetiapine for the treatment of delirium were reviewed. One randomized controlled trial showed no differences in total mean delirium scores, but found the rate of delirium improvement was significantly shorter with quetiapine. The second randomized controlled trial showed the time to first resolution of delirium was shorter with quetiapine compared to placebo. Results of the open-label and retrospective cohort trials have also shown significant resolution of delirium from baseline and equal efficacy with quetiapine compared to amisulpride and haloperidol.

Quetiapine appears to be an effective and safe agent for the treatment of delirium in both general medicine and intensive care unit patients. The trials summarized suggest that quetiapine resolves symptoms of delirium more quickly than placebo and has equal efficacy compared to haloperidol and the atypical antipsychotic amisulpride. Further study is needed.

Delirium occurs commonly in acutely ill hospitalised patients, particularly in the elderly or in cardiac or orthopaedic surgery patients, or those in intensive care units (ICUs). Delirium worsens outcome. Pharmaceutical agents such as antipsychotics and, in the critically ill, dexmedetomidine, are considered therapeutic despite uncertainty regarding their efficacy and safety. Using MEDLINE, we reviewed randomised controlled trials (RCTs) published between 1977 and April 2012 evaluating a pharmacologic intervention to prevent or treat delirium in critically ill and non-critically ill hospitalised patients. The number of prospective RCTs remains limited. Any conclusions about pharmacologic efficacy are limited by the small size of many studies, the inconsistency by which non-pharmacologic delirium prevention strategies were incorporated, the lack of a true placebo arm and a failure to incorporate ICU and non-ICU clinical outcomes. A research framework for future evaluation of the use of medications in both ICU and non-ICU is proposed.

Delirium is a complex neuropsychiatric syndrome presenting primarily with disturbances of cognition, perception and sensorium, alertness, sleep/wake cycle, and psychomotor behavior in the context of a medical etiology. The presentation can be quite variable among patients and even within a given patient because of its waxing and waning course. This variability and overlap with other psychiatric syndromes has led to substantial underrecognition and undertreatment in clinical settings. Considering the significant morbidity and mortality associated with delirium and its tremendous economic burden, the failure to diagnose, refer, and treat such patients represents a critically important public health care issue. Clinicians should be systematically educated about delirium symptoms. Also, caregivers and family members of medically compromised patients should be educated about recognizing delirium. The use of structured diagnostic instruments and scales to follow the severity of symptoms has been an improvement in the field. However, much more research is needed into the use of such instruments and how they can be applied to clinical situations to improve the detection and treatment of delirium. Similarly, research is warranted that focuses on preventing delirium, potentially by identifying susceptible patients and intervening early. It is particularly challenging to devise cost-effective interventions for preventing and identifying delirium early in its course, given the rapid pace and resource limitations in inpatient and intensive care settings, and current data do not clearly indicate that such systems have proven benefit. Still, the indisputable health and financial costs of delirium indicate that prevention and identification should be a high priority.

The analysis of clinical trials in delirium is typically complicated by treatment dropouts and by the fact that even untreated individuals may have a good prognosis. These features of delirium trials warrant special statistical attention; implications for each stage of a trial planning process are described.

Choice of outcome, patient sample, and data collection in delirium trials are discussed. Descriptions are given, together with examples, of time-to-event, imputation-based, linear and nonlinear models for the analysis of randomised controlled trials for delirium.

Imputation allows evaluation of the plausibility of individual recovery trajectories, but some simple imputations are found to be unsuitable for delirium research. Time-to-event and nonlinear models encourage a global perspective on analysis, which is often preferable to cross-sectional end-of-trial assessments. It is suggested that nonlinear random effects models for longitudinal trajectories are particularly suitable in a delirium context.

It is hoped that the methods described, and nonlinear models in particular, will play a part in convincing analyses of future delirium research.

Delirium is an acute alteration of consciousness and cognition. Atypical antipsychotics (AA) have recently become a main part of its treatment. Studies in this population generate a series of ethical dilemmas concerning the voluntary participation of patients and their state of vulnerability since their mental faculties are, by definition, compromised.

To assess whether studies with AA for the treatment of delirium obtained an approval by an ethics committee on human research (ECHR), if an informed consent (IC) was obtained, whether the IC was verbal or written, and who gave the approval to participate.

Systematic review of Medline for studies of delirium where quetiapine and olanzapine were the main treatment, assessing the existence of an ECHR approval and implementation of an IC.

11 studies were identified (6 of quetiapine and 5 of olanzapine). 5 had an ECHR approval.

