Delirium is a neuropsychiatric syndrome defined by acute decline and fluctuation of attention, cognitive function, and disturbance of awareness (1). Especially in older patients, delirium is a common and serious adverse event of surgery (2) with an incidence ranging from 11 to 51% (3, 4). Postoperative delirium (POD) in older people is often associated with persistent cognitive dysfunction, dementia, higher rates of institutionalization, and increased morbidity and mortality (5, 6). Its etiology is believed to be multifactorial. Besides neuro-inflammation and blood-brain barrier leakage, a neurotransmitter disbalance in terms of acetylcholine deficiency and dopamine excess is thought to be involved in the pathogenesis of delirium (7). Electroencephalographic changes in delirium such as occipital slowing are also indicative of acetylcholine deficiency (8). Multiple pre- and perioperative risk factors are known to predispose to delirium. Preoperative factors comprise age, multimorbidity, frailty, polypharmacy, and deficits in cognitive, sensory, and mobility function (9, 10). Perioperative parameters that have been identified are, for example, type of surgery and anesthesia, surgery time and treatment in intensive care units (2, 9). Because delirium negatively affects patients' safety and quality of life, identifying modifiable risk factors could be of great relevance for its prevention, especially in older patients (11–13). In this regard, preoperative medication use is considered one of the most important potentially modifiable factors in the prevention of POD (14).

Assuming that delirium might be precipitated by an imbalance in cerebral neurotransmission specifically including acetylcholine deficiency (15), drugs with anticholinergic properties (DAPs) could have a significant impact on POD. DAPs are frequently prescribed in older people for a variety of indications such as minor and major depression, bladder disorders, or nausea (16). The cumulative effect of all DAPs taken regularly by an individual is often referred to as the anticholinergic burden (17). However, numerous studies indicated adverse effects of DAPs on cognitive and physical function (18, 19). Anticholinergic burden has been associated with delirium in several settings (18, 20, 21), although results were conflicting (22). Studies on the effect of DAPs on POD are less frequent, and their results were also inconsistent, with one positive (23) and two negatives studies (24, 25). Different results could be caused by the use of different scores calculating anticholinergic burden, small sample sizes, and different definitions of delirium. Therefore, in this study, we used the established Anticholinergic Risk Scale (ARS), which was most consistently associated with delirium (22). In addition, we applied a new, promising score developed in a very large sample of 250,000 participants to assess associations between long-term anticholinergic medication use and the risk of dementia (16). We hypothesized that a high preoperative anticholinergic burden is an independent, potentially modifiable predisposing and precipitating factor for POD in older people.

Preoperative anticholinergic medication exposure was assessed by two different scales estimating the overall anticholinergic burden, the weighted ARS and the more recent ABS. The findings of this study suggest that anticholinergic medication usage might be an independent risk factor for POD in older population undergoing elective surgery. The reduction or omission of these drugs preoperatively might thus be beneficial for the prevention of POD.

Our results are in line with several previous studies, which reported an association between anticholinergic drug exposure measured with the ARS and the occurrence of delirium in older patients (38–41). A recently published systematic review by Egberts et al. showed that among the variety of existing anticholinergic drug scales, the Anticholinergic Risk Scale (ARS) was the only one found to be consistently associated with delirium (22). Also, our findings are in accordance with a published study by Mueller et al. who showed an independent association between preoperative anticholinergic burden and the occurrence of POD (prevalence 10%) in a sample of older cancer patients (mean age 71 years, n = 651) (23). Yet, in contrast to our study, this study used the Anticholinergic Drug Score (42) to determine the anticholinergic burden. Other studies did not find an association between anticholinergic burden and delirium (43, 44). Reasons for the inconsistent results of the studies are manifold. One reason could be that the measurement of the anticholinergic load has not yet been standardized (22). This leads to a large body of existing literature concerning DAPs and a lack of consensus on how to quantify the anticholinergic burden. In recent years, numerous different scales have been developed. However, they vary widely in their structure, focus, application, measurement of anticholinergic properties (serum vs. predefined) and association with outcomes (21). Therefore, comparability of individual study findings is limited, and an international consent on the most feasible instrument is strongly needed. The use of different tools to determine the anticholinergic burden is one explanation for the inconsistent findings of previous studies. Furthermore, there is a large heterogeneity in study populations comprising residents of nursing homes (38), Australian veterans (45), Taiwanese National Health Insurance database (46), palliative care inpatients (39) and acutely ill hospitalized patients (20, 40), making it even more difficult to compare results. Moorey et al. claimed that delirium is not associated with the anticholinergic burden in older patients on admission to an acute hospital (43). In contrast to our study, they used the Anticholinergic Cognitive Burden Scale (47) and the Anticholinergic Drug Score which were both not consistently associated with delirium (22). Pasina et al. also used the Anticholinergic Cognitive Burden Scale in their recently published study and did not find a clear association between anticholinergic burden and delirium in patients admitted to an acute geriatric ward (44). Also, in contrast to our findings, a recently published study by Heinrich et al. found no association between preoperative anticholinergic load and POD using the Anticholinergic Cognitive Burden Scale, the Anticholinergic Drug Score and the ARS (24). However, compared to our study, these patients were significantly younger (POD: 74 years, no POD: 71 years in median) and patients with more than mild cognitive impairment (Mini-Mental State Examination score ≤ 23 points) were excluded.

