Based on strong evidence for cholinergic deficiency in people with dementia12Cholinergic function and Alzheimer's disease. and the evidence that the cholinergic system is likely to be involved in delirium,13van Gool W.A. van de Beek D. Eikelenboom P. Systemic infection and delirium: When cytokines and acetylcholine collide. it is plausible to assume that the use of drugs with anticholinergic properties increases the risk of delirium in patients with pre-existing dementia. However, several studies do not support a specific relationship between these medicines and DSD.14Campbell N. Boustani M. Limbil T. et al.The cognitive impact of anticholinergics: A clinical review.,15Kolanowski A. Mogle J. Fick D.M. et al.Anticholinergic exposure during rehabilitation: Cognitive and physical function outcomes in patients with delirium superimposed on dementia. These studies were performed in patients admitted to general hospitals, whereas the most frail older persons with dementia live in nursing homes (NHs). These patients particularly may be at increased risk of anticholinergic side effects because of higher rates of multimorbidity, associated polypharmacy, and age-related changes of pharmacokinetics and pharmacodynamics.16Welsh T.J. van der Wardt V. Ojo G. et al.Anticholinergic drug burden tools/scales and adverse outcomes in different clinical settings: A systematic review of reviews.

The availability of a database with patient characteristics from different European countries provides a unique opportunity to investigate the effect of anticholinergic drugs on delirium prevalence in a large NH population. The aim of this study is to investigate to what extent the use of drugs with anticholinergic properties in NH patients is associated with prevalence of delirium, particularly in people with dementia and to explore whether such an association would allow for clear recommendations with respect to clinical diagnosis and management of delirium in NH patients.

ResultsThe study group was composed of 4156 NH patients. A total of 228 participants without drug information at baseline and 4 participants with missing dementia diagnosis at baseline were excluded, resulting in a final sample size of 3924 participants. No imputations were used for the small number of missing values, 1.9% or less (Table 1).

Table 1Sociodemographic and Clinical Characteristics and Use of Anticholinergic Drugs of the Total Study Population According to Dementia Status

The sociodemographic, clinical characteristics and use of anticholinergic drugs according to dementia status are summarized in Table 1.

The study population was composed of 73% women and 27% men with an average age of, respectively, 84 and 80 years and with a diagnosis of dementia in 53.7% of all cases. The prevalence of delirium was higher in the dementia group (21.1%) than in participants without dementia (10.9%).

Overall, 2216 of all 3924 patients (56.1%) received at least 1 anticholinergic drug according to the ACB list and 1101 (28.1%) according the ARS. The 10 most commonly used somatic medications with anticholinergic properties according to the ACB list were (in descending order) furosemide, metoprolol, digoxin, atenolol, warfarin, morphine, fentanyl, prednisone, diazepam, and venlafaxine. The most frequently used antipsychotics were quetiapine, risperidone, and haloperidol.

Overall, the ACB was more capable in documenting anticholinergic effects, with classifying anticholinergic burden as “strong” in 16.6% in both the dementia group and the nondementia group vs a similar classification according to the ARS in 5.0% in the dementia group and 7.1% in the nondementia group. The Charlson Comorbidity Index indicated, as expected, more morbidity in the dementia group as well as more frequent cognitive impairment as rated by CPS (Table 1).All analyses showed an increased OR for the association of delirium with anticholinergic burden, in all models adjusted for age, Charlson Comorbidity Index, and cognitive function (Table 2). The ORs in patients with dementia were higher than in those without dementia. The odds of having a delirium diagnosis increased significantly by 17% with each 1-point increase on the ARS, reflecting an increased anticholinergic burden (OR 1.17, 95% CI 1.04-1.31), contrasting with a nonsignificant increase by 7% for each ARS point in the nondementia group (OR 1.07, 95% CI 0.94-1.31). The anticholinergic burden, as reflected in ACB scores, was also significantly associated with delirium in the dementia group (OR 1.14, 95% CI 1.06-1.23), whereas this association was not significant in the nondementia group (OR 1.07, 95% CI 0.97-1.18). Recoding of the ARS and ACB scores on an ordinal scale gave essentially the same results, with slightly higher ORs, whereas the association between delirium and the ordinal ARS now failed to reach significance in the dementia group (Table 2).

