The focus of the current article is the prevention of delirium, a disturbance of consciousness and attention (American Psychiatric Association [APA], 2013), in older persons with dementia (PWD), also known as delirium superimposed on dementia (DSD). Worldwide, there are approximately 50 million people with dementia (World Health Organization [WHO], 2019), which is a non-curable progressive terminal syndrome affecting brain function that is more prevalent in the older population. Each year, 10 million new dementia cases will be diagnosed (WHO, 2019). With increases in life expectancy and shifts in the relative size of the population aged ≥65 years (Anderson & Hussey, 2000), the prevalence of dementia is projected to trend upward exponentially over the next few decades, resulting in approximately 70 million and 120 million PWD in the years 2030 and 2050, respectively (Alzheimer's Disease International, 2015; Prince et al., 2013).
Older age and a dementia diagnosis are two of the most significant predisposing risk factors for delirium (Inouye et al., 2014). Delirium can occur in older PWD, especially when they have urinary tract infections, respiratory tract infections, pain, hypoxia, or constipation (i.e., precipitating risk factors). Often, delirium has an organic cause and by definition results in acute changes in a person's mental abilities, including poor thinking skills, behavior changes, and emotional disturbances that can fluctuate throughout the day (APA, 2013; Setters & Solberg, 2017).
Prevalence rates (i.e., existing cases) of DSD in individuals aged ≥65 years have been reported to be 22% in community populations and as high as 89% in hospitalized populations (Fick et al., 2002). Within emergency departments, the prevalence rate of delirium at admission for older patients living at aged care homes is up to 40%, with even higher rates reported in intensive and palliative care units (Hosker & Bennett, 2016; Hshieh et al., 2018; Slooter et al., 2017). Delirium is often under-diagnosed, especially in those with dementia (Fick et al., 2007), due to overlapping symptoms between delirium and dementia. Compared to delirium not superimposed on dementia, DSD has worse associated health outcomes (Fick et al., 2002). When superimposed on dementia, delirium has multiple negative prognostic implications, including accelerated functional and cognitive decline, as well as increased hospitalization rates, admission into institutional care, suffering and burden for older adults and their caregivers, morbidity, and mortality compared to dementia alone (Avelino-Silva et al., 2017; Fick et al., 2002; Fick et al., 2013; Fong et al., 2019).
Although relevant guidelines for detecting delirium have been established (National Clinical Guideline Centre, 2010), detection remains difficult and cases are still missed (Barron & Holmes, 2013; Collins et al., 2010). The misidentification of delirium, the paucity of therapies for established delirium (Caplan, 2019; Herling et al., 2018), and the negative consequences for PWD who experience delirium and their families (Fick & Foreman, 2000) highlight the importance of seeking measures to ensure delirium is primarily prevented where possible. This approach focuses on primary prevention measures aimed at reducing the incidence of delirium (i.e., preventing delirium from occurring), rather than secondary and tertiary measures focusing on clinical management of the condition once it has already occurred (Wass et al., 2008).
There is evidence that delirium in adults without dementia can sometimes be prevented (Inouye et al., 2014; Martinez et al., 2015). An understanding of the risk factors for delirium and nonpharmacological multi-component approaches addressing those modifiable risk factors are considered an integral step in its prevention (Australian Commission on Safety and Quality in Health Care, 2016; Hshieh et al., 2018). In consideration of the growing number of PWD and dementia's known associated risk of delirium, a review of preventive measures for delirium in this population is warranted. There is an increasing responsibility on health care professionals to apply evidence-based strategies to prevent delirium. Therefore, the purpose of this article is to examine the evidence available to guide the prevention of delirium in a highly vulnerable population.
The aim of the current review was to answer the following questions: (a) How effective are primary prevention interventions targeting delirium in older PWD?; (b) Do the identified studies provide a strong evidence base for clinical practice?; and (c) What are the research priorities for preventing delirium in PWD?
A systematic process was followed to identify all interventions that target the prevention of delirium occurrence in older adults with a pre-existing dementia diagnosis. The review was registered with PROSPERO and we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology to guide our study (Moher et al., 2009). Interventions in any health care or community setting were included. The search strategy methodology (i.e., selected databases, search terms, and use of limiters/filters/hedges) was developed in collaboration with the Queensland University of Technology Liaison Health Librarian.
PubMed, PsycINFO, CINAHL, and Embase were searched for articles published between the start of the databases to February 2019, using a combination of controlled vocabulary (e.g., MeSH) and free text terms related to the target population (i.e., older adults with a dementia diagnosis), type of interventions (i.e., preventive), and the outcome (i.e., delirium incidence). All database search strategies followed the same approach but were appropriately revised according to operators and controlled vocabulary of each separate database. We also searched ALOIS, an open access register of dementia studies, for additional studies. Searches were limited to peer-reviewed journal articles published in English. Table A (available in the online version of this article) displays an example of the search strategy for PubMed. To check references, we also searched the libraries of the Joanna Briggs Institute, Cochrane, and PROSPERO for protocol details and results of systematic reviews and meta-analyses relevant to delirium prevention. To complete the search strategy, the reference lists of identified key articles and forward citation were hand-searched.
Search method for the PubMed database
Two authors (L.S., A.N.) independently reviewed the title, abstract, and full text of the retrieved studies using the inclusion and exclusion criteria (Table 1).
Literature Review Inclusion and Exclusion Criteria
Throughout the review screening process, authors discussed discrepancies in their initial judgments and attempted to reach a consensus. Where a consensus could not be reached, a third reviewer considered the article for inclusion until a majority decision was reached. For reporting of the search, the PRISMA flow diagram was used. Data were extracted by one author (L.S.) and cross-checked for accuracy by another author (A.N.). Two authors (L.S., A.N.) independently assessed the quality of included studies using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool that classifies the quality of evidence in one of four levels: very low, low, moderate, and high (Balshem et al., 2011). A third author (D.M.F.) considered the quality of evidence derived from the articles until a majority decision was reached.
The titles and abstracts of 804 citations were screened against the inclusion and exclusion criteria. After examining 69 full-text articles, seven studies were ultimately included in the current review (Andro et al., 2012; Freter et al., 2017; Kwok et al., 2008; Moretti et al., 2004; Robinson et al., 2008; Stenvall et al., 2012; Tabet et al., 2006). Figure 1 displays the detailed search outcomes. Table 2 presents data extraction results recording details of aim, study design, sample and setting, intervention details, outcome measures, major findings, and GRADE scores of the included studies. Studies were not homogeneous and therefore were not combined for a meta-analysis.
