Abstract
Background
International guidelines discourage antipsychotic use for delirium; however, concerns persist about their continued use in clinical practice.
Objectives
We aimed to describe the prevalence and patterns of antipsychotic use in delirium management with regard to best-practice recommendations. Primary outcomes investigated were prevalence of use, antipsychotic type, dosage and clinical indication.
Methods
Eligibility criteria: studies of any design that examined antipsychotic use to manage delirium in adults in critical care, acute care, palliative care, rehabilitation, and aged care were included. Studies of patients in acute psychiatric care, with psychiatric illness or pre-existing antipsychotic use were excluded. Information sources: we searched five health databases on 16 August, 2023 (PubMed, CINAHL, Embase, APA PsycInfo, ProQuest Health and Medical Collection) using MeSH terms and relevant keywords, including ‘delirium’ and ‘antipsychotic’. Risk of bias: as no included studies were randomised controlled trials, all studies were assessed for methodological quality using the Mixed Methods Appraisal Tool. Synthesis of results: descriptive data were extracted in Covidence and synthesised in Microsoft Excel.
Results
Included studies: 39 studies published between March 2004 and August 2023 from 13 countries (n = 1,359,519 patients). Most study designs were retrospective medical record audits (n = 16). Synthesis of results: in 18 studies, participants’ mean age was ≥65 years (77.79, ±5.20). Palliative care had the highest average proportion of patients with delirium managed with antipsychotics (70.87%, ±33.81%); it was lower and varied little between intensive care unit (53.53%, ±19.73%) and non-intensive care unit settings [medical, surgical and any acute care wards] (56.93%, ±26.44%) and was lowest in in-patient rehabilitation (17.8%). Seventeen different antipsychotics were reported on. In patients aged ≥65 years, haloperidol was the most frequently used and at higher than recommended mean daily doses (2.75 mg, ±2.21 mg). Other antipsychotics commonly administered were olanzapine (mean 11 mg, ±8.54 mg), quetiapine (mean 64.23 mg, ±43.20 mg) and risperidone (mean 0.97 mg, ±0.64 mg).
Conclusions
The use of antipsychotics to manage delirium is strongly discouraged in international guidelines. Antipsychotic use in delirium care is a risk for adverse health outcomes and a longer duration of delirium, especially in older people. However, this study has provided evidence that clinicians continue to use antipsychotics for delirium management, the dose, frequency and duration of which are often outside evidence-based guideline recommendations. Clinicians continue to choose antipsychotics to manage delirium symptoms to settle agitation and maintain patient and staff safety, particularly in situations where workload pressures are high. Sustained efforts are needed at the individual, team and organisational levels to educate, train and support clinicians to prioritise non-pharmacological interventions early before deciding to use antipsychotics. This could prevent delirium and avert escalation in behavioural symptoms that often lead to antipsychotic use.
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Avoid common mistakes on your manuscript.
Use of antipsychotics in delirium management is common despite limited evidence of their effectiveness. |
There is a significant gap between clinical practice and guideline recommendations, especially regarding the use of antipsychotics such as haloperidol, which potentially impacts quality of care. |
It is critical that healthcare organisations follow evidence-based guidelines for delirium prevention and provide practical support for early and sustained use of non-pharmacological strategies to reduce delirium and its associated behaviours that potentially drive antipsychotic use. |
1 Introduction
Delirium is a serious neurocognitive disorder that is common in patients with acute medical illnesses, chronic medical conditions and cognitive impairment. Incidence rates vary across clinical settings, and have been reported as between 33% [1] and 80% [2] in intensive care units (ICUs), between 26% and 62% during hospitalisation in inpatient palliative care units [3], 26% in acute stroke settings [4] and 3–29% in medical in-patients [5]. Additionally, an Australian study identified approximately 15% [6] of residents living in aged care homes presented to hospital with symptoms of delirium. Moreover, a study in Canada in 12 nursing homes found the incidence was as high as 40% during a nursing home stay (on average 32 months) [7].
Delirium is a sudden change in cognition characterised by inattention, disorganised thinking and an altered level of consciousness, the course of which fluctuates [8]. Three subtypes are commonly described: hyperactive, hypoactive and mixed delirium in which those affected move between the hyperactive and hypoactive states. Psychomotor agitation, aggression and perceptual disturbances, such as paranoia and hallucinations [9, 10], are often associated with hyperactive and mixed delirium.
These behavioural manifestations [9] can interfere with provision of care to people with delirium in hospitals and residential aged care [11], especially if staff lack the requisite knowledge, skills and resources to prevent and de-escalate behaviours [12]. A recent qualitative descriptive study that examined doctors’ and nurses’ experiences (n = 42) of antipsychotic use for people with delirium in Australia [13] identified that concerns for safety of nurses and the patient with delirium were the most common reasons antipsychotics were administered. Nurses also reported being unable to complete clinical work unless the person with disruptive delirium symptoms was sedated [13]. Both doctors and nurses reported they chose to use antipsychotics in anticipation that behavioural symptoms could escalate [13]. In a similar study, interviews with 21 physicians, nurses and pharmacists in an ICU in Canada also found that reasons given for antipsychotic use were to ensure patient and staff safety, promote sleep and settle patients when staffing was inadequate, and workloads were high [14]. International guidelines allow for antipsychotic use when safety is a concern and non-pharmacological strategies have not been effective. However, in these two studies [13, 14] it was not clear whether non-pharmacological strategies were implemented prior to antipsychotic use. It is a grave concern that systems issues around staffing and workload are a driver for antipsychotic use. Antipsychotics can be considered a ‘chemical restraint’ when used to make patients more manageable and to serve the perceived best interests of healthcare providers rather than patients [15]. Further research is needed to fully understand the prescribing and use of antipsychotics for people with delirium.