Table 2Prevalence of Delirium Associated With Anticholinergic Drugs According to ACB and ARS in Nursing Home Patients With and Without Dementia

Figure 1 presents the distribution of the prevalence of delirium in relation to anticholinergic drug burden according to the ACB in patients with and without dementia. Distribution of delirium prevalence is expressed as a percentage of patients with delirium within the anticholinergic burden category. The nondementia group showed almost no difference according to the ordinal increasing anticholinergic burden. In the dementia group, delirium prevalence was higher, and the distribution in the anticholinergic burden categories increased from 20% (with none or minimal anticholinergic burden), to 25% (with moderate burden) and 27% delirium (with strong burden scores). A stratification of the anticholinergic burden and delirium according to the severity of cognitive impairment following CPS is presented in Figure 2. As reported by Hartmaier et al,30Hartmaier S.L. Sloane P.D. Guess H.A. et al.Validation of the Minimum Data Set Cognitive Performance Scale: Agreement with the Mini-mental State Examination. a CPS score of ≥4 corresponds to a dementia diagnosis.

Fig. 1Distribution of the prevalence of delirium in relation to anticholinergic drug burden according to ACB in patients with and without dementia, within 95% confidence intervals.

Fig. 2Distribution of the prevalence of delirium according to cognitive impairment severity levels measured with CPS in relation to anticholinergic drug burden in ACB. Cognitive Performance Scale: 1 = borderline intact, 2 = mild impairment, 3 = moderate impairment, 4 = moderate severe impairment, 5 = severe impairment, 6 = very severe impairment. ADB, anticholinergic drug burden.

DiscussionIn the present study, we explored the relationship between the prevalence of delirium and the use of drugs with anticholinergic activity in 3924 patients in European long-term care facilities. We found that the use of anticholinergic drugs, as characterized by the ARS and ACB, is associated with delirium both in patients with and without dementia. The risk for delirium in the dementia group was approximately twice as high. These results are in agreement with previous studies. Egberts et al. found a positive association between delirium prevalence and use of anticholinergic drugs among acutely ill older patients admitted to a hospital.31Egberts A. van der Craats S.T. van Wijk M.D. et al.Anticholinergic drug exposure is associated with delirium and postdischarge institutionalization in acutely ill hospitalized older patients. A higher risk for delirium in nursing home patients with dementia and use of anticholinergic drugs was described by Landi et al.17Landi F. Dell'Aquila G. Collamati A. et al.Anticholinergic drug use and negative outcomes among the frail elderly population living in a nursing home. Foebel et al32Foebel A.D. Liperoti R. Onder G. et al.Use of antipsychotic drugs among residents with dementia in European long-term care facilities: Results from the SHELTER study. found in the SHELTER study a positive relationship for delirium and the specific use of antipsychotic drugs with anticholinergic properties among patients with dementia in European NHs. However, Kolanowski et al15Kolanowski A. Mogle J. Fick D.M. et al.Anticholinergic exposure during rehabilitation: Cognitive and physical function outcomes in patients with delirium superimposed on dementia. found no effect of anticholinergic drugs, according to ACB, on delirium severity among patients with delirium superimposed on dementia admitted to a post-acute care facility. Lackner et al33Lackner T.E. Wyman J.F. McCarthy T.C. et al.Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. described that short-term treatment with an anticholinergic drug for urge incontinence in female NH patients was not associated with delirium. Pasina et al34Pasina L. Colzani L. Cortesi L. et al.Relation between delirium and anticholinergic drug burden in a cohort of hospitalized older patients: An observational study. reported a dose-effect relationship between ACB score and delirium in older patients admitted to an acute geriatric ward. However, after adjustment for dementia status, the association was not statistically significant anymore, thus highlighting the overriding effect of dementia as a strong risk factor for delirium.34Pasina L. Colzani L. Cortesi L. et al.Relation between delirium and anticholinergic drug burden in a cohort of hospitalized older patients: An observational study.