Studies Investigating Delirium Prevention Strategies in Older Persons With Dementia (PWD)
Types of Interventions
Nonpharmacological. One article specifically focused on the prevention of delirium in adults aged ≥75 years with dementia admitted to an acute care geriatric unit in France (Andro et al., 2012). All participants had a diagnosis of dementia (i.e., Alzheimer's disease, dementia with Lewy bodies, cerebrovascular lesions). The intervention consisted of a protocol targeting cognitive impairment focused on temporospatial orientation (e.g., orientating objects) and communication (e.g., reorientation and explaining communication), in addition to usual geriatric care focusing on hydration, nutrition, mobilization, sensory input, pain assessment, and medication review. The researchers found a 66% relative risk reduction (RRR) of incident delirium between participants prior to (19/123, 15.5%) and after (7/133, 5.3%) implementation of the intervention.
Stenvall et al. (2012) performed a subgroup analysis of 64 persons (28 persons in the intervention group) with dementia aged ≥70 years within a randomized controlled trial that focused on a multi-disciplinary postoperative intervention. The intervention comprised staff education on preventing, detecting, and treating postoperative complications, including delirium. Participants were admitted to a geriatric ward after they underwent hip fracture surgery. Participants who were randomized to the control group (n = 36) received conventional care in an orthopedic ward. Delirium symptoms in both groups were retrospectively identified (in the medical record) by a geriatrician. Stenvall et al. (2012) found significantly more people in the control group (35/36, 97%) who experienced postoperative delirium, compared to 19 people in the intervention group (19/28, 68%) (RRR = 0.3).
The current review also identified a pragmatic, controlled, and single-blinded study by Freter et al. (2017), who performed a sub-analysis on data collected in hospitalized older adults who had previously been diagnosed with dementia and had a hip fracture. Patients in the intervention group received care according to delirium-friendly, pre-printed postoperative orders performed by ward staff addressing delirium risk factors, including bowel function, pain, sleep, urinary catheters, nausea, and hydration status. They found that care recipients in the intervention group experienced significantly less (p = 0.001) postoperative delirium (33%) compared to those who did not receive the intervention (51%) (RRR = 0.4).
Robinson et al. (2008) performed a sub-analysis of 24 PWD admitted to a renal unit. This pre-/post-intervention study tested an intervention that included delirium training for staff and delirium risk factors assessment and management using a delirium prevention protocol. The researchers found that less PWD developed delirium in the post-intervention group (1/12, 8.3%) compared to the control group (6/12, 50%) (RRR = 0.83). Another study by Tabet et al. (2006) found that preventive staff educational packages addressing delirium awareness and risk factors resulted in less cases of delirium in the treatment group (6/26, 23%) compared to PWD who received usual care (12/20, 60%) (RRR = 0.62).
Pharmacological. A 2-year case-control study investigated whether rivastigmine (3 to 6 mg/day), an acetylcholinesterase inhibitor, had an effect on the development of delirium in 115 older adults with vascular dementia (Moretti et al., 2004). Delirium incidence was compared with 115 people with vascular dementia who were prescribed aspirin (100 mg/day). Over the 2-year period, significantly (p < 0.001) more people in the aspirin (n = 71, 62%) group experienced an episode of delirium compared to people in the rivastigmine group (n = 46, 40%) (RRR = 35%). Another study by Kwok et al. (2008) evaluated PWD and vitamin B12 deficiency. They recruited patients aged ≥60 years with Alzheimer's disease and vascular dementia attending a memory clinic and had a vitamin B12 deficiency (<200 picomoles/L). The aim of the study was to identify if vitamin B12 supplementation over 40 weeks would positively impact cognitive function. Although researchers did not find a considerable change in cognitive function, a significant difference in delirium symptoms was found (using the Delirium Rating Scale) at Weeks 6 and 40, compared to baseline data.
The current study aimed to review the health literature concerning the primary prevention of delirium in older adults who have a dementia diagnosis. The findings demonstrated that there is limited quantity and quality of studies to quantify the effectiveness (or ineffectiveness) of delirium prevention in the increasing population of PWD. We found only one study that used a design that is in the top hierarchy of evidence (i.e., a randomized controlled trial) (Stenvall et al., 2012); however, the study was a sub-analysis, resulting in a small sample size (N = 54), thus negatively impacting the precision and generalizability of the results. Due to this limitation, the study was downgraded in the assigned GRADE score from high to moderate. A review by Ford (2016) similarly concluded that evidence in this area is relatively modest. The studies included in Ford's (2016) review differ slightly to those collated in the current review.
We considered those studies that included older adults with a preexisting dementia diagnosis according to pre-set criteria and excluded those studies that used a cognitive screener (e.g., Mini Mental State Examination [MMSE], AD8 Dementia Screening Instrument, RUDAS) to determine if participants had dementia. However, only three of the seven included studies' participants had a formal diagnosis of dementia using one of the internationally accepted criteria (Kwok et al., 2008; Moretti et al., 2004; Stenvall et al., 2012). The remaining four studies included patients with the term “dementia” documented in their medical record or dementia was confirmed by participants' family members. Although it is likely that these participants had dementia, the extension of the study findings and conclusions may not be applicable for individuals with an official dementia diagnosis. It is important to know what works in people with a dementia diagnosis—a significant delirium risk factor—to prevent the negative health outcomes associated with DSD (Fick et al., 2002).