The rapid sedating effects of antipsychotics contributes to their frequent use in the management of disruptive behaviours [13, 15]. In a study that examined the occurrence of delirium in a cohort of over 2 million hospital patients in the USA, 29% (n = 24,787) of patients with delirium were treated with antipsychotics [16]. Similarly, a retrospective chart review study of 212 acutely ill patients aged ≥65 years in a geriatric ward identified the prevalence of antipsychotic use to manage delirium was 58% (n = 123) with an additional 23.1% (n = 49) receiving a combination of an antipsychotic and lorazepam [17]. In a retrospective cross-sectional study of patients aged ≥65 years (n = 133) admitted to an acute geriatric care unit, antipsychotic use was prescribed to 74% (n = 73) of patients in the management of delirium symptoms [18].
There is limited evidence that antipsychotic use in any clinical setting is either effective for managing delirium or enhancing clinical outcomes. In a multi-centre, blinded, placebo-controlled trial of adults admitted to an ICU (n = 987), treatment with haloperidol did not increase the number of ‘days alive’ [19]. Additionally, a randomised double-blinded trial of patients (n = 1183) with acute respiratory failure or shock and hypoactive or hyperactive delirium in an ICU found that antipsychotics did not significantly alter the duration of delirium [20]. The REDUCE Randomized Clinical Trial, which investigated the prophylactic haloperidol use in critically ill adults (n = 1789) at high risk of delirium in 21 ICUs in the Netherlands, found no improvement in survival at 28 days (p = 0.93) [21]. A randomised clinical trial (RCT) in 11 Australian inpatient hospice and palliative care services (n = 247, mean age 74.9, standard deviation [SD] 9.8 years) investigated the efficacy of risperidone or haloperidol on delirium severity, extrapyramidal effects, sedation and survival [22]. Those in both the risperidone (0.73; 95% confidence interval [CI] 0.09–1.37; p = 0.03) and haloperidol (0.79; 95% CI 0.17–1.41; p = 0.01) groups experienced more extrapyramidal effects than those in the placebo group [22]. Moreover, those receiving haloperidol also had worse overall survival (hazard ratio, 1.73; 95% CI 1.20–2.50; p = 0.003). The authors concluded that individualised management of delirium precipitants with non-pharmacological strategies in the placebo group resulted in less severe symptoms and a shorter duration of symptoms than when antipsychotics were given [22]. A systematic review of delirium in surgical (mean age range 61–87 years) and mixed medical/surgical/ICU (mean age range 39–84 years) settings, which included 16 RCTs (2288 participants), two prospective cohort trials (458 participants) and one historical controlled trial (476 participants), showed that antipsychotic use did not decrease the duration of delirium, length of stay or mortality [23]. Similarly, a systematic review of the efficacy of antipsychotics in hospitalised non-ICU patients, which included nine randomised and quasi‐randomised trials (727 participants), found no reduction in delirium severity, symptom duration or rate of mortality [24]. Moreover, a systematic review of the benefits and harms of antipsychotic use to manage delirium in hospitalised adults, which examined 16 RCTs (1768 participants) and ten observational studies (3839 participants), concluded there was little evidence to support the routine use of antipsychotics for delirium and there was an increased risk for cardiac side effects [25].
Older people (aged ≥65 years) are at a heightened risk of delirium, and the use of antipsychotics in this population is linked to significant harm. The anticholinergic, extrapyramidal and sedative effects associated with antipsychotics increase the risk of falls [26]. Polypharmacy in older people also increases the likelihood of drug interactions, and side effects such as QT prolongation (leading to rapid heartbeats) and extrapyramidal symptoms (parkinsonism, akathisia and tardive dyskinesia), as well as being associated with an increased risk of stroke, pneumonia [26,27,28] and death [26, 29].
Internationally, current evidence-based guidelines do not recommend routine antipsychotic use for the prevention or first-line management of delirium. The American Geriatrics Society’s ‘Beers Criteria for Potentially Inappropriate Medication Use in Older Adults’ [28, 30] strongly recommends, based on moderate-quality evidence, to avoid antipsychotic use for behavioural management unless non-pharmacologic interventions have failed and/or there is a high risk of the person harming themself or others. If used, they recommend only the lowest effective dose [28, 30]. Similarly, the ‘Screening Tool of Older Persons’ Prescriptions (STOPP)—Screening Tool to Alert to Right Treatment (START)’ criteria [31] recommends to cease antipsychotic use in older people unless other care avenues have failed. In Australia, the Delirium Clinical Care Standard states that non-pharmacological strategies are first-line treatment, and antipsychotics are not recommended [32]. In situations where non-drug strategies are not working and there is imminent risk of harm because of behavioural symptoms, only using the lowest appropriate dose for the shortest possible duration is recommended (ACSQHC, 2021:28). Despite an international consensus that antipsychotics are to be avoided in the treatment and management of delirium (see summary of guidelines in Table 1), there are concerns that their use persists in clinical practice.
A preliminary search found no existing systematic review reported on the prescribing and use of antipsychotics in delirium. Hence, there is a lack of synthesised evidence on the rates of use and prescribing patterns of antipsychotics for delirium management across healthcare settings. Therefore, this review aimed to describe the prevalence and patterns of antipsychotic use in adult delirium management, with a specific focus on the proportions of people with delirium given antipsychotics, the types of antipsychotics used, the dosages, including the amount, frequency and duration, and the indications for use.
2 Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [33].
