Anticholinergic Drug Burden and Delirium: A Systematic Review

A systematic literature search was performed in Medline Ovid, Embase, PsycINFO, Web of Science, CINAHL, Cochrane library, and Google Scholar covering the period up until January 31, 2020 using relevant terms for anticholinergic drugs and delirium. The search queries were developed with the assistance of an experienced biomedical information specialist and can be found in the Supplementary Data, Appendix 2. Reference lists of review articles and included studies were manually screened to identify additional eligible studies.

Studies that met each of the following criteria were eligible for inclusion: (1) the association between ADB and delirium or delirium severity was investigated; (2) ADB was measured with an anticholinergic drug scale and expressed as a total score; and (3) the study was published in the English language. In case full text articles were not available, the corresponding authors were contacted and whenever answers were not obtained despite reminders, articles were excluded. Case studies, case series, review articles, commentaries, letters, editorials, conference abstracts, and studies that used the Drug Burden Index without stratification into the anticholinergic and sedative components were excluded.

All references identified by the search queries were downloaded in Endnote X9 (Clarivate Analytics, Philadelphia, PA) and duplicates were removed. Three reviewers (A.E., R.M.G., and H.A.) independently screened titles and abstracts for potentially eligible studies, and assessed full-text articles against the eligibility criteria. Disagreements at any stage were resolved through consensus.

Data from all studies that met the inclusion criteria were independently extracted by 2 authors (A.E. and F.M.R.) using a predefined extraction table, including author, year of publication, study design, population and setting, sample size, participant age and sex, number of persons with delirium, methods of measuring ADB, tools used to assess delirium and delirium severity, type of delirium (prevalent or incident), information on the statistical analyses, and the results with regard to the possible association between ADB and delirium (odds ratios, hazard ratios, relative risks, differences in proportions or regression coefficients). When studies used multiple models to investigate the association between ADB and delirium, the results of the model including the most covariates were extracted. Authors were contacted when study details were missing and data were considered unattainable if no answer was obtained despite several reminders. Any uncertainties were resolved through discussion.

Two reviewers (A.E. and G.Z.) independently assessed the methodological quality of the included studies using the Newcastle-Ottawa Scale for cohort and case-control studies. The scale used for case-control studies was additionally used for cross-sectional studies. The Newcastle-Ottawa Scale evaluates 3 aspects of the study methodology: the selection of study groups (score range 0‒4), comparability of the groups (score range 0‒2), and the quality of outcome/exposure ascertainment (score range 0‒3). The total score ranges from 0 to 9 (highest quality). Disagreements were resolved through discussion.

The association between ADB and delirium was investigated separately for prevalent and incident delirium. To explore any variations in results across the studies and anticholinergic drug scales, the results were additionally grouped based on the clinical settings where the studies were performed, regardless of delirium type. Furthermore, we planned to perform subgroup analyses to explore the influence of potential confounding factors, such as dementia and severity of illness. Furthermore, the association between ADB and delirium severity was investigated.

The primary literature search resulted in 3085 records. After exclusion of duplicates, 1960 records remained; of these, 1829 were excluded based on titles and abstracts. In total, 131 records were assessed for eligibility. Sixteen studies met the inclusion criteria and were included in the final review. An overview of the study selection process is presented in Figure 1.

The characteristics of the sixteen included studies are presented in Table 1. There were 8 prospective cohort studies,^{,  ,  ,  ,,,,} 5 retrospective cohort studies,^{,,,  ,}  1 nested case-control study, and 2 retrospective cross-sectional studies.^, A total of 148,756 persons were studied (sample size range 90–118,750; mean = 9297.25; median = 420.5). Thirteen studies were conducted in the hospital setting,^{,  ,  ,  ,  ,,  ,  ,  ,  ,  ,,} of which 10 on a medical ward^{,,  ,  ,,  ,  ,  ,,} and 3 on a surgical ward,^,, 1 study was performed in nursing homes, 1 study was performed in community-dwelling patients with dementia, and 1 study was performed in the general population. Delirium was assessed with the Diagnostic and Statistical Manual of Mental Disorders (4^th and 5^th edition) criteria,^, the Confusion Assessment Method,^,,,,,, the Nursing Delirium Scale, the Delirium Rating Scale, codes for delirium according to the International Classification of Diseases, 9^th and 10^th edition,^,, the 4 ‘A's test, and a validated chart-based instrument developed by Inouye et al for the identification of delirium and documented diagnoses of delirium in discharge summaries. Delirium severity was assessed with the Delirium Index and the Memorial Delirium Assessment Scale. ADB was measured with the Anticholinergic Risk Scale (ARS),^{,,  ,  ,} the Anticholinergic Cognitive Burden scale (ACB),^{,,  ,  ,  ,} the list of Chew, the Anticholinergic Drug Scale (ADS),^{,  ,  ,,,} a modified version of the ARS, and a modified version of the ACB. Characteristics of these anticholinergic drug scales are outlined in Table 2. Studies were performed in the United States,^{,  ,  ,} the Netherlands,^, Italy,^, Canada,^, Korea,^, Norway, the United Kingdom, Germany, and Portugal.