During the review, several studies were excluded due to having participants with no formal dementia diagnosis, although there was evidence of cognitive impairment (Hasemann et al., 2016; Inouye et al., 1999; Marcantonio et al., 2001; Sieber et al., 2010; Wand et al., 2014). Marcantonio et al. (2001) found no significant differences between people with cognitive impairment (using the Blessed Dementia Rating Scale score of ≥4) who underwent hip surgery and were randomly allocated to a consulting geriatrician who made daily care recommendations to impact delirium incidence compared to people receiving usual care (p = 0.60). A study by Sieber et al. (2010) investigated if sedation depth during spinal anesthesia in patients with hip fractures impacted delirium incidence. They found that people who had cognitive impairment not related to delirium prior to surgery (MMSE score ranging from 20 to 23) and underwent light sedation experienced significantly less delirium (5/35, 14%) compared to those in the deep sedation group (14/32, 44%). A study by Hasemann et al. (2016) comprised 138 patients with cognitive impairment (MMSE < 27/30, and clock drawing test <5/7) without delirium who were admitted to a medical ward due to a non-surgical medical condition. Participants were exposed to the DemDel intervention, a multicomponent intervention including delirium education for health care professionals, screening for cognitive impairment and delirium, delirium prevention by nonpharmacological (e.g., avoid pain, improve oxygenation, early mobilization) and pharmacological (e.g., avoid benzodiazepines, prescribe atypical neuroleptics in case of delirium) strategies. Delirium incidence rates of patients in the intervention group were compared to 130 patients with cognitive impairment who were admitted to the same medical wards when the DemDel intervention was not implemented and showed a non-significant difference, 31.9% versus 33.1%, respectively (Hasemann et al., 2016).
A pilot study by Fick et al. (2011) tested the use of computerized decision support for DSD and electronic prompting for nurses performing the Confusion Assessment Method (CAM) and non-drug interventions with older adults. In this pilot, 14/15 participants improved their MMSE scores by >3 points, nursing staff had a high rate of adherence to the intervention, and nurses stated they wanted more non-drug approaches for older adults in acute care (Fick et al., 2011). Furthermore, in a study by Inouye et al. (1999), testing the well-known Hospital Elder Life Program (HELP) provided data on patients with cognitive impairment and found significant reduction in delirium incidence in those patients with cognitive impairment receiving the multicomponent intervention.
There were also issues concerning the use of measures to determine if participants had delirium. Most of the studies (six of seven) used a recognized method to identify delirium; however, the study by Robinson et al. (2008) used a chart-based method for the identification of delirium (Inouye et al., 2005). There is evidence that health care professionals often do not recognize or misdiagnose delirium (Inouye et al., 2014), especially in PWD (Caplan, 2019; Fick & Foreman, 2000). It is possible that more participants with dementia in Robinson et al.'s (2008) study had delirium, but that this was not recognized by care staff and therefore there was no documentation of terms, such as acute confusion, mental status change, inattention, disorientation, or inappropriate behavior, indicating delirium. Delirium symptoms could be interpreted as symptoms of severe dementia or the progression of dementia.
It is timely and important to identify the evidence-based practices to prevent delirium in the increasing population of PWD. However, two questions remain: What can be done to effectively prevent delirium in older adults with a dementia diagnosis, and what is currently being done to prevent delirium in individuals with dementia (i.e., in aged care homes, community)? Most of the studies were performed in acute care settings, where an episode of delirium in a PWD may be triggered by an acute medical condition, surgery, or a change in environment. Surprisingly, there were no studies identified that performed their research in aged care homes or specialist dementia care units. The home and community are both important areas to test, as many PWD already have delirium when entering hospital settings, and thus, prevention is not effective. PWD, especially those with an acute organic medical condition, are constantly at risk of developing delirium. Other studies were identified that performed research in aged care homes; however, they did not perform a sub-analysis of PWD (Boockvar et al., 2016; Culp et al., 2003; Featherstone et al., 2010; Lapane et al., 2011). Three of these studies were also identified through a systematic review by Woodhouse et al. (2019). Their studies focused on hydration (Culp et al., 2003) and medication monitoring (Lapane et al., 2011)—two important strategies to address delirium risk factors. One study was performed among home-dwelling older adults but focused on secondary prevention (Verloo et al., 2015). The Stop Delirium intervention was developed for aged care home staff in the form of an enhanced educational package to improve the recognition of delirium and its prevention (Featherstone et al., 2010).
Our findings are in line with evidence derived from older populations without cognitive impairment, suggesting that delirium prevention should adopt a geriatric approach, be person- and family-centered, and systematically address those multiple modifiable delirium risk factors using a nonpharmacological and multi-disciplinary approach (Andro et al., 2012; Boockvar et al., 2016; Inouye et al., 1999; Lapane et al., 2011; Marcantonio et al., 2001; Martinez et al., 2015; Tabet & Howard, 2009). Preventive measures also include environment modification (McCusker et al., 2001) and staff education to ensure delirium risk factors are managed and delirium is identified and treated in a timely manner (Travers et al., 2018a,b; Wand, 2011). The next step is to form an expert panel, including key stakeholders, to decide how the identified evidence from this review would translate into practice (Brożek et al., 2011). In addition, increasing research is required to identify the effectiveness of these interventions in PWD. Furthermore, the role of anti-psychotic medication (e.g., haloperidol) in delirium prevention is unclear (Neufeld et al., 2016). Two studies found no significant difference in delirium incidence between patients with hip fractures and high delirium risk (including those with dementia) using a low dose of haloperidol compared to those who did not use the antipsychotic (Kalisvaart et al., 2005; Vochteloo et al., 2011). However, it is suggested that haloperidol can be beneficial to critically ill patients in intensive care (van den Boogaard et al., 2013), but further investigation is required.
The literature search criteria related to older adults with dementia (population) in whom health care workers act (intervention) to prevent delirium (outcome) and this search may have been too narrow. Furthermore, only articles published in the English language were considered for this review, potentially missing non-English results that met inclusion criteria. Although we used reference searching, it is possible that broader search terms may have revealed further evidence. Many studies also included a description of cognitive impairment that was not a definitive characteristic of a dementia diagnosis. As a result, articles that included such participants were not considered for this review, although participants in those studies may have had a dementia diagnosis.
Gerontological nurses play a key role in prevention, early recognition, and treatment of delirium. Along with a multi-disciplinary team, nurses can provide care that addresses key delirium risk factors, such as cognitive impairment, visual and hearing impairment, and immobilization, and can observe/identify when their patients experience an acute change in their baseline cognition (suggestive for delirium). They also have the first level of contact with family members, who can also play a key role in delirium prevention and recognition (Boltz et al., 2015; Paulson et al., 2016). A comprehensive geriatric assessment will support the medical profession to identify and treat potential organic causes of delirium (e.g., pneumonia, urinary tract infection, constipation, pain).