As mentioned above, to our best knowledge, this is the first study using the ABS to explore the effect of DAPs on delirium. In comparison to the ARS, ORs for occurrence of POD were clearly higher using the ABS than the ARS. Our results suggest a 2.7-fold risk of developing a POD for each drug included in the ABS. Therefore, our findings provide a strong argument for modifiable delirium risk assessment by ABS in older patients scheduled for surgery. The PAWEL study's intervention bundle AKTIVER (Alltags- und Kognitions-Training & Interdisziplinarität verbessert Ergebnis und mindert das Risiko [“everyday skills and cognition training and interdisciplinarity improves outcome and mitigates risk”]) has been shown to reduce delirium by 33% in patients undergoing elective orthopedic and abdominal surgery by daily application of individualized modules on activation, relaxation and diagnostic chaperonage during the hospital stay (37). In addition to those actions for delirium prevention, software programs, or an app could be implemented into the hospital clinical information system to raise awareness of detrimental drugs even before surgery of older patients to enable discontinuation or substitution prior to anesthesia to avoid postoperative delirium. In most cases, alternatives more appropriate for older people are available or medication is not crucial during the vulnerable perioperative period. However, further studies are required to validate ABS as a useful tool to reduce the risk of POD in older patients in addition to the AKTIVER bundle.

This study has several limitations. First, our approach to measure anticholinergic drug exposure did not include the dosages of DAPs. It is quite conceivable that higher dosages of DAPs have a stronger negative impact on the development of POD. Second, the ARS was developed in 2008 and was not updated since then. This could lead to an underestimation of anticholinergic burden due to an abandonment of newer DAPs. Third, we collected our information from patients' medication lists and verbal information but had little information about adherence to prescriptions prior to hospital admission. Finally, we did not consider delirium severity and duration in this study. The strengths of our study are the prospective multicenter study-design, the large number of patients and the usage of two different tools to measure anticholinergic burden. In addition to the established ARS as a weighted score, we used ABS as a quick and simple instrument to quantify anticholinergic burden in delirium patients for the first time. A further strength is the relatively high number of strong confounders like cognition included in our multivariable regression analysis.

This study of 899 older patients undergoing various elective surgical procedures shows that the preoperative anticholinergic burden, assessed by ARS or ABS, is an independent risk factor for POD in older patients. Delirium occurrence was more than 2.7 times higher if a patient took at least one of the 56 drugs listed in the ABS (16), even after controlling for the most known delirium risk factors. The POD rate increased from 21.7 to 42.3% in patients receiving one or two ABS drugs. Identifying DAPs prior to hospital admission might be an opportunity to terminate or substitute anticholinergic drugs preoperatively and prevent delirium after elective surgery.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Ethics Commission of the Faculty of Medicine of the Eberhard-Karls University and University Hospital Tübingen with number 233/2017BO1 on October 12, 2017 and by the Ethics Commission of the University of Potsdam with number 38/2017 on December 11, 2017. The study was registered on the German Clinical Trials Register (DRKS-ID: DRKS00012797) in July, 2017. The patients/participants provided their written informed consent to participate in this study.

MH, CT, and GE designed this secondary analysis of the PAWEL-Study, planned the data collection, performed the statistical analysis, and prepared and revised the manuscript. CB, CM, FK, EM, SW, LC, BF, MR, CA, and MD were involved in data collection and critically revised the manuscript for final approval of the version to be published. All authors contributed to the article and approved the submitted version.

This study was funded by the Innovationsfonds (Fund of the Federal Joint Committee, Gemeinsamer Bundesausschuss, G-BA; AZ: VF1_2016-201), which had no role in the design of the study and had no role either during its execution, analyses of the data, or in the decision to submit any results. We acknowledge support by the Open Access Publication Fund of the University of Freiburg.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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