2.1 Literature Search Strategy
An initial search of MEDLINE and CINAHL was undertaken and was followed by an analysis of text in titles and abstracts, and of the index terms used to describe relevant articles. This then informed development of the search strategy, which was tailored for each information source. Database-specific search strategies were developed (as shown in the Electronic Supplementary Material) with assistance from a university health librarian. Using MeSH terms and relevant keywords, an example of the keyword combinations used were: ((deliri* OR confus*OR “cognitive dysfunction”) AND (antipsychotic OR “'chemical restraint” OR “pharmacological management”) AND (prescription OR “prescribing practice OR “medication administration”)). The reference lists of all studies selected for critical appraisal were also screened for additional studies using backward and forward reference searching. The searches were rerun immediately prior to analysis in August 2023 to ensure that the most current information was retrieved.
2.2 Criteria for Inclusion in the Review
2.2.1 Population
This review considered studies of adults (aged ≥18 years) diagnosed with delirium. For the purposes of this review, delirium was defined as “a disturbance of attention or awareness that is accompanied by a change in baseline cognition that cannot be better explained by a pre-existing or evolving neurocognitive disorder” [8]. We considered delirium to have been present if diagnosed using validated and reliable delirium diagnostic tools, such as the Confusion Assessment Method [34], and a clinician diagnosis using criteria of the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders (DSM) in accordance with versions DSM-III, DSM-III-R, DSM-IV or DSM-5. This review included studies set in acute care (e.g. ICUs, medical, surgical settings), aged care (residential care), palliative care, sub-acute in-patient rehabilitation and community settings. Studies of patients in acute psychiatric care, with psychiatric illness or pre-existing antipsychotic use were excluded.
2.2.2 Outcomes
Outcome measures of interest were the description of prescribing and administration patterns (rates of use) of antipsychotics. Studies were included if they provided data regarding prevalence of use, or patterns of prescribing, such as the type of antipsychotic, the dosage including the amount, frequency and duration, and clinical indications for use.
2.2.3 Types of Studies
We included cross-sectional, case-control, correlational, prospective, or retrospective cohort, retrospective audits or observational research study designs. Surveys of practice were also included.
2.3 Study Screening and Selection
Retrieved studies were downloaded into Covidence (Version 2) where initial title and abstract screening were undertaken independently by two authors (ET and LS). Studies that met inclusion criteria were retrieved and their full text independently assessed for eligibility by two authors (ET and LS). Any disagreements over the eligibility of studies were resolved through discussion with a third author (PC).
2.4 Assessment of Methodological Quality
All included studies were critically appraised using the Mixed Methods Appraisal Tool (MMAT) for quantitative non-randomised studies or quantitative descriptive studies [35]. The MMAT tool allows appraisal of methodological quality against five categories for a range of study designs [35]. In MMAT Part 1, studies are screened using two questions to determine if they are empirical studies; non-empirical studies were excluded [35]. In Part 2, five methodological quality criteria were assessed [35]. Each criterion is rated as ‘Yes’ or ‘No’ or ‘Can’t Tell’. The ‘Can’t Tell’ response signifies that the appropriate information is not reported. Studies were rated on a scale of 5 (all five criteria met) to 1 (only one criterion met). Each study was appraised independently by two authors (ET, LS or PC) with the third person as the arbiter when required.
2.5 Data Extraction
Descriptive and quantitative data were extracted using a tool specific to the outcomes of this study, developed within Covidence Review Software. Data were abstracted by one author (ET) and checked by a second (LS or PC). Descriptive data included demographic information on study participants (age in years, sex, setting) and method of delirium diagnosis. Data on prescribing patterns included (i) the rates of use of antipsychotics, (ii) generic name/s of medication, (iii) prescription frequency, (iv) dose, (v) number of antipsychotics given, (vi) days of treatment, (vii) reasons for administration and (viii) continuation of antipsychotics on discharge.
2.6 Analysis and Synthesis Method
The results of the studies included in the analysis were systematically summarised. Data gathered in Covidence were exported to Microsoft Excel (Version 2312) for the final synthesis. Only studies containing pertinent data related to each specific objective were included in the synthesis for that particular outcome. The summarised results are presented in tables, and any data suitable for graphical representation were compiled in Excel. Descriptive data analyses, including mean, median and standard deviation calculations, were performed in Excel. The presentation of findings is organised according to the research objectives. In order to address the risk of bias arising from any potential missing results in our synthesis, we contacted authors of one study [36] for additional information regarding their findings.
3 Results
3.1 Search Findings
A total of 2359 references were imported for screening from the initial search strategy and 428 duplicates were removed. The authors screened 1931 against title and abstract. Of these, 178 studies underwent a full text review for eligibility. One study was identified by citation searching of the relevant literature that was not identified in the search strategy. Thirty-nine studies (n = 1,359,519 patients) met the inclusion criteria and were included in this review (Fig. 1).
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flow diagram for new systematic reviews, which included searches of databases [33] (diagram created using Haddaway et al. [89]). APA American Psychiatric Association, CINAHL Cumulated Index to Nursing and Allied Health Literature
3.2 Study Characteristics
3.2.1 Surveys of Practice
Nine studies reported data from self-report questionnaires/surveys (Table 2). Survey cohorts were psychiatrists (n = 2), pharmacists (n = 1), palliative medicine physicians (n = 1), hospital doctors (n = 1), geriatric specialists (n = 1), ICU physicians (n = 1), health professionals who cared for patients with delirium (n = 1) and delirium experts (n = 1). Response rates were reported from five studies and rates varied between 21.1% and 92%. Study samples ranged in size from 48 to 2122 participants.