Evidence-based care practices are available that guide the care of those admitted to acute care (e.g., older adults, people with hip fractures, adults who undergo surgery), but they were designed and tested in persons without dementia and there is a need for more high-quality evidence focusing on PWD. We currently do not know if other approaches are better for prevention and treatment in DSD. In addition to traditional approaches to delirium such as HELP, it is critical to evaluate whether different approaches that focus more on environmental, behavioral, communication, or psychological interventions may be more effective. In the United States, there is currently a campaign to increase public awareness of the health burden of delirium in PWD as a way to decrease disability in those persons and this review contributes to the advancement of that work (Hayden et al., 2018).
Such studies will inform evidence-based care that can improve health outcomes for older adults with dementia. Research in this population is crucial; however, there are concerns in relation to providing informed consent, decision capacity, and intervention/care adherence (Provencher et al., 2014), and therefore PWD are often excluded from research studies. Exclusion of PWD from future delirium research is both impractical and unethical, as appropriate methods to attain consent now exist (Prusaczyk et al., 2017). Establishing an objective research foundation for DSD interventions is crucial to meaningfully inform health care staff on evidence-based best practices for preventing delirium, as well as to inform policy and optimize patient-centric outcomes. It is essential to find out how to prevent the development of delirium and reduce the number of adults with dementia developing delirium to avoid these adverse health outcomes. PWD cared for in community, residential aged care, emergency department, and acute care settings will benefit from research to improve future health care for those affected by dementia.
Delirium is a medical emergency that affects many older PWD. Due to the negative health outcomes associated with delirium, particularly in PWD, health care professionals are required to put effort into preventing delirium in this increasing population. Research evidence shows that it is possible to prevent delirium; however, this review demonstrates that there is limited high-quality evidence to guide delirium prevention practice for health care workers caring for older adults with a formal dementia diagnosis. Despite the identified studies, more research is required to identify effective prevention strategies in PWD, especially for those living in residential aged care facilities.
- Alzheimer's Disease International. (2015). The global impact of dementia: An analysis of prevalence, incidence, cost and trends. https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). doi:10.1176/appi.books.9780890425596 [CrossRef]
- Anderson, G. F. & Hussey, P. S. (2000). Population aging: A comparison among industrialized countries. Health Affairs, 19(3), 191–203 doi:10.1377/hlthaff.19.3.191 [CrossRef] PMID:10812799
- Andro, M., Comps, E., Estivin, S. & Gentric, A. (2012). Prevention of delirium in demented hospitalized patients. European Journal of Internal Medicine, 23(2), 124–125 doi:10.1016/j.ejim.2011.05.011 [CrossRef] PMID:22284240
- Australian Commission on Safety and Quality in Health Care. (2016). Indicator specification: Delirium clinical care standard. https://www.safetyandquality.gov.au/sites/default/files/migrated/Delirium-CCS_Indicators-PDF.pdf
- Avelino-Silva, T. J., Campora, F., Curiati, J. A. & Jacob-Filho, W. (2017). Association between delirium superimposed on dementia and mortality in hospitalized older adults: A prospective cohort study. PLoS Medicine, 14(3), e1002264 doi:10.1371/journal.pmed.1002264 [CrossRef] PMID:28350792
- Balshem, H., Helfand, M., Schünemann, H. J., Oxman, A. D., Kunz, R., Brozek, J., Vist, G. E., Falck-Ytter, Y., Meerpohl, J., Norris, S. & Guyatt, G. H. (2011). GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology, 64(4), 401–406 doi:10.1016/j.jclinepi.2010.07.015 [CrossRef] PMID:21208779
- Barron, E. A. & Holmes, J. (2013). Delirium within the emergency care setting, occurrence and detection: A systematic review. Emergency Medicine Journal, 30(4), 263–268 doi:10.1136/emermed-2011-200586 [CrossRef] PMID:22833596
- Boltz, M., Chippendale, T., Resnick, B. & Galvin, J. E. (2015). Testing family-centered, function-focused care in hospitalized persons with dementia. Neurodegenerative Disease Management, 5(3), 203–215 doi:10.2217/nmt.15.10 [CrossRef] PMID:26107319
- Boockvar, K. S., Teresi, J. A. & Inouye, S. K. (2016). Preliminary data: An adapted hospital elder life program to prevent delirium and reduce complications of acute illness in long-term care delivered by certified nursing assistants. Journal of the American Geriatrics Society, 64(5), 1108–1113 doi:10.1111/jgs.14091 [CrossRef] PMID:27160212
- Brożek, J. L., Akl, E. A., Compalati, E., Kreis, J., Terracciano, L., Fiocchi, A., Ueffing, E., Andrews, J., Alonso-Coello, P., Meerpohl, J. J., Lang, D. M., Jaeschke, R., Williams, J. W. Jr.. , Phillips, B., Lethaby, A., Bossuyt, P., Glasziou, P., Helfand, M., Watine, J. & Schünemann, H. J.the GRADE Working Group. (2011). Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations. Allergy, 66(5), 588–595 doi:10.1111/j.1398-9995.2010.02530.x [CrossRef] PMID:21241318
- Caplan, G. A. (2019). Delirium superimposed upon dementia. Journal of the American Medical Directors Association, 20(11), 1382–1383 doi:10.1016/j.jamda.2019.09.019 [CrossRef] PMID:31676026
- Collins, N., Blanchard, M. R., Tookman, A. & Sampson, E. L. (2010). Detection of delirium in the acute hospital. Age and Ageing, 39(1), 131–135 doi:10.1093/ageing/afp201 [CrossRef] PMID:19917632
- Culp, K., Mentes, J. & Wakefield, B. (2003). Hydration and acute confusion in long-term care residents. Western Journal of Nursing Research, 25(3), 251–266 doi:10.1177/0193945902250409 [CrossRef] PMID:12705111
