This study demonstrates that incident delirium accelerates the trajectory of cognitive decline in hospitalized patients with AD. Prior studies have shown that patients with dementia who develop delirium have increased rates of hospitalization, institutionalization, and mortality.6,13–15
In this sample, after adjusting for baseline differences, the change in score on the Blessed IMC prior to an episode of delirium was 2.5 points per year, consistent with prior reported increases in patients with AD of about 3 points per year.16–18
In the delirium group, the relative change in IMC score doubled from 2.5 points per year at baseline to a postdelirium rate of 4.9 points per year. In comparisons across groups, the rate of change in IMC score occurred about three times faster in those who had delirium compared to those who did not. In other words, these data estimate a 53% absolute increase in the rate of change. From a clinical standpoint, this study suggests that over 12 months, patients with AD who become delirious experience the equivalent of an 18-month decline compared to those who do not experience delirium.
Delirium used to be viewed as a transient cognitive disorder, but research has shown that delirium is not always temporary and can often result in persistent functional19,20
and cognitive losses among general medical hospitalized elderly. For example, delirium has been linked to long-term cognitive impairment, as demonstrated by lower Mini-Mental State Examination scores and lowered performance on tasks of executive functioning, attention, and processing speed.14,21–23
Furthermore, subjective memory complaints, newly diagnosed dementia, and need for long-term care have been associated with delirium in elderly patients after hospitalization24
or hip surgery.25,26
While these studies demonstrate adverse long-term outcomes, this study is noteworthy in that it demonstrates the adverse impact of an episode of delirium on cognitive trajectory in patients with AD.
There are a number of strengths of this study. First is the relatively large sample size from the well-characterized MADRC cohort. Second, although baseline differences emerged between the patients with AD with and without delirium, these factors were controlled in all subsequent analysis. Of note, these differences, including age, male gender, lower baseline education, and higher number of comorbid illnesses, are well described risk factors for delirium27
and such group differences were not unexpected. The delirium group demonstrated lower baseline IMC scores on average than the nondelirium group. While this difference was significant, the impact of lesser degrees of cognitive impairment at baseline would be a conservative bias. An analysis using baseline IMC scores in the logistic regression model was conducted (data not shown) and the results did not substantively alter the findings of our study. Further, substantially worsened cognitive functioning in the delirium group despite this baseline difference lends support for the robustness of the finding. Third, duration of follow-up time was consistent in the analyses. Fourth, the time of delirium onset was identified from medical chart review. Finally, this work is proof of concept for what is commonly observed in clinical practice, that is, older patients—particularly those with dementia—may decline at a faster rate or never fully recover their cognitive function following an episode of delirium.
Bias may have been introduced into the analysis by missing data, or by excluding those patients who experienced delirium before a baseline cognitive trajectory could be established (n = 27), or who lacked a final measure to establish their trajectory following delirium (n = 13). To evaluate for the possibility of survivor bias in the 72 patients with data at all three timepoints, the analyses were repeated using multiple imputation for missing observations to model adjusted slopes in all 112 patients with delirium, and still demonstrated significant acceleration in cognitive trajectory following delirium.
There are limitations in the current study that should be noted. First, this was a single site study with a low representation of minorities and findings may not be generalizable to all patient populations. Second, the diagnosis of delirium was made by chart diagnosis, and although a validated method was utilized,12
some cases of delirium may have been missed due to lack of documentation. Moreover, duration and severity of delirium could not be determined by chart review, which represents an important area for future investigation. Third, while inclusion of an additional timepoint post-delirium (point D) would have been ideal, we were unable to conduct such analyses due to substantial attrition from this frail, elderly, cognitively impaired cohort over time (55% did not have point D). An important limitation of the current analysis is that the concurrent effects of delirium, which may not have resolved during the delirium interval (BC), may confound the cognitive trajectory. Future studies with longer-term follow-up post-delirium will be required to validate our findings. Fourth, 43% of the hospitalized patients (83 of 195) did not develop delirium, and the effects of hospitalization on cognitive trajectory could not entirely be disentangled from the current study. Finally, not all patients in the MADRC cohort had complete chart reviews or hospitalization data.
Replication of this study is needed to confirm that delirium alters the trajectory of cognitive decline in AD. Other important features that might affect cognitive trajectory will need to be studied, including more diverse populations, longer time periods, and specific causes, duration, and severity of delirium. If delirium does indeed precipitate a more rapid decline in dementia severity, such a finding would necessitate changes in the standard of care for patients with dementia. For example, patients with AD would need to be monitored closely for delirium, and when in high-risk settings, delirium prevention strategies should be utilized. It has been previously shown that multicomponent risk factor strategies,28
proactive geriatric consultation,7
educational interventions targeted toward staff,29
and avoidance of medications with high risk for delirium can be beneficial. Treating patients as outpatients where the risk of delirium may be lower could be another potential strategy for minimizing delirium. The area of delirium among hospitalized patients with AD has been largely unaddressed.30
Given their high risk of accelerated long-term decline, new approaches to care for these patients to improve early identification and prevention of delirium are greatly needed.
Ultimately, the information derived from this study provides the foundation for future randomized intervention studies to determine whether prevention of delirium might ameliorate and/or delay cognitive decline in patients with AD. Understanding the pathophysiologic mechanisms for how delirium impacts cognitive trajectory in dementia is another area of important future work.