3.2.2 Prospective Studies
Three studies used prospective designs including: prospective cohort, point prevalence survey and prospective observational clinical audit (Table 3). Two were conducted in palliative care settings and one in a medical/surgical setting. No RCTs were included. The total number of patients in the prospective studies was 4480.
3.2.3 Retrospective Studies
Retrospective medical record audits were the most common study design (n = 16). This included retrospective cohort studies (n = 8), a retrospective case/control study (n = 1), a repeated cross-sectional study (n = 1) and a retrospective cross-sectional study (n = 1). The total number of patients in the retrospective studies was 1,355,039. Summarised characteristics of these studies are reported in Table 4.
3.3 Methodological Quality Assessment
The MMAT [35] was used to appraise the methodological quality of studies. Methodological quality of studies was generally high; six studies met all five MMAT criteria and 28 met four criteria. Quality assessment ratings of each study are provided in Tables 2, 3 and 4.
3.4 Patient Characteristics
Retrospective and prospective studies reported on antipsychotic prescribing for individuals with delirium across several settings. This included general acute care wards (n = 12), palliative care (n = 5), ICU (n = 5), medical and surgical wards (n = 4), geriatric care (n = 1), stroke centre (n = 1) and skilled nursing facility [sub-acute rehabilitation] (n = 1). No studies were identified from aged care/residential care settings. Methods of diagnosing delirium varied, however, clinical diagnosis was the most common (n = 16). The average age (years) of patients by setting was 65.31 (SD 8.17) in palliative care, 62.03 (SD 5.00) in the ICU and 75.07 (SD 8.59) in general acute surgical/medical (non-ICU). Eight studies included only older hospitalised patients (aged ≥65 years). In 18 studies, there were patient populations whose mean age exceeded 65 years; across these studies the average age (years) was 77.79 (SD 5.20). Demographics of populations in the included studies are summarised in Table 5.
3.5 Administration of Antipsychotics
Twenty studies reported on the proportions of people with delirium prescribed antipsychotics for its management (Fig. 2). The average proportion of people receiving antipsychotics in all settings was 54.89% (median 58.00%, range 17.80–95.00%). Palliative care settings had the greatest proportion of people with delirium who were prescribed antipsychotics for its management (mean 70.87%, SD 33.81%, median 83.50%, range 21.50–95.00%). The average proportions varied little between ICU (mean 53.53%, SD 19.73%, median 45.60%, range 39.00–76.00%) and non-ICU settings [medical, surgical and any acute care wards] (mean 56.93%, SD 26.44%, median 64.34%, range 18.30–93.20%).
Proportion of people prescribed antipsychotics for the management of delirium
In patients aged ≥65 years in non-ICU settings (surgical/medical/acute care), the average proportion administered antipsychotics was 53% (mean 53.06%, SD 27.34%, median 61.17%) (see Table 6). For all studies across settings with patients aged ≥65 years (including nine acute hospital/medical, one skilled nursing facility and two palliative care), the average proportion of antipsychotic administration was 50.78% (SD 27.27%, median 58.00%).
Reppas-Rindlisbacher et al. [37] reported increased monthly rates of new prescriptions for antipsychotics (per 1000 discharges) from 6.9 before the COVID-19 pandemic (1 January, 2017, to 31 March, 2020) to 8.8 during the first 2 years of the COVID pandemic (1 March, 2020 to 31 March, 2022). The online survey by Hosie et al. [38] reported that 55% of respondents had used antipsychotics to manage delirium in the past 12 months. Of those, 60% reported using antipsychotics in one third of patients experiencing delirium, whereas 21% reported using antipsychotics in more than two thirds. The highest proportion of antipsychotic use to treat delirium (in the last 12 months) was reported by respondents from palliative care (79%, n = 112/142).
3.6 Types of Antipsychotics
Nineteen studies reported on the types of antipsychotics used (Table 7). Thirteen different antipsychotics were reported. The typical antipsychotic haloperidol was the most frequently prescribed (n = 16), followed by atypical antipsychotics such as quetiapine (n = 13), risperidone (n = 9) and olanzapine (n = 10). Flurie et al. [39] reported that 98% of patients with delirium in the medical ICU were prescribed haloperidol. On average, 57.74% of patients received a typical antipsychotic and 37.05% received an atypical antipsychotic.
In studies that surveyed clinical practice (n = 4), between 35% and 98% of clinicians self-reported haloperidol as the medication of choice when managing delirium (Table 8).
3.7 Doses of Antipsychotics
Thirteen studies reported daily average or daily median doses of antipsychotics administered to manage delirium. For all antipsychotics, the daily doses varied widely (Table 9). Haloperidol was the most frequently reported antipsychotic for which doses were reported. Across studies and settings, the mean daily dose of haloperidol ranged from 1.5 mg to 9.4 mg and averaged 4.01 mg/day (SD 2.63, median 3.42 mg/day). Intensive care units had the highest average daily dose of haloperidol (8.45 mg/day, SD 1.34, median 8.45 mg/day). Patients in palliative care settings received an average of 3.05 mg/day of haloperidol (SD 1.34, median 3.05 mg/day). In general medical and surgical settings, older people received an average of 3.23 mg/day of haloperidol (SD 2.01, median 2.71 mg/day). The average daily dose of olanzapine across studies was 8.91 mg/day (SD 5.52, median 8.4 mg/day). Refer to Table 9 for doses of other reported medications (including risperidone and quetiapine).
Given the high risk for delirium in older people, a sub-group analysis was performed on studies where the average participant age was over 65 years (Table 10). In this sub-analysis, most studies were conducted in medical/acute (non-ICU) areas. The average daily dose of haloperidol to manage delirium in patients aged over 65 years in these settings was 2.75 mg (SD 2.21, median 2.25mg) and 11 mg for olanzapine (SD 8.54) (Table 10). In survey methodology studies, respondents recommended daily dose of haloperidol varied from 0.5 mg to 30 mg across the settings (Table 11).