- Featherstone, I., Hopton, A. & Siddiqi, N. (2010). An intervention to reduce delirium in care homes. Nursing Older People, 22(4), 16–21 doi:10.7748/nop2010.05.22.4.16.c7732 [CrossRef] PMID:20503675
- Fick, D. & Foreman, M. (2000). Consequences of not recognizing delirium superimposed on dementia in hospitalized elderly individuals. Journal of Gerontological Nursing, 26(1), 30–40 doi:10.3928/0098-9134-20000101-09 [CrossRef] PMID:10776167
- Fick, D. M., Agostini, J. V. & Inouye, S. K. (2002). Delirium superimposed on dementia: A systematic review. Journal of the American Geriatrics Society, 50(10), 1723–1732 doi:10.1046/j.1532-5415.2002.50468.x [CrossRef] PMID:12366629
- Fick, D. M., Hodo, D. M., Lawrence, F. & Inouye, S. K. (2007). Recognizing delirium superimposed on dementia: Assessing nurses' knowledge using case vignettes. Journal of Gerontological Nursing, 33(2), 40–47 doi:10.3928/00989134-20070201-09 [CrossRef] PMID:17310662
- Fick, D. M., Steis, M. R., Mion, L. C. & Walls, J. L. (2011). Computerized decision support for delirium superimposed on dementia in older adults. Journal of Gerontological Nursing, 37(4), 39–47 doi:10.3928/00989134-20100930-01 [CrossRef] PMID:21053810
- Fick, D. M., Steis, M. R., Waller, J. L. & Inouye, S. K. (2013). Delirium superimposed on dementia is associated with prolonged length of stay and poor outcomes in hospitalized older adults. Journal of Hospital Medicine, 8(9), 500–505 doi:10.1002/jhm.2077 [CrossRef] PMID:23955965
- Fong, T. G., Racine, A. M., Fick, D. M., Tabloski, P., Gou, Y., Schmitt, E. M., Hshieh, T. T., Metzger, E., Bertrand, S. E., Marcantonio, E. R., Jones, R. N. & Inouye, S. K. (2019). The caregiver burden of delirium in older adults with Alzheimer disease and related disorders. Journal of the American Geriatrics Society, 67(12), 2587–2592 doi:10.1111/jgs.16199 [CrossRef] PMID:31605539
- Ford, A. H. (2016). Preventing delirium in dementia: Managing risk factors. Maturitas, 92, 35–40 doi:10.1016/j.maturitas.2016.07.007 [CrossRef] PMID:27621236
- Freter, S., Koller, K., Dunbar, M., MacKnight, C. & Rockwood, K. (2017). Translating delirium prevention strategies for elderly adults with hip fracture into routine clinical care: A pragmatic clinical trial. Journal of the American Geriatrics Society, 65(3), 567–573 doi:10.1111/jgs.14568 [CrossRef] PMID:27874185
- Hasemann, W., Tolson, D., Godwin, J., Spirig, R., Frei, I. A. & Kressig, R. W. (2016). A before and after study of a nurse led comprehensive delirium management programme (DemDel) for older acute care inpatients with cognitive impairment. International Journal of Nursing Studies, 53, 27–38 doi:10.1016/j.ijnurstu.2015.08.003 [CrossRef] PMID:26323529
- Hayden, K. M., Inouye, S. K., Cunningham, C., Jones, R. N., Avidan, M. S., Davis, D., Kuchel, G. A., Tang, Y. & Khachaturian, A. S. (2018). Reduce the burden of dementia now. Alzheimer's & Dementia, 14(7), 845–847 doi:10.1016/j.jalz.2018.06.3039 [CrossRef] PMID:29959910
- Herling, S. F., Greve, I. E., Vasilevskis, E. E., Egerod, I., Bekker Mortensen, C., Møller, A. M., Svenningsen, H. & Thomsen, T. (2018). Interventions for preventing intensive care unit delirium in adults. Cochrane Database of Systematic Reviews, 11, CD009783. doi:10.1002/14651858.CD009783.pub2 [CrossRef] PMID:30484283
- Hosker, C. M. & Bennett, M. I. (2016). Delirium and agitation at the end of life. BMJ (Clinical Research Ed.), 353, i3085 doi:10.1136/bmj.i3085 [CrossRef] PMID:27283962
- Hshieh, T. T., Inouye, S. K. & Oh, E. S. (2018). Delirium in the elderly. The Psychiatric Clinics of North America, 41(1), 1–17 doi:10.1016/j.psc.2017.10.001 [CrossRef] PMID:29412839
- Inouye, S. K., Bogardus, S. T. Jr.. , Charpentier, P. A., Leo-Summers, L., Acampora, D., Holford, T. R. & Cooney, L. M. Jr.. (1999). A multicomponent intervention to prevent delirium in hospitalized older patients. The New England Journal of Medicine, 340(9), 669–676 doi:10.1056/NEJM199903043400901 [CrossRef] PMID:10053175
- Inouye, S. K., Leo-Summers, L., Zhang, Y., Bogardus, S. T. Jr.. , Leslie, D. L. & Agostini, J. V. (2005). A chart-based method for identification of delirium: Validation compared with interviewer ratings using the confusion assessment method. Journal of the American Geriatrics Society, 53(2), 312–318 doi:10.1111/j.1532-5415.2005.53120.x [CrossRef] PMID:15673358
- Inouye, S. K., Westendorp, R. G. & Saczynski, J. S. (2014). Delirium in elderly people. Lancet, 383(9920), 911–922 doi:10.1016/S0140-6736(13)60688-1 [CrossRef] PMID:23992774
- Kalisvaart, K. J., de Jonghe, J. F., Bogaards, M. J., Vreeswijk, R., Egberts, T. C., Burger, B. J., Eikelenboom, P. & van Gool, W. A. (2005). Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: A randomized placebo-controlled study. Journal of the American Geriatrics Society, 53(10), 1658–1666 doi:10.1111/j.1532-5415.2005.53503.x [CrossRef] PMID:16181163
- Kwok, T., Lee, J., Lam, L. & Woo, J. (2008). Vitamin B12 supplementation did not improve cognition but reduced delirium in demented patients with vitamin B12 deficiency. Archives of Gerontology and Geriatrics, 46(3), 273–282 doi:10.1016/j.archger.2007.05.001 [CrossRef] PMID:17561285
- Lapane, K. L., Hughes, C. M., Daiello, L. A., Cameron, K. A. & Feinberg, J. (2011). Effect of a pharmacist-led multicomponent intervention focusing on the medication monitoring phase to prevent potential adverse drug events in nursing homes. Journal of the American Geriatrics Society, 59(7), 1238–1245 doi:10.1111/j.1532-5415.2011.03418.x [CrossRef] PMID:21649623
- Marcantonio, E. R., Flacker, J. M., Wright, R. J. & Resnick, N. M. (2001). Reducing delirium after hip fracture: A randomized trial. Journal of the American Geriatrics Society, 49(5), 516–522 doi:10.1046/j.1532-5415.2001.49108.x [CrossRef] PMID:11380742
- Martinez, F., Tobar, C. & Hill, N. (2015). Preventing delirium: Should nonpharmacological, multicomponent interventions be used? A systematic review and meta-analysis of the literature. Age and Ageing, 44(2), 196–204 doi:10.1093/ageing/afu173 [CrossRef] PMID:25424450
- McCusker, J., Cole, M., Abrahamowicz, M., Han, L., Podoba, J. E. & Ramman-Haddad, L. (2001). Environmental risk factors for delirium in hospitalized older people. Journal of the American Geriatrics Society, 49(10), 1327–1334 doi:10.1046/j.1532-5415.2001.49260.x [CrossRef] PMID:11890491