Most studies examining the treatment of delirium with quetiapine or olanzapine were not subject to approval by an ECHR and most of them did not obtain an IC from the patient's legal guardian. It is essential that future studies of antipsychotics and other drugs for the treatment of delirium have the protocol approved by an ECHR and a written IC signed by the patient's legal representative, since by definition delirium is a condition that compromises superior mental processes.

To examine evidence of the efficacy of antipsychotics in the treatment of delirium in older hospitalized adults.

Systematic literature review.

Hospital.

Older adults with delirium.

The MEDLINE (January 1980-December 2010) and Cochrane Databases were searched using the keywords "delirium" and "antipsychotics." References of review articles were reviewed to identify additional studies. Study selection criteria included prospective design, more than 10 participants (in treatment arms), mean age 60 and older, standardized criteria for diagnosing delirium, and validated delirium rating scales for reporting outcomes.

Thirteen articles met selection criteria: six single-agent and seven comparison studies. Of these, eight (62%) had fewer than 25 participants in treatment arms, 10 (77%) recruited participants from psychiatry referrals, and eight (62%) did not clearly describe their screening methods. All single-agent studies were open-label studies. Of the comparison studies, five (71%) used randomization, but only one of these (a placebo-controlled study) used adequate allocation concealment methods, and only one other study (comparing two antipsychotics) described a double-blind method in detail. In the only placebo-controlled study (which was stopped early), no statistically significant differences in mean delirium severity scores were found at individual time points (Days 2, 3, 4, 7, 10). The other 12 studies reported improvements in delirium severity or resolution of delirium based on cutoff scores of the scales, but it is not clear from any of these studies what the natural course of delirium would have been without use of antipsychotics.

Because of severe methodological limitations, the studies in this review do not support the use of antipsychotics in the treatment of delirium in older hospitalized adults. Additional well-designed randomized placebo-controlled trials are needed.

Delirium is a common yet under-diagnosed syndrome of acute brain dysfunction, which is characterized by inattention, fluctuating mental status, altered level of consciousness, or disorganized thinking. Although our recognition of risk factors for delirium has progressed, our understanding of the underlying pathophysiologic mechanisms remains limited. Improvements in monitoring and assessment for delirium (particularly in the intensive care setting) have resulted in validated and reliable tools such as arousal scales and bedside delirium monitoring instruments. Once delirium is recognized and the modifiable risk factors are addressed, the next step in management (if delirium persists) is often pharmacological intervention. The sedatives, analgesics, and hypnotics most often used in the intensive care unit (ICU) to achieve patient comfort are all too frequently deliriogenic, resulting in a longer duration of ICU and hospital stay, and increased costs. Therefore, identification of safe and efficacious agents to reduce the incidence, duration, and severity of ICU delirium is a hot topic in critical care. Recognizing that there are no medications approved by the Food and Drug Administration (FDA) for the prevention or treatment of delirium, we chose anti-psychotics and alpha-2 agonists as the general pharmacological focus of this article because both were subjects of relatively recent data and ongoing clinical trials. Emerging pharmacological strategies for addressing delirium must be combined with nonpharmacological approaches (such as daily spontaneous awakening trials and spontaneous breathing trials) and early mobility (combined with the increasingly popular approach called: Awakening and Breathing Coordination, Delirium Monitoring, Early Mobility, and Exercise [ABCDE] of critical care) to develop evidence-based approaches that will ensure safer and faster recovery of the sickest patients in our healthcare system.

The objective of the study was to assess the efficacy and safety of second-generation antipsychotics olanzapine and risperidone vs. haloperidol in patients of delirium admitted to medical and surgical wards.

Prospective follow-up single-blind randomized controlled trials were performed. Consecutive patients with delirium referred to the consultation-liaison psychiatry team were eligible for the study. The study sample comprised 64 patients, with 20 subjects in the haloperidol group, 21 subjects in the risperidone group and 23 subjects in the olanzapine group. A flexible dose regimen (haloperidol -0.25 to 10 mg; risperidone -0.25 to 4 mg; olanzapine -1.25 to 20 mg) was used. Delirium Rating Scale-Revised-98 (DRS-R98) was used as the primary efficacy measure, and mini mental status examination (MMSE) was used as a secondary efficacy measure.

There was no significant difference in mean baseline DRS-R98 severity scores and MMSE scores between the three groups. However, there were a significant reduction in DRS-R98 severity scores and a significant improvement in MMSE scores over the period of 6 days, but there was no difference between the three groups. Four patients in the haloperidol group, six subjects in the risperidone group and two subjects in the olanzapine group experienced some side effects.