In our study, after adjustment for age, comorbidity, and degree of cognitive function, overall, the odds for the association of anticholinergic effects with delirium was greater than 1, irrespective of dementia status, although not significant in patients free from dementia. The latter may be explained by the lower prevalence of delirium in this group, making this analysis prone to a type I statistical error, or it may also reflect a lower sensitivity to anticholinergic effects, because of a better preserved central cholinergic system in patients free from dementia.

Taken together with the higher percentages of patients with anticholinergic burden according to the ACB, this can possibly be taken as a reflection of the overall greater capability of the ACB for characterizing anticholinergic properties.

Our findings indicate that the effect of dementia status on delirium prevalence is larger than the effect of anticholinergic burden (Figure 1). Delirium prevalence was clearly higher among patients with dementia than in those without cognitive decline. Within these groups, the effect of anticholinergic burden was also different. Delirium prevalence did not increase with increasing anticholinergic burden in patients without dementia. However, delirium prevalence increased slightly with increasing anticholinergic burden in patients with dementia. In accordance with the present study findings, Landi et al17Landi F. Dell'Aquila G. Collamati A. et al.Anticholinergic drug use and negative outcomes among the frail elderly population living in a nursing home. reported a higher probability of delirium incidence on taking drugs with higher anticholinergic properties among NH patients. The findings of Lagarto et al35Identification of sub-groups in acutely ill elderly patients with delirium: A cluster analysis. are also consistent with the present results, reporting an association between increased anticholinergic drug exposure and delirium prevalence, especially in patients with brain disease, in their study mostly of cerebrovascular origin.The apparent inconsistencies between the results of the present analysis and those in literature can be explained in many ways. Methodological differences such as the methods used to characterize anticholinergic burden, characteristics and size of the study population, and the nature and severity of comorbidity all do play a potential role.15Kolanowski A. Mogle J. Fick D.M. et al.Anticholinergic exposure during rehabilitation: Cognitive and physical function outcomes in patients with delirium superimposed on dementia.,31Egberts A. van der Craats S.T. van Wijk M.D. et al.Anticholinergic drug exposure is associated with delirium and postdischarge institutionalization in acutely ill hospitalized older patients.,33Lackner T.E. Wyman J.F. McCarthy T.C. et al.Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence.,36Campbell N. Perkins A. Hui S. et al.Association between prescribing of anticholinergic medications and incident delirium: A cohort study. Specifically, the influence of assessment of anticholinergic burden may be important: the ACB list includes more drugs (97) compared with ARS (44) that contribute to the anticholinergic burden score. Especially in ACB level 1, 44 frequently prescribed drugs in the elderly are represented.37Mate K.E. Kerr K.P. Pond D. et al.Impact of multiple low-level anticholinergic medications on anticholinergic load of community-dwelling elderly with and without dementia. This may affect the amount of drugs used when applying a linear or ordinal scale in a large study population. For clinical practice, our modest discriminatory findings in anticholinergic burden levels give little guidance for identification of those at risk of delirium or for drugs management in nursing home patients suffering from delirium. Only a modest dose-response relationship was found, and therefore these findings do not support the association of increased anticholinergic burden as a robust explanation for increased delirium risk in individual cases. However, in addition to increased risks of delirium, anticholinergic agents are also associated with a wide spectrum of other adverse effects than delirium, including dizziness, blurred vision, urinary retention, and constipation,38Collamati A. Martone A.M. Poscia A. et al.Anticholinergic drugs and negative outcomes in the older population: From biological plausibility to clinical evidence. leading to geriatric syndromes with negative outcome on mortality and a poor quality of life.39Inouye S.K. Studenski S. Tinetti M.E. et al.Geriatric syndromes: Clinical, research, and policy implications of a core geriatric concept.,40Aalto U.L. Roitto H.M. Finne-Soveri H. et al.Use of anticholinergic drugs and its relationship with psychological well-being and mortality in long-term care facilities in Helsinki. Findings by Ah et al41Ah Y.M. Suh Y. Jun K. et al.Effect of anticholinergic burden on treatment modification, delirium and mortality in newly diagnosed dementia patients starting a cholinesterase inhibitor: A population-based study. suggest that especially the combination of anticholinergic drugs with cholinesterase inhibitors may be problematic as this was associated with a reduced treatment response or symptom exacerbation and an increased risk of delirium. Combined with the present findings, these insights from the literature concerning anticholinergic side effects should warrant reservations concerning the use of this class of drugs in geriatric populations. Possibly the ACB scale may be helpful in identifying and characterizing specific drugs, and as such this scale may perhaps play a role in more general guidelines, in addition to other guidelines like the AGS Beers Criteria42American Geriatrics Society
2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. that advise to stop unnecessary medication as a component of a prescribing cascade,43The prescribing cascade revisited. to switch to alternative medication44Hanlon J.T. Semla T.P. Schmader K.E. Alternative medications for medications in the use of high-risk medications in the elderly and potentially harmful drug-disease interactions in the elderly quality measures. or to stimulate nonpharmacologic interventions to manage clinical problems.45Livingston G. Kelly L. Lewis-Holmes E. et al.Non-pharmacological interventions for agitation in dementia: Systematic review of randomised controlled trials.