- Moher, D., Liberati, A., Tetzlaff, J. & Altman, D. G.the PRISMA Group. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Medicine, 6(7), e1000097 doi:10.1371/journal.pmed.1000097 [CrossRef] PMID:19621072
- Moretti, R., Torre, P., Antonello, R. M., Cattaruzza, T. & Cazzato, G. (2004). Cholinesterase inhibition as a possible therapy for delirium in vascular dementia: A controlled, open 24-month study of 246 patients. American Journal of Alzheimer's Disease and Other Dementias, 19(6), 333–339 doi:10.1177/153331750401900607 [CrossRef] PMID:15633941
- National Clinical Guideline Centre. (2010). Delirium: Diagnosis, prevention and management. https://www.nice.org.uk/guidance/cg103/evidence/full-guideline-pdf-134653069
- Neufeld, K. J., Yue, J., Robinson, T. N., Inouye, S. K. & Needham, D. M. (2016). Anti-psychotic medication for prevention and treatment of delirium in hospitalized adults: A systematic review and meta-analysis. Journal of the American Geriatrics Society, 64(4), 705–714 doi:10.1111/jgs.14076 [CrossRef]
- Paulson, C. M., Monroe, T., McDougall, G. J. Jr.. & Fick, D. M. (2016). A family-focused delirium educational initiative with practice and research implications. Gerontology & Geriatrics Education, 37(1), 4–11 doi:10.1080/02701960.2015.1031896 [CrossRef] PMID:26165565
- Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W. & Ferri, C. P. (2013). The global prevalence of dementia: A systematic review and metaanalysis. Alzheimer's & Dementia, 9(1), 63–75.e2. doi:10.1016/j.jalz.2012.11.007 [CrossRef] PMID:23305823
- Provencher, V., Mortenson, W. B., Tanguay-Garneau, L., Bélanger, K. & Dagenais, M. (2014). Challenges and strategies pertaining to recruitment and retention of frail elderly in research studies: A systematic review. Archives of Gerontology and Geriatrics, 59(1), 18–24 doi:10.1016/j.archger.2014.03.006 [CrossRef] PMID:24745811
- Prusaczyk, B., Cherney, S. M., Carpenter, C. R. & DuBois, J. M. (2017). Informed consent to research with cognitively impaired adults: Transdisciplinary challenges and opportunities. Clinical Gerontologist, 40(1), 63–73 doi:10.1080/07317115.2016.1201714 [CrossRef] PMID:28452628
- Robinson, S., Rich, C., Weitzel, T., Vollmer, C. & Eden, B. (2008). Delirium prevention for cognitive, sensory, and mobility impairments. Research and Theory for Nursing Practice, 22(2), 103–113 doi:10.1891/1541-6522.214.171.124 [CrossRef] PMID:18578220
- Setters, B. & Solberg, L. M. (2017). Delirium. Primary Care: Clinics in Office Practice, 44(3), 541–559 doi:10.1016/j.pop.2017.04.010 [CrossRef] PMID:28797379
- Sieber, F. E., Zakriya, K. J., Gottschalk, A., Blute, M. R., Lee, H. B., Rosenberg, P. B. & Mears, S. C. (2010). Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clinic Proceedings, 85(1), 18–26 doi:10.4065/mcp.2009.0469 [CrossRef] PMID:20042557
- Slooter, A. J., Van De Leur, R. R. & Zaal, I. J. (2017). Delirium in critically ill patients. Handbook of Clinical Neurology, 141, 449–466 doi:10.1016/B978-0-444-63599-0.00025-9 [CrossRef] PMID:28190430
- Stenvall, M., Berggren, M., Lundström, M., Gustafson, Y. & Olofsson, B. (2012). A multidisciplinary intervention program improved the outcome after hip fracture for people with dementia—Subgroup analyses of a randomized controlled trial. Archives of Gerontology and Geriatrics, 54(3), e284–e289 doi:10.1016/j.archger.2011.08.013 [CrossRef] PMID:21930310
- Tabet, N. & Howard, R. (2009). Nonpharmacological interventions in the prevention of delirium. Age and Ageing, 38(4), 374–379 doi:10.1093/ageing/afp039 [CrossRef] PMID:19460856
- Tabet, N., Stewart, R., Hudson, S., Sweeney, V., Sauer, J., Bryant, C., Macdonald, A. & Howard, R. (2006). Male gender influences response to an educational package for delirium prevention among older people: A stratified analysis. International Journal of Geriatric Psychiatry, 21(5), 493–497 doi:10.1002/gps.1532PMID:16676296 [CrossRef]
- Travers, C., Henderson, A., Graham, F. & Beattie, E. (2018a). CogChamps: Impact of a project to educate nurses about delirium and improve the quality of care for hospitalized patients with cognitive impairment. BMC Health Services Research, 18(1), 534 doi:10.1186/s12913-018-3286-4 [CrossRef] PMID:29986686
- Travers, C., Henderson, A., Graham, F. & Beattie, E. (2018b). Turning education into action: Impact of a collective social education approach to improve nurses' ability to recognize and accurately assess delirium in hospitalized older patients. Nurse Education Today, 62, 91–97 doi:10.1016/j.nedt.2017.12.026 [CrossRef] PMID:29306752
- van den Boogaard, M., Schoonhoven, L., van Achterberg, T., van der Hoeven, J. G. & Pickkers, P. (2013). Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Critical Care (London, England), 17(1), R9 doi:10.1186/cc11933 [CrossRef] PMID:23327295
- Verloo, H., Goulet, C., Morin, D. & von Gunten, A. (2015). Effect estimation of an innovative nursing intervention to improve delirium among home-dwelling older adults: A randomized controlled pilot trial. Dementia and Geriatric Cognitive Disorders. Extra, 5(1), 176–190 doi:10.1159/000375444 [CrossRef] PMID:26034489
- Vochteloo, A. J., Moerman, S., van der Burg, B. L., de Boo, M., de Vries, M. R., Niesten, D. D., Tuinebreijer, W. E., Nelissen, R. G. & Pilot, P. (2011). Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium. BMC Geriatrics, 11, 39 doi:10.1186/1471-2318-11-39 [CrossRef] PMID:21834991
- Wand, A. P. (2011). Evaluating the effectiveness of educational interventions to prevent delirium. Australasian Journal on Ageing, 30(4), 175–185 doi:10.1111/j.1741-6612.2010.00502.x [CrossRef] PMID:22176561
- Wand, A. P., Thoo, W., Sciuriaga, H., Ting, V., Baker, J. & Hunt, G. E. (2014). A multifaceted educational intervention to prevent delirium in older inpatients: A before and after study. International Journal of Nursing Studies, 51(7), 974–982 doi:10.1016/j.ijnurstu.2013.11.005 [CrossRef] PMID:24332570
- Wass, S., Webster, P. J. & Nair, B. R. (2008). Delirium in the elderly: A review. Oman Medical Journal, 23(3), 150–157 PMID:22359704