Risperidone and olanzapine are as efficacious as haloperidol in the treatment of delirium.

This article reviews the pathophysiology, prevalence, incidence, and consequences of delirium, focusing on the evaluation of delirium, the published models of care for prevention in patients at risk of delirium, and management of patients for whom delirium is not preventable. Evidence on why physical restraints should not be used for patients with delirium is reviewed. Current available evidence on antipyschotics does not support the role for the general use in the treatment of delirium. An example of a restraint-free, nonpharmacologic management approach [called the TADA approach (tolerate, anticipate, and don't agitate)] is presented.

To survey the awareness and observation of delirium, and interventions used for delirium in Swedish intensive care units (ICUs) and to examine the influence of hospital categories and staff education on the afore-mentioned.

A questionnaire was sent to all Swedish adult patient ICUs (n=82) and completed by 55 units.

The reported prevalence of delirium was 9.4%. Assessment of delirium was performed by 62% of the ICUs, commonly by observing symptoms. Most of the suggested non-pharmacologic interventions were reported to be used by at least 85% of the units. Drugs were used by 96%, most commonly haloperidol, propofol and benzodiazepines. Written pharmacological guidelines existed in 26% of the units, while 9% had non-pharmacological guidelines. Regular observation of delirium was more common in larger hospitals than in smaller ones and education was associated with reporting a higher prevalence of delirium.

As in other countries, this study demonstrated that the awareness of delirium in ICUs is low with a lack of implementation of validated screening tools for its diagnosis. Emphasis should be placed on education and implementation of these tools to improve the quality of care for ICU patients.

Delirium is a commonly occurring complex neuropsychiatric disorder. Evidence for its treatment based on randomized controlled trials (RCTs) is poor.

To determine the efficacy and acceptability of quetiapine in the treatment of delirium.

A double-blind, RCT was conducted. A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. Other scales used were the Brief Psychiatric Rating Scale, Mini-Mental State Examination and Clinical Global Improvement. In order to account for missing data, a nonlinear mixed-effects model was used to estimate the difference between the two groups.

The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score. In terms of the DRS-R-98 noncognitive subscale, the quetiapine group improved 57.7% faster (S.E. 29.2%, P=.048) than the placebo group.

Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results.

Delirium is defined as an acute change in cognition that cannot be better accounted for by a preexisting or evolving dementia. This form of organ dysfunction commonly occurs in older patients in the emergency department (ED) and is associated with a multitude of adverse patient outcomes. Consequently, delirium should be routinely screened for in older ED patients. Once delirium is diagnosed, the ED evaluation should focus on searching for the underlying cause. Infection is one of the most common precipitants of delirium, but multiple causes may exist concurrently.

Delirium is common in all medical settings. Atypical antipsychotics are increasingly used for the management of delirium symptomatology but their effectiveness has not been systematically studied. The aim of the present study was therefore to provide an up-to-date review on the use of atypical antipsychotics in the treatment of delirium. A search was conducted of the databases of MEDLINE, PsycINFO and EMBASE from 1997 to 2008 for English-language articles using the key words 'delirium' and the names of all the atypical antipsychotics. A total of 23 studies were used for this review. Fifteen of the studies were single-agent trials. Four studies were comparison trials, including one double-blind trial, and four studies were retrospective, including three comparison studies. All studies reported improvement of delirium symptomatology after the administration of atypical antipsychotics. No study included a placebo group. Other limitations included sample heterogeneity, small sample size, different rating scales for delirium, and lack of adequate controls. The improvement in delirium was observed within a few days after treatment initiation and the doses given were relatively low. Atypical antipsychotics were well tolerated, but safety was not evaluated systematically. Atypical antipsychotics appear to be effective and safe in symptomatic treatment of delirium but the evidence is limited and inconclusive. There are no double-blind, placebo-controlled studies assessing the efficacy and safety of these agents in delirium. Further research is needed with well-designed studies.

To evaluate the efficacy and safety of amisulpride in medical inpatients who present with delirium.

Open label prospective study with 7-day follow-up. Forty hospital inpatients with delirium were recruited, seven of whom died and two of whom refused medication. The average dose of amisulpride for delirium treatment was 200-300 mg/day. Daily assessments were performed with Delirium Rating Scale (DRS), Positive Subscale of the Positive and Negative Syndrome Scale (PANSS-P), Mini Mental State Examination (MMSE), Neurological Subscale of the UKU side effect rating scale. Variance analysis was performed through repeated measurements, with the general linear model with paired comparisons and Bonferroni correction for each measured variable.