3.8 Number of Doses of Antipsychotics Administered
Only three studies reported the number of antipsychotic doses that people with delirium received (Table 12). In the study by Flurie [39], mean number of doses of haloperidol were 7.7 (SD 9.1) in the medical ICU and 2.8 (SD 1.7) in the medical ward (p = 0.01) whereas mean number of doses of olanzapine were 9.8 (SD 13.7) in the medical ICU and 19 (SD 19.8) in the medical ward (p = 0.53). Nguyen et al. [18] reported both the scheduled and pro re nata (PRN) number of prescriptions. Different quantities were noted between scheduled and PRN dosing for haloperidol, with eight scheduled prescriptions and 112 PRN prescriptions. Notably, only 2% of the PRN doses for haloperidol were administered [18].
3.9 Number of Types of Antipsychotics Administered
Four studies reported on the number of different types of antipsychotics administered for each person with delirium (Table 13). All four studies examined patient cohorts aged over 60 years. A single type of antipsychotic was used for between 29.5% (n = 26/156) and 76.3% (n = 119/156) of people with delirium. Two types of medications were used for between 9% (n = 14/156) and 43% (n = 34/79) of people with delirium (Table 13). The medications reported were haloperidol, risperidone, quetiapine and olanzapine. Data that specify the combination of these types of antipsychotics for those patients receiving two or more was not provided.
Halavonich et al. [40] reported the median number of antipsychotics used differed between patients with delirium seen by a psychiatric consult group (median =2) compared with those in the non-consult group (median =1). Flurie et al. [39] also reported that the median number of antipsychotics administered per patient in the medical ICU was 1, whereas it was 1.5 in the medical ward.
3.10 Days of Antipsychotic Treatment
Seven studies reported on the number of days (median or mean) that antipsychotics were used to manage delirium (Table 14). Most studies reported all antipsychotics together and did not specify the medication type. The median number of days of treatment with any antipsychotic ranged from 4 to 7 days (mean 3.6–16.8 days). In three survey studies, respondent recommendations on the duration of antipsychotics were reported. One quarter (27%, n = 32) of survey respondents in the study by Morandi et al. [41] stated that antipsychotics should be continued until delirium resolution. Survey respondents in the study by Alexopoulos et al. [42] stated that if there is an inadequate response to an antipsychotic, the medication should be changed, or dose altered after 1 day. Respondents also recommended antipsychotics be continued for 1 week after a response to medication was observed before considering discontinuing treatment [42]. Similarly, in the study by Franco et al. [43], survey respondents indicated pharmacological treatment could be continued for 1 week (18.8%, n = 19/101), 1–2 weeks (10.9%, n = 11/101), until the patient improves (9.9%, n = 10/101) or 2 weeks (8.9%, n = 9/101).
3.11 Clinical Indications for Administration
Eight studies reported on the reasons that antipsychotics were administered to people with delirium. The most common response cited was acute agitation (Table 15). Moreover, Hosie et al. [38] reported the most common goals of care when using antipsychotics for patients with delirium were to decrease the intensity of patient distress (79%, n = 153) and/or to restrain unsafe behaviours (67%, n = 130, e.g. physical aggression).
3.12 Continuation of Antipsychotic Therapy on Discharge
Three studies reported on the continuation of antipsychotics at discharge, where ‘discharge’ included transfer from the ICU to an acute care ward, or from acute care to home/place of residence. Halavonich et al. [40] reported that 34.2% (n = 52) of patients with delirium (from areas including critical care units and general medicine floors) remained on antipsychotics at discharge from hospital, the majority of which were prescribed as regular scheduled doses. In the study by Boncyk et al. [44], 20.6% (n = 804) of patients newly initiated on antipsychotics in the ICU were discharged from the hospital still on the medication. Additionally, Flurie et al. [39] reported that 26% (n = 23) of patients with delirium were continued on antipsychotic therapy after transfer from a medical ICU to the medical ward, and 39% (n = 9) of those patients remained on antipsychotics when discharged from hospital [39]. Likewise, in the study by Nguyen et al. [18], one third of patients who started antipsychotics continued after discharge (n = 24).
3.13 Antipsychotic Use According to Delirium Subtype
Two studies described the use of antipsychotics according to delirium subtype. Nguyen et al. [18] reported that 22% of patients (n = 11) with hypoactive delirium, 25% (n = 11) with hyperactive delirium and 51% (n = 2) with mixed delirium were administered antipsychotics. Furthermore, Fang et al. [45] reported that in palliative care, antipsychotics were administered to 8.2% (n = 73) of patients with hypoactive delirium (all were haloperidol), 65.2% (n = 23) of patients with hyperactive delirium (of which most were haloperidol) and 18.2% (n = 2) of patients classified as having mixed delirium.
In the survey conducted by Morandi et al. [41], a majority of respondents would adopt a combined pharmacological/non-pharmacological approach (60%, n = 103) in the management of hyperactive delirium, whereas 30% (n = 51) would use a non-pharmacological approach and 9.4% (n = 16) would use only a pharmacological approach. Haloperidol (62%, n = 92) and risperidone (12%, n = 18) were the antipsychotics most commonly suggested to manage hyperactive delirium. Respondents took a different approach for the management of hypoactive delirium, with most applying non-pharmacological approaches only (67.5%, n = 108) and only 3% (n = 5) reporting they would only use pharmacological measures. Haloperidol was again the antipsychotic of choice for managing hypoactive delirium (46%, n = 31) followed by risperidone (16%, n = 11).