- Woodhouse, R., Burton, J. K., Rana, N., Pang, Y. L., Lister, J. E. & Siddiqi, N. (2019). Interventions for preventing delirium in older people in institutional long-term care. Cochrane Database of Systematic Reviews, 4(4), CD009537. doi:10.1002/14651858.CD009537.pub3 [CrossRef] PMID:31012953
- World Health Organization. (2019). Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia
Literature Review Inclusion and Exclusion Criteria
|Studies: Randomized controlled trials and non-randomized/quasi-experimental trials that determine the effectiveness of interventions targeting delirium incidence.|
|Participants: Those aged >65 years who have a dementia diagnosis (e.g. Alzheimer's disease, vascular dementia, Lewy body disease). Participants to be included were diagnosed with dementia according to internationally accepted criteria such as ICD-10, the DSM, and NINCDS-ADRDA. Participants were also included if the term “dementia” was found in their medical record data (comorbidity) confirmed by other health care workers or family.|
|Interventions: Delirium prevention interventions that target delirium incidence (new occurrence).|
|Outcome measures: The primary outcome of interest was delirium incidence. Due to the complexity of delirium diagnosis, included studies needed to specify delirium using a recognized method or measure pertaining to delirium incidence (e.g., DSM criteria, CAM or CAM-ICU, CTD, DSI, DRS, the SPMSQ, or MDS indicators for delirium) (Morandi et al., 2012). Studies using a retrospective chart-based method were also considered.|
|Articles published in a language other than English.|
|Articles not involving older adults with a dementia diagnosis; articles involving older adults with cognitive impairment measured by applying cognitive screening (e.g., MMSE).|
|Articles not addressing the primary prevention of delirium.|
|Articles not measuring delirium as an outcome measure; articles reporting delirium severity as an only outcome.|
|Reviews, case reports, and editorials.|
Studies Investigating Delirium Prevention Strategies in Older Persons With Dementia (PWD)
|Study||Aim||Study Design||Participants||Setting||Type and Time Frame||Outcome Measures||Results||GRADE|
|Nonpharmacological Delirium Prevention Practices|
|Andro et al. (2011)||To compare the in- cidence of delirium in two cohorts of older PWD||Quasi-experimental, pre/post study||Non-delirious patients with dementia aged 75 years hospitalized in a geriatric unit in France.
Before implementation, data were collected from 123 patients with dementia (89 Alzheimer's disease, 17 Lewy body disease, 17 mixed); after implementation, data were collected from 133 patients with dementia (92 Alzheimer's disease, 19 Lewy body disease, 22 mixed).
Dementia measure: No formal dementia measure used. Not clearly stated whether patients had a diagnosis of dementia prior to admission.||Acute care (medical)||A protocol targeting cognitive impairment that included temporospatial orientation (the use of orientating objects) and communication (reorientation and reassurance) supplementing usual care (addressing hydration, nutrition mobilization, sensory input, pain, and medication).||Delirium incidence measured using the CAM.
Not clearly stated how often CAM was applied during hospital admission.
Blinding: Not stated.||7/133 (5%) developed delirium in the intervention cohort compared to 19/123 (15%) in the control cohort (66% relative risk reduction) (p ≤ 0.05)||Low|
|Freter et al. (2017)||To compare the effectiveness of delirium-friendly pre-printed post-operative orders with usual care on the development of delirium||Quasi-experimental, non-randomized control study||77 postoperative patients aged 65 years with an existing dementia diagnosis admitted to two orthopedic wards in Canada due to hip fracture (48 participants in the intervention group). Patients from one orthopedic unit were admitted to the intervention group and the other ward served as the control (usual care).
Dementia measure: No formal dementia measure used. A dementia diagnosis recorded in medical record and confirmed by family members.||Acute care (surgical)||Postoperative orders concerning scheduled pain management, sleep enhancement, management of post-operative nausea, timely removal of urinary catheter, laxatives, postoperative blood work, management of severe agitation (i.e., low dose of haloperidol).||Delirium measured using the CAM in conjunction with the MMSE and review of patients' medical records on Days 1, 3, and 5.
Blinding: Single.||60% (29/48) of patients with dementia in the intervention group had delirium compared to 97% (28/29) in the usual care group (p < 0.05)||Moderate|
|Robinson et al. (2008)||To determine if a delirium prevention protocol could prevent delirium in older adults||Quasi-experimental, pre/post study– retrospective record review||24 patients aged 65 years with dementia with various delirium risk factors (vision impairment, hearing impairment, mobility impairment). Intervention and control groups comprised 12 patients each. Study was performed in the United States.
Dementia measure: No formal dementia measure used. Dementia diagnosis recorded in medical record on admission.||Acute care (medical, renal)||Targeted delirium risk factors, including cognitive impairment (e.g., optimal communication, pain management), vision impairment (e.g., glasses, large-print signage), hearing impairment (e.g., hearing aids in place, limit background noise), mobility impairment (e.g., early mobilization, sitting up)||Delirium using daily chart-based methodology for the identification of delirium
Blinding: Not stated.||1 (8.3%) patient in the intervention group developed delirium compared to 6 (50%) in the control group||Low|
|Stenvall et al. (2012)||To investigate whether a multidisciplinary postoperative intervention could reduce postoperative complications, including delirium, among PWD||Experimental: randomized controlled trial subgroup analyses||64 patients aged 70 years with dementia and hip fracture admitted to a surgical orthopedic hospital in Sweden. 28 patients in the intervention group.
