The Search for Effective Delirium Treatment for Persons with Dementia in the Postacute‐Care Setting

With the unprecedented rise in the proportion of older adults in most industrialized countries, the treatment of cognitive impairment in older adults has emerged as a leading healthcare priority. Delirium and dementia are each among the most common causes of cognitive impairment across clinical settings, but they also commonly coexist as delirium superimposed on dementia (DSD). An estimated 22–89% of older adults in the hospital and the community with dementia develop DSD.1 DSD has serious prognostic implications, including a worsening trajectory of cognitive decline;2 substantial functional decline;3 longer hospital stay;3, 4 and higher rates of rehospitalization,1, 2 institutionalization,5, 6 and death.1, 6 DSD is associated with longer duration of delirium and slower recovery than delirium without dementia.7 Moreover, healthcare costs and use are significantly higher in individuals with DSD than in those with dementia alone, delirium alone, or neither delirium nor dementia.4 Previous studies have found that individuals with DSD are more frequently diagnosed with hyperactive delirium and have symptoms such as agitation, aggression, and irritability.8 Such complex behavioral problems and functional needs often necessitate postacute care after hospitalization. Delirium has been shown to be persistent in more than half of individuals with delirium admitted to postacute care at 1 month,9 but despite the increasing importance of postacute care in individuals with DSD and other age-related conditions, this setting remains largely unexamined in research studies because of daunting logistical and ethical constraints in conducting high-quality research in vulnerable institutionalized populations with cognitive impairment, frailty, and multimorbidity. The present study10 was a single-blind randomized controlled trial of cognitively stimulating activities applied for up to 30 minutes daily, 5 days per week in 283 older adults with DSD in eight postacute care facilities in Pennsylvania. The primary hypothesis was that individualized cognitively stimulating activities would reduce the duration and severity of delirium, but the study demonstrated no significant differences in the primary outcomes of delirium duration or severity between the intervention group and those receiving usual care. Significant differences favoring the intervention were found for secondary outcomes, including a significantly shorter average length of stay of 36 days in the intervention group as opposed to 53 days in usual care (P = .01), and statistically significantly better cognition, specifically on the executive control portion (CLOX1) of a clock-drawing task (P = .009). After adjusting for baseline differences, CLOX1 differences remained significant, although no differences were found on the copy portion (CLOX2) (P = .11). This finding is consistent with the idea that impairment in frontal systems controlling clock drawing affects CLOX1 more than CLOX2.11 Kolanowski and colleagues10 followed rigorous methodological approaches, including a randomized design achieving balanced comparison groups, carefully blinded outcome assessment with assurance of maintenance of blinding at the end of the study, verification of high interrater reliability for all critical study measures, adequate sample size and power to test hypotheses, and an intention-to-treat analysis approach. This was a high-quality randomized controlled study, with a high modified Jadad score of 5 out of 6 points; 1 point was lost for single rather than double blinding, which was not feasible with the intervention approach.12 The one major limitation of the study was the complexity of the intervention. This was an individualized “prescription” of 15 activities that trained research assistants administered in individual sessions for up to 30 minutes each day, 5 days per week for 30 days or until discharge. Activities were selected from a large database13 that included activities such as describing steps to prepare a meal, discussing current events, and generating a list of three similar items. The selection of activities for each participant was adjusted depending on their level of cognitive performance for level of difficulty (mild, moderate, difficult) and accounting for any functional impairment, such as low vision or impaired hearing. Activities were also selected based on the leisure interests of the participant. For example, activities for a person with a mild degree of cognitive impairment without visual impairment who enjoys movies might include identifying Famous Faces, a visually based activity of moderate difficulty. This activity would not be appropriate for participants with severe dementia and macular degeneration; an alternative activity such as an easy oral task of reciting the alphabet to the letter L would be selected instead. The authors chose to customize the activities in this manner to engage and capture interest, but such a personalized approach might prove difficult to reproduce across sites, and the potency—the potential for effectiveness of each individualized intervention approach, analogous to the “dose” of a medication—is difficult to standardize and quantify. In addition, although missing data and study dropouts were carefully documented, description of the approaches to address these missing data in the analyses was not fully detailed or well explained. Typically, in this type of high-quality randomized trial, sensitivity analyses would be performed using multiple approaches or imputation procedures