First-generation antihistamines: simple adjustments to reduce delirium

Delirium remains one of the most feared complications in hospitalized seniors. Frequent and often preventable, delirium increases mortality, length of stay and the risk of cognitive decline. In this context, every modifiable factor counts. Yet certain antihistamines continue to be used for a variety of indications, sometimes far removed from their pharmacological target. A study conducted in Ontario sheds particularly relevant light on this issue. The authors point out that, “first-generation antihistamines are among the leading causes of adverse drug reactions in older adults.” Their anticholinergic and sedative potential is well known, but their exact contribution to delirium in hospitals remained largely undetermined. This large-scale analysis was conducted to clarify this grey area, which has been fueled by limited data and inconsistent practices.Rates of prescribingPublished in the Journal of the American Geriatrics Society, the study analyzed 328,140 hospitalizations of patients aged 65 and older admitted between 2015 and 2022 to 17 Ontario hospitals. The researchers compared the risk of delirium based on each hospitalist's rate of prescribing first-generation antihistamines—mainly diphenhydramine, hydroxyzine, cyproheptadine and chlorpheniramine. Delirium was identified using a validated machine learning detection tool, and analyses were adjusted for age, sex, comorbidities, pre-existing dementia, clinical severity and patient origin.The results showed a clear association between individual physicians' propensity to prescribe first-generation antihistamines and their patients' risk of delirium. Across the entire cohort, delirium was identified in 34.8% of hospitalizations. This proportion increased according to medical practices. Adjusted analyses reveal a clear gradient:32.3% delirium among patients treated by the least prescribing physicians36.6% among those followed by the most prescribing physicianseach 1% absolute increase in the prescription rate associated with an 8% increase in the odds of delirium (adjusted odds ratio [aOR] 1.08; 95% confidence interval [CI] 1.05–1.10)patients treated by clinicians in the highest quartile had a 41% increased risk compared to those in the lowest quartile (aOR 1.41; 95% CI 1.28–1.56)Concrete lever for improvementThe authors said that these results “suggest that first-generation antihistamines may be a modifiable risk factor for delirium in hospitalized older adults.” This signal persists in most sensitivity analyses and in all subgroups studied, whether based on age, sex, pre-existing dementia, or origin from a long-term care facility. Limitations remain, notably the lack of a precise time sequence between drug administration and the onset of delirium, but the overall body of data points in the same direction.For the authors, these results should encourage clinicians to reevaluate the use of first-generation antihistamines in hospitalized seniors. These molecules offer no proven clinical advantage over non-sedating antihistamines, while increasing the risk of confusion and delusional interactions. The study also points out that “first-generation antihistamines offer no efficacy benefits over non-sedating antihistamines, which are associated with fewer adverse effects.”It also highlights significant variability in prescribing practices, which, according to the researchers, suggests “opportunities for improving the quality of care.” On the ground, the challenge is clear: Systematically favour non-sedative alternatives, reserve these drugs for strictly necessary indications, and integrate this vigilance into delirium prevention strategies. A simple review of prescribing habits could help reduce a major clinical burden in the context of a rapidly aging population.Call to revisit practicesThis study shows that therapeutic choices, rooted in everyday acute care, can influence the cognitive development of elderly patients more than we think. It calls for a review of these practices in light of current data. The authors also emphasize that “first-generation antihistamines may contribute to the risk of delirium due to their ability to cross the blood-brain barrier and interact with other delirium-inducing drugs.”In a context where the prevention of delirium remains a major challenge, the issue goes beyond pharmacology alone. It affects the consistency of protocols, clinical reflexes and the culture of safety that governs the care of the elderly. It remains to be seen how this new data will be integrated into hospital practices. It paves the way for simple adjustments, but with potentially significant impact.

First-generation antihistamines: simple adjustments to reduce delirium

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