Impact of drug burden index on delirium in community-dwelling older adults with dementia: A longitudinal observational study

Abstract

Background

The Drug Burden Index (DBI) is a validated tool for assessing the dose-dependent cumulative exposure to sedative and anticholinergic medications. However, the increased risk of delirium superimposed dementia (DSD) with high DBI levels has not yet been investigated.

Aim

This study aimed to examine the longitudinal association between high DBI levels and delirium in community-dwelling older adults with dementia.

Method

A total of 1105 participants with cognitive impairment underwent a comprehensive geriatric assessment. Experienced geriatricians made the final diagnosis of delirium based on DSM-IV-TR and DSM-V. We calculated the DBI as the sum of all sedatives and anticholinergics taken continuously for at least four weeks before admission. We classified the participants as having no exposure (DBI=0), low exposure (0<DBI<1), and high exposure (DBI≥1).

Results

Of the 721 patients with dementia, the mean age was 78.3±6.7 years, and the majority were female (64.4%). In the whole sample, low and high exposures to anticholinergic and sedative medications at admission were 34.1% (n=246) and 38.1% (n=275), respectively. Patients in the high-exposure group had higher physical impairment (p=0.01), higher polypharmacy (p=0.01), and higher DBI scores (p=0.01). In the multivariate Cox regression analysis, high exposure to anticholinergic and sedative medications increased the risk of delirium 4.09-fold compared to the no exposure group (HR=4.09, CI: 1.63-10.27, p=0.01).

Conclusion

High exposure to drugs with sedative and anticholinergic properties was common in community-dwelling older adults. A high DBI was associated with DSD, highlighting the need for an optimal prescription in this vulnerable population.

Trial registration

The trial was retrospectively registered at ClinicalTrials.gov. Identifier: NCT04973709 Registered on 22 July 2021.

Introduction

Delirium is an acute-onset, multifactorial geriatric syndrome characterized by alterations in attention, cognition, and consciousness [1]. It is associated with a worsening clinical course and progression of cognitive decline in patients with dementia [2]. Despite its clinical implications, delirium superimposed dementia (DSD) is often under-recognized or under-reported because in many cases behavioral and psychological changes are often misattributed to diurnal variations in dementia symptoms [3]. Delayed diagnosis of DSD promotes adverse consequences such as deterioration of cognition, functional decline, and increased mortality [4, 5].

In recent years, more attention has been paid to preventable and reversible risk factors in patients who are particularly susceptible to delirium [6]. Accordingly, medications appear to be one of the most notable modifiable risk factors for delirium in the older population [7]. Recent studies have shown an association between anticholinergic medication exposure and delirium in patients diagnosed with dementia [8, 9]. In addition, sedative exposure is associated with cognitive and physical impairment in community-dwelling older adults [10, 11]. In this context, total medication exposure should be considered when evaluating the increased risk of adverse events, especially in vulnerable individuals [12].

The Drug Burden Index (DBI) is a pharmacologic evidence-based tool that assesses both anticholinergic and sedative medication burdens in older adults [13–15]. DBI has specific advantages over other evidence-based pharmacological tools [16]. For instance, DBI is a noninvasive method calculated using medication prescriptions [16]. Furthermore, the DBI considers the dosage of each anticholinergic and sedative medication [16]. In addition, DBI has been shown to be one of the most appropriate measurement tools for the older adult population [17]. However, few studies have examined the effects of total medication exposure in community-dwelling older adults with dementia [18]. Therefore, knowledge about the impact of medications on adverse effects in these populations is still limited and cognitive impairment in older adults remains an additional challenge in clinical investigation.

Growing evidence suggests that high DBI levels are associated with impaired mobility, slow gait speed, decline in cognitive function, increased falls, frailty, hospitalization, and mortality [19]. However, to date, no study has examined the increased risk of delirium associated with DBI levels. In this study, we aimed to reveal the potential association between DBI scores and DSD, hypothesizing that the cumulative effect of medications with sedative or cholinergic properties may contribute to delirium in community-dwelling older adults with dementia.

Ethics Approval

This study was approved by the Clinical Research Ethics Committee of Gulhane Training and Research Hospital, University of Health Sciences, and was conducted in accordance with the Declaration of Helsinki (Clinical Trials.gov: NCT04973709). Patient informed written consent was waived because of the retrospective nature of the study using medical records.

Methods

Study design, setting, and participants

The present study is a secondary analysis of data collected from a community-based longitudinal study of DSD admitted to a tertiary outpatient clinic between 2010 and 2022 [20]. During the study period, more than 10.000 older adults visited our geriatric outpatient clinic. Of these, a total of 1105 participants aged 65 years and older with cognitive impairment underwent regular comprehensive geriatric assessments. In 721 of these participants, the diagnosis of dementia was confirmed by specialized geriatricians.

We excluded subjects who had no information about regular medication use, severe psychiatric disorders such as schizophrenia or major depression, substance abuse, mild cognitive impairment, dementia with Lewy bodies, or severe end-stage disease (renal, liver, cardiac).

