Delirium, Dementia, and Adverse Outcomes

Contributed by Thiago J. Avelino-Silva, MD, PhD*; Flávia B. Garcez, MD, PhD*
*Faculty of Medicine, University of São Paulo, São Paulo, Brazil

Delirium results from an intricate combination of dozens of possible predisposing and precipitating factors1. Older age, functional dependence, and preexisting cognitive impairment are key determinants for its occurrence, but the latter is a particularly strong risk factor2. On the other hand, delirium is a primary cause of acute hospitalizations in patients with Alzheimer’s disease and related dementias (ADRD)3. Delirium superimposed on dementia (DSD) can affect a substantial proportion of hospitalized ADRD patients4, but remains a challenging diagnosis5. Even in specialized units, DSD frequently goes underrecognized or underreported6.

Patients with baseline cognitive impairment are more vulnerable to functional and cognitive decline and death when hospitalized7. Delirium is associated with several adverse outcomes during and after hospitalization8, and appears to operate as an additive risk factor for such complications in the context of ADRD9. Therefore, DSD potentially modifies the natural trajectories of function and cognition in dementia and, over time, might lead to adverse outcomes at a magnitude disproportionate to what would be expected in the presence of dementia or delirium alone10.

Delirium causing dementia graphic

One previous study screened medical inpatients for dementia and delirium and found that those with DSD experienced the most significant cognitive and functional declines11. Although the authors found long-term deterioration in cognitive function and physical independence caused by delirium alone, this effect was considerably superior when associated with preexisting dementia.

Further studies examining long-term cognitive outcomes in delirium and DSD have confirmed these results12. Whether this cumulative damage to brain functioning shares underlying mechanisms or neuropathological signatures with injuries found in chronic cognitive disorders is still unclear. Even so, there is substantial evidence to support delirium as a potent prognostic factor that accelerates cognitive impairment in patients with ADRD.

The association between delirium and mortality has also been widely investigated and consistently verified across several populations8. Mortality rates have been reported to quadruple in medical and surgical patients who experienced delirium, and twofold increases have been described in intensive care settings13.

As patients with dementia have a higher probability of developing delirium and are vulnerable to many of its associated outcomes, it is imperative to explore delirium as a predictor of death in patients with cognitive disorders. In a recent study, Hshieh et al. found in a cohort of 352 medical and surgical patients that severe delirium was associated with increased risk for poor clinical outcomes in participants with and without ADRD14. In patients with ADRD, delirium was more severe and associated with a trend toward increased short-term mortality. Results from another large cohort verified that hospital mortality in patients with DSD was three times higher than in those who only had ADRD4. However, other studies have been unable to find an independent association between DSD and higher mortality15.

The complexity of care inherent to ADRD or delirium might be one of the reasons it is so difficult to get a clear picture of how each of these conditions affects prognosis. Delirium, for example, frequently complicates hospitalizations, exposing patients to a myriad of potential iatrogenic events, such as the prescription of psychoactive medications and physical restraints. Delirium patients have also been observed to have a higher risk of developing aspiration pneumonia and pressure ulcers16. On the other hand, persons with cognitive disorders share a similar predisposition to hospital-associated hazards and could develop several clinical complications in the absence of delirium17.

Another relevant factor that could explain the discrepant results for the association between DSD and mortality resides in the challenge that diagnosing delirium, and even more so DSD, represents to most healthcare providers5. Misdiagnosis, misclassification, and underreporting could bias research conclusions for many of these issues and understate the importance of DSD as a predictor of mortality18. Finally, it is also possible that DSD and delirium in cognitively normal individuals have different phenomenologies. For example, a patient with dementia might have an underlying vulnerability that requires a less aggressive insult to trigger the delirious episode; consequently, delirium would have a milder clinical meaning and a reduced effect on prognosis15.

Despite the discrepancies in existing studies regarding the specific association between DSD and mortality and regarding the long-term survival of these patients, ample evidence points to a significant effect of acute mental disturbances on the short-term survival of hospitalized patients. Further understanding the mechanisms that lead to this incremental risk is undoubtedly a key to consolidating the role of delirium assessment as a prognostic tool in managing patients with chronic cognitive disorders.


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