3.14 Outcome of Antipsychotic Use
In the study by Boncyk et al. [44], a significantly increased hazard of mortality was associated with the use of haloperidol (hazard ratio 1.46, 95% CI 1.10–1.93, p = 0.01) and olanzapine (hazard ratio 1.67, 95% CI 1.14–2.45, p = 0.01). Furthermore, people with delirium who received antipsychotics experienced a longer median length of stay (median 10.0, interquartile range 7.0–14.0) compared with those who did not receive antipsychotics (median 8.0, interquartile range 5.3–10.8). Furthermore, Egberts et al. [17] found that the incidence of post-discharge institutionalisation was notably higher in persons who received antipsychotics compared with those who did not (59.3% vs 45.0%).
4 Discussion
This review aimed to describe antipsychotic use for delirium management in clinical practice. We examined how often people diagnosed with delirium were given antipsychotics, the types of antipsychotics they received, the doses of those medications and if the initiated antipsychotic was continued at discharge. Currently, no drug is approved to treat delirium by either the Australian Therapeutic Guidelines (Psychotropic) [hereafter referred to as the Australian Guideline] [46] or the US Food and Drug Administration. The Australian Guideline recommendations on antipsychotic use in delirium were identified by the authors of this review as the most comprehensive available and served as the benchmark in this discussion. Delirium guidelines specific to clinical settings are also discussed regarding the findings where appropriate. The key findings of this review were that contrary to recommendations in international guidelines, in everyday clinical practice, antipsychotics were used to manage delirium: (1) in a high proportion of patients; (2) off-label and in doses that exceeded recommendations for safe use; and (3) for longer than recommended. Each of these are discussed in turn in the following sections.
High prescribing rates of antipsychotics to manage delirium found in this review indicated that the gap between best practice and clinical practice remains. Given the recommendation by numerous international guidelines to avoid antipsychotic use, especially in older people [32, 47,48,49,50,51,52,53], this finding is particularly concerning. All guidelines suggest antipsychotics only be used after first addressing contributory predisposing and precipitating factors, or when symptoms are unsafe or causing significant distress to the individual [54], and, that they only be used in low doses for short periods [46, 51, 55]. We speculate the reasons for prescribing antipsychotics are related in part to the clinical context in which delirium occurs.
Delirium is a complex fluctuating condition that often occurs in medically unwell patients in settings where staff and resources can be suboptimal, and this can influence clinicians’ decisions to prescribe and use antipsychotics [13, 14]. Eight studies in this review reported indications for prescribing antipsychotics for delirium, such as behavioural concerns, acute agitation, to decrease patient distress, or restrain unsafe behaviours, e.g. physical or verbal aggression [16, 38, 56,57,58,59,60,61]. This suggests safety concerns were commonly a factor in clinicians’ decisions to use antipsychotics, although there was little evidence provided to explain how the clinical context influenced the decision. In addition to safety concerns, Tomlinson et al. [13] identified that nurses were concerned by the considerable amounts of time and attention needed to provide care for people with hyperactive or mixed delirium especially when they had high workloads and were time poor. Nurses wanted people with delirium to be calm and settled otherwise they “can’t do my job” properly [13]. Nurses’ also experienced stress when they struggled to manage aggressive behaviours and would pressure doctors into prescribing antipsychotics [13]. A lack of people and staff trained to deploy non-pharmacological interventions for delirium, which are recommended first-line management [9], may contribute to the use of antipsychotics [13, 15].
Evidence has shown that the addition of trained personnel (e.g. volunteers) in the care of patients with delirium can reduce antipsychotic use. A pilot study in Poland investigated the effectiveness of a volunteer-led multi-component non-pharmacological intervention on the reduction in outcomes including antipsychotic prescriptions in internal medicine patients (n = 130) [62]. The intervention, which included regular patient visits to support orientation, physical activity, nutrition, hydration and sleep quality [62], significantly reduced the initiation of antipsychotics (16.9% intervention [n = 65] versus 32.3% control [n = 65], p = 0.04) [62]. The benefit of non-pharmacological interventions has also been corroborated in a study from the USA that examined the effect of the Hospital Elder Life Program (HELP), which involved a personalised care plan delivered by trained volunteers [63], on a range of outcomes including the prevalence of newly prescribed antipsychotics to hospitalised patients aged ≥65 years (N = 12,281) [64]. Antipsychotics were ordered significantly less often in the HELP group (n = 1411) than in the standard care group (n = 10,807) [8.9% n = 125 vs 31.5% n = 3400, p < 0.001] [64]. Of the 31.5% (n = 3400) of patients in the standard care group who received an antipsychotic, 85.3% (n = 2899) received a first-generation antipsychotic (including chlorpromazine, haloperidol, perphenazine, prochlorperazine, fluphenazine) [64]. For patients who were diagnosed with delirium in the HELP group (2.7%, n = 38), approximately 50% (n = 19) were given an antipsychotic compared with 62.4% of patients (n = 918) with delirium in the standard care group. However, more research is needed, not only to explore the effects of non-pharmacological strategies on antipsychotic use, but also how evidence-based approaches to implementation could support clinicians to adhere to best practices.
In this review, consistent with previous research, we identified that amongst the wide range of antipsychotics used, haloperidol was the most frequent across settings. Findings from two systematic reviews indicate that available evidence does not support the use of haloperidol or other second-generation antipsychotics to treat the symptoms of delirium in older adults [23, 25]. Furthermore, there is mixed evidence regarding the efficacy of haloperidol, it has potential for serious side effects [55] and has been linked to adverse outcomes [65]. Additionally, in a recent review of the use of haloperidol in older people with delirium, the Medicines and Healthcare products Regulatory Agency [55] advised special caution is needed. Evidence is lacking as to why, despite emerging evidence, haloperidol continues to be so widely used in delirium management.