Details on the methodological quality of the included studies according to the Newcastle-Ottawa Scale are provided as Supplementary Data (Appendix 3). Quality scores ranged from 5 to 9 stars (median 8 stars). One study scored the maximum 4 stars for the study selection criteria. Fourteen out of 16 studies scored the maximum 2 stars for the comparability of the study groups, and 14 studies achieved the maximum 3 stars for the outcome/exposure criteria.

The possible association between ADB and delirium was investigated in 15 of the 16 studies.^{,  ,  ,  ,,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  Four studies investigated prevalent delirium,^,,, 7 studies incident delirium,^{,  ,  ,  ,,,} 2 studies delirium at some point during the hospital stay (combination of prevalent and incident delirium),^, 1 study delirium during 3 months follow-up, and 2 studies delirium during 1-year follow-up.^, The studies investigating incident delirium, delirium at some point during the hospital stay, and delirium during follow-up are combined in this review.

Four studies reported on the possible association between ADB and prevalent delirium (delirium on admission in 3 studies^,, and preoperative delirium in 1 study). A total of 1993 persons were studied (659 with delirium). Three studies were performed in acutely ill patients admitted to the hospital^,, and 1 study in patients admitted with a hip fracture. In all 4 studies, the median or mean age was >80 years. Delirium was assessed with the Diagnostic and Statistical Manual of Mental Disorders (4^th and 5^th edition),^, the 4 ‘A's test, and the Confusion Assessment Method. ADB was assessed with the ARS, the ACB,^,, the ADS,^, and the list of Chew. The study results are presented in Table 3. Only a moderate and high ADB, measured with the ARS, was associated with delirium on admission. No associations were found with the other anticholinergic drug scales.

Twelve studies reported on the possible association between ADB and incident delirium.^{,  ,  ,  ,,  ,  ,,,  ,  ,}  A total of 146,849 persons were studied (1703 with delirium; in 1 study, the number of patients with delirium was not defined). Nine studies were performed in patients admitted to the hospital (palliative inpatients, patients with cognitive impairments, patients admitted to the Intensive Care Unit, patients with a hip fracture undergoing surgery, patients with Parkinson's disease, patients undergoing transcatheter aortic valve implantation, patients with malignancies, cancer patients undergoing surgery, and acutely ill patients), 1 study in nursing home patients, 1 study in community-dwelling patients with dementia, and 1 study in the general population. In 9 studies, the median or mean age was >70 years,^{,,,,,,,  ,}  in 1 study 60.9% of the patients were 75 years or older, in 1 study the mean age was 60 years, and in 1 study the mean age was 41.5 years. Delirium was assessed with the Confusion Assessment Method,^,,,,, the Nursing Delirium Scale, the Delirium Rating Scale, International Classification of Diseases, 9^th and 10^th edition codes for delirium,^,, and a validated chart-based instrument developed by Inouye et al for the identification of delirium and documented diagnoses of delirium in discharge summaries. ADB was assessed with the ARS,^{,,  ,}  the ACB,^,, the ADS,^,,, a modified version of the ARS, and a modified version of the ACB. The study results are presented in Table 4. In all 4 studies using the ARS, an association was found between ADB and incident delirium. A moderate and high ADB as well as an increase in burden during the hospital stay, measured with the ARS, was associated with an increased risk of developing delirium. In addition, with the modified versions of the ARS and ACB, an association was found between a high ADB and delirium during follow-up. Conflicting results were found when the ADB was assessed with the ACB or ADS.