Does Delirium Cause Long-Term Cognitive Decline?

Delirium was linked to long-term cognitive decline in both surgical and nonsurgical patients, a meta-analysis showed.

Patients who experienced an episode of delirium were more than twice as likely to show long-term cognitive decline than patients without delirium (OR 2.30, 95% CI 1.85-2.86), reported Terry Goldberg, PhD, of Columbia University in New York City, and co-authors.

Delirium was associated with long-term cognitive decline with a Hedges g effect size of 0.45 (95% CI 0.34-0.57, P<0.001) in a meta-analysis of 23 observational studies (after one outlier study with an exceptionally high OR was excluded), they wrote in JAMA Neurology. Effect sizes were similar between surgical and nonsurgical groups.

“The connection between delirium and cognitive decline that we observed was highly significant and remarkably consistent,” Goldberg said.

“What we propose is that delirium is not simply a marker for those patients already on a downward trajectory, but may be causative in and of itself,” he told MedPage Today. “This may be especially relevant to COVID patients, many of whom experience delirium in the ICU.”

Delirium is “ubiquitous and spares no age groups or populations, occurring in 20% to 70% of hospitalized patients, with the higher numbers seen in critically ill patients on mechanical ventilation,” said Pratik Pandharipande, MD, co-director of the Critical Illness, Brain Dysfunction and Survivorship Center at Vanderbilt University in Nashville, who wasn’t involved with the meta-analysis.

“This study has great implications in the COVID era,” Pandharipande told MedPage Today. “Mechanically ventilated patients with COVID are at a much higher risk of developing delirium because they are subject to all the major risk factors — deeper levels of sedation, high severity of illness, often older age, and additionally, social isolation due to limited visitation rules in the hospital and the fact that the virus can directly affect the brain and lead to neuroinflammation.”

“The meta-analysis reported here shows a consistent message; all selected studies showed that delirium and longer duration of delirium were associated with cognitive impairment,” Pandharipande continued.

“While it is unclear if delirium causes dementia, there is mounting evidence — and the meta-analysis adds to this — that there are structural brain changes with delirium and this puts you at a worse cognitive trajectory,” he said.

“Incorporating strategies such as the ABCDEF bundle from the Society of Critical Care Medicine into the care of your patients — including mechanically ventilated COVID patients — is likely to reduce delirium and possibly its long-term consequences,” he added.

The meta-analysis included a systematic search of articles from 1965 through 2018. The researchers looked for studies that contrasted patients with and without delirium, had objective continuous or binary measures of cognitive outcome, and had a final time point of 3 months or later after the delirium episode.

Data from 24 observational studies, including 3,562 patients who experienced delirium and 6,987 controls who did not, were used. One study with an OR greater than 41 — an order of magnitude greater than any other study — was excluded from some analyses.

Mean study age was about 75 and mean follow-up after a delirium episode was 2.4 years. On average, men made up about 47% of the study populations. The Confusion Assessment Method (CAM) or CAM–intensive care unit was the most frequent delirium measure used, and the Mini-Mental State Examination was used most frequently as a cognitive outcome.

“In all studies, the group that experienced delirium had worse cognition at the final time point,” Goldberg and co-authors wrote.

Meta-regression did not show differences in cognitive outcomes between surgical and nonsurgical studies, suggesting “the underlying pathophysiological events associated with delirium may be similar and speculatively may be associated with inflammatory processes common to both contexts,” they added.

The researchers also did not find significant differences between cognition treated as a continuous variable based on neurocognitive test scores or as a binary variable based on the presence or absence of dementia.

The I² measure of between-study variability in g was 0.81. Studies of longer duration yielded greater differences, while those with more covariates, and those without baseline cognitive matching, yielded smaller differences.

The observational studies used in this meta-analysis cannot show that delirium is a causative factor in subsequent cognitive decline, the researchers noted. Differences in cognitive outcome measures and the way dementia was diagnosed may be sources of variability, but meta-regressions did not find significant differences among them in terms of their effect on g, they added.

Importantly, the study could not evaluate delirium in the context of other factors, such as frailty, and unmeasured confounders may have influenced results.

Last Updated July 13, 2020