to assess for any potential biases from the missing data and to evaluate their potential effect on the study conclusions. Despite these limitations, this study is groundbreaking and highly significant for addressing a topic of utmost clinical importance, with noteworthy methodological rigor in the difficult and highly relevant setting of postacute care. This randomized clinical trial was conducted despite the constraints and challenges of studying a frail, vulnerable, cognitively impaired population in the postacute care setting in eight facilities. Despite the success of delirium prevention trials, particularly of multicomponent nonpharmacological intervention strategies,14 successful treatment of delirium once it occurs has lagged. Studies of delirium treatment in different patient populations (e.g., surgical, medical, intensive care unit) and hospital settings (e.g., acute, postacute, long-term care) have been largely disappointing, with little effect on delirium duration or severity or important clinical outcomes in trials with antipsychotics,15, 16 cholinesterase inhibitors,17, 18 and other medications.19 Furthermore, individuals with DSD who are undergoing management of delirium with antipsychotics have lower rates of delirium resolution than those with delirium alone.20 Unfortunately, the current study is consistent with previous work showing no effect on the primary outcomes of delirium duration and severity. The demonstration in this study of significant findings for improvement in executive functioning and shorter length of stay are noteworthy and clinically relevant. Because executive functioning is a critical cognitive domain involved in delirium—as a risk factor and disease marker—cognitively stimulating activities may have a role in future delirium prevention trials by improving cognitive performance and strengthening cognitive reserve as a protection against delirium risk factors. In addition, the length-of stay benefit suggests that, perhaps even the subtle changes noted in delirium severity and duration—along with the improvement in executive functioning—may be enough to result in a positive effect in this highly vulnerable population. The findings in this study are not surprising, because the treatment of delirium is known to be especially challenging because of its fluctuating course, affecting individuals in a variety of clinical settings, and its multifactorial etiology. It is likely that successful delirium treatment requires targeted approaches to multiple etiological contributors simultaneously, rather than a single unified intervention strategy, as tested here. It is likely that delirium treatment will be even more complex in persons with underlying dementia, in whom baseline cognitive status is already impaired, and clinical symptomatology may arise from the underlying dementia, the acute delirium, or both. The next steps in searching for effective treatment of DSD will be to replicate findings from high-quality studies similar to this one in other populations and to investigate whether combining cognitively stimulating activities with other targeted approaches for the multiple etiological contributors to delirium in persons with underlying dementia can increase treatment effectiveness (Table 1). Other strategies, such as targeting pathophysiological mechanisms that delirium and dementia share, bolstering cognitive reserve, and investigating interventions in different care settings, are equally critical areas of potential treatments to be considered. This study, by showing the potential for effective treatment of DSD, lays an important foundation for this future work. Develop predictive model Choose group most likely to benefit from intervention Single versus multicomponent Pharmacological versus nonpharmacological Earlier recognition of DSD Targeted interventions toward etiological factors Prevention of complications Improve identification of delirium—diagnosis, phenomenology, severity, subtypes Targeted interventions toward etiological contributors (e.g., drugs, infections, metabolic derangements) Prevent complications, including falls, aspiration, pressure ulcers, functional decline Inflammation Neuronal stress Acceleration of dementia pathology Identify potential disease-modifying treatment strategies to lay groundwork for intervention development studies Identify inflammatory biomarkers for delirium Investigate novel neuronal injury markers associated with endothelial damage and blood–brain barrier disruption in delirium Explore effect of delirium on dementia markers Physical and cognitive intervention trials Transcranial direct current stimulation trials Combined approaches to management (i.e., multicomponent strategies such as Hospital Elder Life Program) Limited use of pharmacological approaches This work is dedicated to the memory of Joshua Bryan Inouye Helfand. Conflict of Interest: None of the authors report any conflicts of interest. All coauthors fully disclose they have no financial interests, activities, relationships and affiliations. The coauthors also declare they have no potential conflicts in the 3 years before submission of this manuscript. This manuscript was funded by P01AG031720 (SKI) and K07AG041835 (SKI) from the National Institute on Aging. Dr. Inouye holds the Milton and Shirley F. Levy Family Chair at Hebrew SeniorLife/Harvard Medical School. Author Contributions: All authors: interpretation of data, critical review, intellectual contributions, drafting the manuscript, approval of final manuscript. Sponsor's Role: The funding sources had no role in the design, conduct, or reporting of this study.