The dosages of antipsychotics reported in studies in this review varied across settings but consistently exceeded that recommended in guidelines. Guidelines across all clinical settings recommend antipsychotics be only used at the lowest appropriate dose for the shortest possible duration [32, 51, 55, 66]. The Australian Guideline recommends haloperidol only be used if clinically indicated and then be given as a single oral dose of 0.5 mg, or up to 1 mg for younger patients [46]. However, we found reported haloperidol doses across all settings far exceed guideline recommendations.
In addition to haloperidol, use of olanzapine also exceeded recommended doses. Although numerous studies did not report every individual dose, the high daily average dose reported suggests multiple doses were given in a single day. The Australian Guideline suggests that, if used, a single oral dose of olanzapine between 1.25 and 2.5 mg be given, and up to 5 mg for younger patients [46]. We found daily doses of olanzapine generally exceeded guideline recommendations. Notably, use of risperidone adhered more closely to the recommended guideline of a single oral 0.5-mg dose with up to 1 mg for younger patients [46]. Studies in this review reported doses that ranged from 0.5 mg to 1.7 mg. However, in the subgroup analysis of people aged ≥65 years, the average dose of 0.97 mg was higher than recommended. In addition to excessive dosages, these findings highlight a significant variation in the amounts of antipsychotics used for delirium management.
International guidelines for antipsychotic use in delirium management are consistent and vary little between settings or clinical contexts and as such should be followed as closely as possible in all patients with delirium. Clinical Practice Guidelines for Adults in the Intensive Care Unit [53] recommend not routinely using haloperidol or an atypical antipsychotic to treat delirium. The recommendation is based on evidence that typical antipsychotics (e.g. haloperidol) and atypical antipsychotics (e.g. quetiapine, ziprasidone) are not associated with a shorter duration of delirium or decreased mortality. They further state that patients who experience significant distress or are at risk of harm may benefit from short-term haloperidol or an atypical antipsychotic until symptoms resolve [53]. A multicentre blinded placebo-controlled trial of 987 patients admitted to the ICU [19] identified that treatment of delirium using haloperidol did not lead to a greater number of days alive. Furthermore, a randomised, double-blind, placebo-controlled trial of 566 ICU patients [20] found that neither haloperidol nor ziprasidone significantly altered the duration of delirium (odds ratio, 0.88 [95% CI 0.64–1.21]. Doses of haloperidol used in ICUs in studies included in this review were extremely high and well above the recommendations for use of haloperidol in the ICU Clinical Practice Guidelines [53].
Guidelines for delirium management at the end of life [52] recommend avoiding antipsychotics in terminal patients. If pharmacological treatment is needed, a short-term low-dose antipsychotic is recommended for symptoms of perceptual disturbance, to control severe agitation, or if there are safety concerns [52]. Our review identified that ~70% of patients in palliative care settings had delirium managed with antipsychotics, and the average daily haloperidol dose of 3.05 mg exceeds recommendations. Even though patients may be terminal, potential risks associated with antipsychotic use should still be considered. A recent Cochrane systematic review [67] that investigated four RCTs of drug therapies in terminally ill adults (n = 399) concluded that haloperidol may slightly worsen delirium symptoms (median 0.49, 95% CI 0.10–0.88; n = 123) and increase extrapyramidal adverse events (median 0.79, 95% CI 0.17–1.41; n = 123). Furthermore, antipsychotics can appear to reduce some delirium symptoms through their sedating action but do not treat the underlying pathology of delirium [52]. Adding an antipsychotic can change delirium from hyperactive to hypoactive, which is equally distressing for the patient [52]. Shared decision making between clinicians, patients and family caregivers prior to antipsychotic use could reduce the risk of inappropriate prescribing and dosing, and facilitate active decision making to consider discontinuation when clinically appropriate [52].
There were very few studies that reported the use of antipsychotics according to the subtype of delirium. It is not surprising that for patients with hyperactive delirium, who may experience increased agitation and combative or uncooperative behaviour [9], there was a trend towards higher rates of antipsychotic use. As antipsychotics can reduce agitation and psychotic symptoms, and have a sedating effect, they are recommended if the patient is severely distressed and at risk of harming themselves or others [46]. However, studies in this review highlighted that some patients with hypoactive delirium also received antipsychotics [18, 45]. Patients with hypoactive delirium have reduced motor activity, increased lethargy and are quiet and withdrawn, symptoms that do not align with recommendations to consider antipsychotic use for reasons of agitation, distress or safety concerns. Indeed, antipsychotics are not recommended for the management of patients with hypoactive delirium [68]. The use of antipsychotics in patients with hypoactive delirium should be further investigated and future research should look specifically at delirium subtypes.
Antipsychotics were given repeatedly and over several days to many patients in studies in this review. This is well beyond the Australian Guideline’s recommendation of “a single dose of an antipsychotic is usually adequate” [46]. Irrespective of whether the number of doses or days of treatment were described, all studies in this review reported treatment that exceeded recommendations for the use of antipsychotics in people with delirium in all reported settings. The study by Tomlinson et al. [13] offers a possible explanation. In this qualitative study, clinicians (doctors and nurses) described that they would continue antipsychotics in anticipation of worsening behaviours. This means that antipsychotics were prescribed pre-emptively, in the absence of behavioural symptoms, to reduce the likelihood of disruptive agitated behaviours [13]. Regular evaluation of continued treatment with antipsychotics is essential [15]. More research needs to be done to understand clinicians’ rationale for giving repeat doses and prolonged treatment: if the intention is chemical restraint or “delirium treatment”, then an important focus of future research will be to investigate what will support clinicians to adopt best practice and support the use of non-pharmacological strategies early and throughout care.