Dementia measure: DSM-IV criteria retrospectively used by geriatrician.||Acute care (geriatric, surgical)||Comprehensive geriatric assessment and rehabilitation (early mobilization) to prevent, detect, and treat postoperative complications||DSM-IV criteria for delirium.
Blinding: Not stated.||19/28 (68%) patients with dementia in the intervention group developed delirium compared to 35/36 (97%) patients in the control group (p = 0.002)||Moderate|
|Tabet et al. (2006)||To identify whether the presence of dementia influences the effect of a delirium education package||Quasi-experimental: secondary analysis of a case-control study||236 patients aged 70 years; 116 patients in the intervention group, of whom 46 had dementia. Study was performed in the United Kingdom.
Dementia measure: No formal dementia diagnosis used. As indicated in medical records (medical and nursing notes).||Acute care (medical)||A delirium educational package for physicians and nurses that increased awareness of staff to delirium and its prevention (targeting delirium risk factors).
The control group received usual care (no delirium education).||Delirium using modified DRS (scores 12) and the medical chart by a geriatric psychiatrist at baseline and on average 9.5 days following admission.
Blinding: Not stated.||6/26 (23.1%) patients with dementia in the intervention group developed delirium compared to 12/20 (60%) patients in the control group||Low|
|Pharmacological Delirium Prevention Interventions|
|Kwok et al. (2008)||Examine effect of vitamin B12 supplementation on incident delirium in those with dementia and low B12 serum levels||Observational study, cohort study||26 patients with dementia (Alzheimer's disease, vascular, mixed) aged 60 years with low vitamin B12 serum levels (<200 pmol/L) recruited from memory clinics, geriatric and psychogeriatric outpatient clinics in Hong Kong.
Dementia measure: NINCDS-ADRDA criteria for Alzheimer's disease and NINDS-AIREN criteria for vascular dementia.||Community (outpatient clinic)||Vitamin B12 supplementation for 40 weeks (three 1 mg methyl cobalamin injections in the first week then oral methyl cobalamin 1 tablet three times per day for 15 weeks, then cyanocobalamin 1 mg intramuscular injection once per month)||DRS performed at baseline, and after 6, 16, and 40 weeks.
Blinding: Not blinded.||DRS scores decreased significantly (median change of −1) at 6 and 40 weeks (p ≤ 0.05)||Low|
|Moretti et al. (2004)||To determine the effects of rivastigmine (cholinesterase inhibitor) on delirium in people with vascular dementia||Controlled trial||230 participants aged 65 to 80 years with subcortical vascular dementia or multi-infarct dementia; 115 were in the intervention group. The study was performed in Italy.
Dementia measure: DSM-IV, NINDS-AIREN criteria.||Community (outpatient clinic)||Intervention group received rivastigmine 3 to 6 mg/day (starting at 3 mg/day and at 16 weeks 6 mg/day)
Comparison group received aspirin 100 mg/day||Delirium incidence using CAM measured: 1, 3, 9, 12, 15, 18, 21, and 24 months after start of intervention
Blinding: Not stated.||40% (46/115) of the intervention group experienced delirium compared to 62% (71/115) of the comparison group (p < 0.001)||Moderate|
Search method for the PubMed database
|S1||“Delirium”[mesh] OR deliri* OR “post operative cognitive dysfunction” OR POCD OR “acute confusion” OR “acute brain syndrome” OR “acute organic reaction” OR “organic brain syndrome” OR “toxic confusion” OR “acute psycho-organic syndrome” OR “psychoorganic syndrome”|
|S2||“dementia”[mesh] OR dement* OR “alzheimer disease” OR alzheim* OR “lewy body” OR “lewy bodies” OR “primary Progressive aphasia” OR “fronto-temporal degeneration” OR “fronto temporal degeneration” OR “frontotemporal degeneration” OR huntington OR “pick's disease” OR “picks disease” OR “pick disease” OR “creutzfeldt-jakob” OR “creutzfeldt jakob”|
|S3||“Preventive Health Services” [Mesh] OR “Geriatric Nursing” [Mesh] OR “geriatrics” [Mesh] OR “Preventive Health Services” OR “Primary Prevention” OR “Secondary Prevention” OR “Tertiary Prevention” OR prevent* OR reduc* OR avoid*|
|L1||“randomized controlled trial”[pt] OR “controlled clinical trial”[pt] OR randomised[tiab] OR randomized[tiab] OR placebo[tiab] OR trial[tiab] OR groups[tiab] OR “clinical trials as topic”[mesh] OR “random allocation”[mesh] OR “double-blind method”[mesh] OR “single-blind method”[mesh] OR “clinical trial”[pt] OR “research design”[mesh:noexp] OR “comparative study”[pt] OR “evaluation studies”[pt] OR “follow-up studies”[mesh] OR “prospective studies”[mesh] OR “cross-over studies”[mesh] OR “clinical trial”[tw] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw]) AND (mask*[tw] OR blind*[tw])) OR placebo*[tw] OR random*[tw] OR “control”[tw] OR “controls”[tw] OR prospectiv*[tw] OR “cohort studies”[mesh] OR “case-control studies”[mesh] OR “comparative study”[pt] OR “risk factors”[mesh] OR “cohort”[tw] OR “compared”[tw] OR “groups”[tw] OR “case control”[tw] OR “multivariate”[tw]|
|L2||“Aging“[mesh] OR “Nursing Homes“[mesh] OR “Aged“[mesh] OR “Aged, 80 andover“[mesh] OR “Frail Elderly“[mesh] OR elder*[tw] OR “older adult“[tw] ORaged[tw] OR geriatric[tw] OR frail*[tw] OR ageing[tw] OR aging[tw] OR “oldpeople“[tw]|
|L4||(“Animals“ [Mesh] NOT (“Animals“[Mesh] AND “Humans“[Mesh]))|
|S5||S1 AND S2 AND S3 AND L1 AND L2 AND L3 NOT L4|