The present study has several limitations. First, it was a cross-sectional study, which allowed us only the description of prevalence of delirium in relation to the use of drugs with anticholinergic activity. The data available did not allow to establish a follow-up for incidence of delirium in relation to drug prescription. Further, it was not known how long drugs were taken, as drug use was recorded for only 3 days prior to the assessment. Similarly, the SHLETER database did not allow to characterize the exact temporal relation between drug prescription and any mental changes during this period or even before. Another limitation concerning the anticholinergic burden is the fact that both the ACB and ARS list are based only on dichotomous (yes/no) information on use of drugs with or without anticholinergic properties but both do not incorporate dosing information to further characterize in detail the anticholinergic burden.

The diagnosis of delirium, especially in people with dementia, is challenging and concerns a clinical diagnosis supported by a diagnostic tool like the confusion assessment method (CAM).46Inouye S.K. van Dyck C.H. Alessi C.A. et al.Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Based on the SHELTER data, which are accurate and allow access to adequate numbers of participants we had to apply a relatively simple diagnostics algorithm. Thus, in a strict sense our analysis is not based on a formal clinical diagnosis of delirium, but on the presence of the most important symptoms of delirium. This approach has been successfully applied before, using the SHELTER data, and it serves to preserve consistency between various analyses based on these data.24Onder G. Giovannini S. Sganga F. et al.Interactions between drugs and geriatric syndromes in nursing home and home care: Results from Shelter and IBenC projects.,32Foebel A.D. Liperoti R. Onder G. et al.Use of antipsychotic drugs among residents with dementia in European long-term care facilities: Results from the SHELTER study. The algorithm that we applied led to a prevalence of 21% delirium in dementia. This percentage can be considered low according to some of the various percentages from the current literature; however, it is important to note that it is not likely that any diagnostic uncertainty would affect participants using or not using drugs with anticholinergic properties differently. The overrepresentation of mental changes with an acute onset in users of anticholinergic drugs remains, whether this is labeled as “delirium” or as “symptoms of delirium.”

A strong point of the present study is the inclusion of a large sample of NH patients, representing to a large degree the everyday clinical reality in this specific institutional setting. Second, the diagnosis of dementia is well established because dementia is often a reason for admission to a nursing home. Third, because the study population consists of NH patients, a wide range of dementia severity is taken into account, which also included the severely cognitive impaired patients who are often excluded from studies.

Article InfoPublication History

Published online: June 28, 2021

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The SHELTER study was funded by the EU 7th Framework Program ( IGAMH-CR NS-10029-4 ). All researchers, including the coauthors, were independent from the funder, and the funding body did not play any role in the study design; in the collection, analysis, or interpretation of data; in manuscript preparation, or in the decision to submit the article for publication.

The authors declare no conflicts of interest.

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DOI: https://doi.org/10.1016/j.jamda.2021.05.039

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© 2021 Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine.

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