Patients showed significant improvement on the DRS from the first day of treatment DRS = 17.55 until day 7 DRS = 7.26 (F = 92.485; p < 0.001), psychotic symptoms improved from first day PANSS-P = 18.26 to last day PANSS-P = 9.35 (F = 144.83; p < 0.001). Cognitive status showed a significant improvement from day 2 MMSE = 18.71 until day 7 MMSE = 24.06 (F = 96.56; p < 0.001), and the neurological subscale of the UKU side effect rating scale showed a significant improvement the last day with respect to baseline pretreatment level (F = 7.539; p = 0.01).

These results suggest a good response to amisulpride in the acute phase of delirium, although further randomized controlled studies must be performed.

Despite the significant burden of delirium among hospitalized adults, there is no approved pharmacologic intervention for delirium. This systematic review evaluates the efficacy and safety of pharmacologic interventions targeting either prevention or management of delirium.

We searched Medline, PubMed, the Cochrane Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) information systems from January 1966 to October 2008. We included randomized, controlled trials comparing pharmacologic compounds either to each other or placebo. We excluded non-comparison trials, studies with patients aged < 18 years, a history of an Axis I psychiatric disorder, and patients with alcohol-related delirium.

Three reviewers independently extracted the data for participants, interventions and outcome measures, and critically appraised each study using the JADAD scale.

We identified 13 studies that met our inclusion criteria and evaluated 15 compounds: second-generation antipsychotics, first-generation antipsychotics, cholinergic enhancers, an antiepileptic agent, an inhaled anesthetic, injectable sedatives, and a benzodiazepine. Four trials evaluated delirium treatment and suggested no differences in efficacy or safety among the evaluated treatment methods (first and second generation antipsychotics). Neither cholinesterase inhibitors nor procholinergic drugs were effective in preventing delirium. Multiple studies, however, suggest either shorter severity and duration, or prevention of delirium with the use of haloperidol, risperidone, gabapentin, or a mixture of sedatives in patients undergoing elective or emergent surgical procedures.

The existing limited data indicates no superiority for second-generation antipsychotics over haloperidol in managing delirium. Although preliminary results suggest delirium prevention may be accomplished through various mechanisms, further studies are necessary to prove effectiveness.

A 2001 survey found that most healthcare professionals considered intensive care unit (ICU) delirium as a serious problem, but only 16% used a validated delirium screening tool. Our objective was to assess beliefs and practices regarding ICU delirium and sedation management.

Between October 2006 and May 2007, a survey was distributed to ICU practitioners in 41 North American hospitals, seven international critical care meetings and courses, and the American Thoracic Society e-mail database.

A convenience sample of 1384 healthcare professionals including 970 physicians, 322 nurses, 23 respiratory care practitioners, 26 pharmacists, 18 nurse practitioners and physicians' assistants, and 25 others.

A majority [59% (766 of 1300)] estimated that more than one in four adult mechanically ventilated patients experience delirium. More than half [59% (774 of 1302)] screen for delirium, with 33% of those respondents (258 of 774) using a specific screening tool. A majority of respondents use a sedation protocol, but 29% (396 of 1355) still do not. A majority (76%, 990 of 1309) has a written policy on spontaneous awakening trials (SATs), but the minority of respondents (44%, 446 of 1019) practice spontaneous awakening trials on more than half of ICU days.

Delirium is considered a serious problem by a majority of healthcare professionals, and the percent of practitioners using a specific screening tool has increased since the last published survey data. Although most respondents have adopted specific sedation protocols and have an approved approach to stopping sedation daily, few report even modest compliance with daily cessation of sedation.

Delirium is a common manifestation of acute brain dysfunction in critically ill patients with prevalence as high as 75%. In the last years there has been a progressive increase of publications regarding intensive care (ICU) delirium, acknowledging its importance. The occurrence of delirium in ICU is related to more adverse outcomes including self-extubation and removal of catheters, prolonged hospitalization, increased costs, higher mortality, and potentially, long-term cognitive impairment. The pathophysiology explaining the processes subtending the development of delirium is still elusive, though several theories have been discussed. It is known that different risk factors are associated with delirium in the ICU. Patients in ICU frequently receive medications to treat pain and to ensure sedation, but an association between these drugs and delirium has been shown. Therefore, this pharmacological exposure should be modified to reduce the risk factors. Giving the multifactorial genesis of delirium, multicomponent interventions to prevent delirium developed in non-ICU settings can be adapted to critically ill patients with the purpose of reducing the incidence. When delirium is diagnosed the use of typical and atypical antipsychotics may be effective for its treatment. Future studies should evaluate target interventions to prevent delirium in the ICU.