Continuation of newly initiated antipsychotics at discharge was reported in only four studies [18, 39, 40, 44]. The rationale for post-discharge continuation of antipsychotics was not disclosed in the studies. The findings of this review indicated that a large proportion of newly prescribed antipsychotics were continued at discharge. According to the Australian Guideline [46], antipsychotics should be ceased as soon as possible; however, a short course of regular low-dose antipsychotics may be appropriate if the patient experiences severe distress that persists beyond a day [46]. Persistent use of antipsychotics beyond transitions of care may lead to avoidable adverse effects. Our study highlights that opportunities exist to examine the transition of care practices, regarding antipsychotic continuation or discontinuation at discharge. Further research is needed to understand the reluctance clinicians may have in discontinuing antipsychotics for people with delirium in readiness for discharge.
4.1 Strengths and Limitations of the Systematic Review
To the best of the authors’ knowledge, this review is the first to synthesise available evidence on the prevalence of antipsychotic use in the routine clinical management of delirium. It provides evidence of the continual overuse and inappropriate prescribing of antipsychotics for delirium management. This review offers valuable insights for clinicians to think critically about antipsychotic use within their healthcare organisation, and consider how changes in approach to patient care and support for clinicians could reduce current usage.
This research has some limitations that should be considered. Most included studies in this review were retrospective medical record audits, which can present issues with the quality of data available, especially as data may be missing, inaccurate or not accurately represent clinical practices. Additionally, not all research studies provided the same level of detail regarding how medications were used. Some studies reported on only one aspect of the outcomes sought in this review. Furthermore, some studies that may have been eligible were excluded as there was insufficient detail regarding how delirium was diagnosed, or results were not stratified by clinical indication for antipsychotic use. We also acknowledge the risk of publication bias. As this systematic review included published studies in English, there may be missing relevant data on the wider state of antipsychotic use in clinical settings associated with unpublished works and those reported only in other languages. Consequently, the findings of this systematic review may not comprehensively reflect the full spectrum of evidence. Moreover, this review did not include any RCTs as it aimed to provide a descriptive overview of clinical practice, thus correlations and relationships between delirium severity, antipsychotic use and outcomes cannot be provided.
4.2 Implications for Research
There is currently a paucity of prospective observational research that examines how antipsychotics are used for people with delirium. This is particularly the case in aged care, where no published studies were found, and sub-acute care (in-patient rehabilitation) where only one study met inclusion criteria and data were limited to the percentage of people administered antipsychotics. Observational research is needed, as it can elucidate patterns of use (e.g. indications for use, individual doses and route of administration) and the effects on patients and the course of delirium. Additionally, the extent to which first-line non-pharmacological interventions are applied in relation to the initiation of antipsychotics warrants further investigation. The economic implications of reducing antipsychotic use in delirium care are yet to be explored.
4.3 Implications for Clinical Practice, Staff Education and Guidelines
There is a pressing need for healthcare organisations to prioritise the implementation of established clinical practice guidelines for delirium. Practical support for clinicians, such as additional trained personnel or volunteers, should urgently be provided to reduce reliance on antipsychotics without compromising safety. Monitoring antipsychotic use, especially in older individuals, should be undertaken as a routine measure of care quality. Clinician education and training are needed on how to implement non-pharmacological strategies and de-escalate disruptive behaviours early to avoid behavioural control through antipsychotic use. To support clinicians in reaching balanced decisions in using antipsychotics, we recommend delirium guidelines clearly articulate that antipsychotic use is a restrictive practice because of its sedating effects and requires caution equivalent to that used when considering the use of physical restraint. Family and other carers should also be involved in decision making when considering the use of antipsychotics for delirium management.
5 Conclusions
This systematic review presented evidence that antipsychotics are overused in the management of delirium. Studies included in this review demonstrated that antipsychotics remain a common choice to manage symptoms of delirium. Notably, haloperidol was the most frequently administered antipsychotic, often in doses that exceeded the recommended therapeutic amount in all clinical settings. The discrepancy between clinical practice and established guidelines is evident and potentially impacts on the quality of care. Further research is needed to determine the impact of antipsychotics on people with delirium and how to support the clinical workforce to implement evidence-based recommendations for antipsychotic use.
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Acknowledgements
We thank Leslie Brautigam for her work in the initial screening of studies for inclusion in the review.
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Emily J. Tomlinson, Linda M. Schnitker and Penelope A. Casey have no conflicts of interest that are directly relevant to the content of this article.
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Excel files of extracted data and methodological quality checking are available upon request to the corresponding author.
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ET designed the study, implemented the search strategy, screened papers, reviewed the data, conducted quality assessments, extracted the data and wrote the manuscript. LS assisted with developing the search strategy, screened papers, assisted with data extraction, conducted the quality assessment and reviewed the manuscript. PC assisted with data extraction, conducted the quality assessment, and assisted with writing the paper and reviewed the manuscript. All authors have read and approve the final version of the manuscript, and agree to be accountable for the work.
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Tomlinson, E.J., Schnitker, L.M. & Casey, P.A. Exploring Antipsychotic Use for Delirium Management in Adults in Hospital, Sub-Acute Rehabilitation and Aged Care Settings: A Systematic Literature Review. Drugs Aging 41, 455–486 (2024). https://doi.org/10.1007/s40266-024-01122-z
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DOI: https://doi.org/10.1007/s40266-024-01122-z