Ascertainment of dementia

On admission, we interviewed each patient with cognitive impairment and evaluated their previous clinical records and/or accompanying family and/or caregiver information and/or radiologic imaging, such as computed tomography or magnetic resonance imaging, and/or prescribed acetylcholinesterase inhibitors or memantine. An expert geriatrician confirmed the diagnosis and subtype of dementia (probable Alzheimer’s disease, probable vascular dementia, probable frontotemporal lobar degeneration, and mixed or other types) according to the Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition- Text Revision (DSM-IV-TR) or Fifth Edition (DSM-V) [21–23]. The severity of dementia was determined using the Clinical Dementia Rating (CDR) score and graded as stage 1 (mild), 2 (moderate), or 3 (advanced) [24].

Ascertainment of delirium superimposed dementia

As part of our previous research, we followed up patients with dementia at regular intervals. The median follow-up period was 2 years (range 1–12 years). We performed a short form of the confusion assessment method (CAM) as part of a regular interview to detect a possible diagnosis of delirium [25]. Using all clinical data, experienced geriatricians made the final diagnosis of delirium based on DSM-IV-TR and DSM-V [26] [23].

Based on the clinical assessment, we determined psychomotor subtypes of delirium, such as increased psychomotor activity, agitation (hyperactive form) or drowsiness, lethargy, and psychomotor retardation (hypoactive form) or mixed forms [27]. We classified the possible precipitating factors for delirium into four groups: infections, metabolic or endocrine disorders, cerebrovascular disorders, and other diseases [28].

Medication exposure

We quantified drug exposure using the DBI which was used to assess dose-dependent exposure to anticholinergic and sedative drugs [29]. The DBI was calculated using the following equation (DBI = D/ (δ + D)), where D represents the daily dose taken by participants and δ is the minimum recommended daily dose set according to the adult dose approved by the US Food and Drug Administration (FDA) and Turkish authorities in the product information of the drugs [16] [30]. Subsequently, we calculated the total DBI score for each participant by summing the DBI scores for each anticholinergic or sedative drug that had been taken regularly for at least four weeks before admission. Medications with both anticholinergic and sedative effects were included in one group to avoid duplication. In the current study, we classified participants as having no exposure (DBI = 0), low exposure (0 < DBI < 1), or high exposure (DBI ≥ 1) [31].

Covariates for all participants

Clinical and demographic data and comprehensive geriatric assessment parameters were collected from hospital digital databases. These included age, gender, education level, the burden of comorbidities as measured by the Deyo-Charlson Comorbidity Index (D-CCI) [32], functional status (Lawton-Brody Instrumental Activities of Daily Living (IADL) ) [33], polypharmacy (defined as five or more medications) [34], and detailed medication history (including dosage and duration).

Statistical Analysis

All analyzes were performed using the IBM Statistical Package for Social Sciences (IBM SPSS), version 22.0 (SPSS Inc., Chicago, IL, USA). We assessed the normal distribution of the data using the Kolmogorov-Smirnov test. Values with a normal distribution were presented as mean ± standard deviation, and values without a normal distribution were given as median (min-max). Differences in numeric variables with a normal distribution were evaluated using the ANOVA test and numeric variables without a normal distribution were analyzed using the Kruskal-Wallis H test. The chi-square test was used to compare categorical data. Tukey’s HSD (for parametric variables) and Bonferroni adjustment Mann-Whitney U-test (for nonparametric variables) were used as post hoc tests for multiple comparisons between groups of drug exposure. We performed a univariate Cox regression analysis to assess the association between DBI and delirium (Crude model). Hazard ratios (HRs) with 95% confidence intervals (CIs) for DBI were estimated using a multivariable Cox proportional hazards model to adjust for potential confounders, such as age, gender, CCI score, Lawton-Brody IADL score, CDR score, and polypharmacy in patients with DSD. A value of p < 0.05 in the statistical analyzes was considered significant.

Results

Cohort and Clinical Characteristics

Table 1 shows the demographic and clinical characteristics of the cohort stratified by the DBI score. Regarding the characteristics of eligible patients, the mean age of patients was 78.3 ± 6.7 years, and the majority were female (64.4%). The most common possible subtypes of dementia were Alzheimer's dementia (71.2%), vascular dementia (20.5%), and frontotemporal dementia (1.4%). In the whole sample, high and low exposure to anticholinergic and sedative drugs were 38.1% (n = 275), and 34.1% (n = 246), respectively. About one-quarter of the patients (27.7%) were not exposed to these types of medications. There were no significant differences among the three groups in baseline characteristics, such as age, gender, education level, D-CCI scores, dementia subtypes, and CDR scores. However, patients in the high-exposure group had significantly higher levels of physical impairment (p = 0.01), polypharmacy (p = 0.01), and higher DBI scores (p = 0.01).

In the overall population, 27.0% (n = 195) of the patients with dementia were diagnosed with delirium during the follow-up period. Of note, the most common delirium subtype was hyperactive delirium (54.4%) and within all delirium subtypes, the most common delirium etiology was infectious causes (10.1%). The prevalence of delirium was higher in the high-exposure group (33.2%) than in the low- (24.8%) and non-exposure (21.0%) groups (p = 0.01). There were no statistically significant associations between the three groups in terms of delirium subtypes (p > 0.05).

Effects of high medication exposure on delirium

Table 2 shows the unadjusted and adjusted hazard ratios for delirium associated with exposure to anticholinergic and sedative medications. In the unadjusted cumulative hazard regression analysis (Crude model), advanced age (HR = 1.06, CI: 1.03–1.08, p = 0.01), higher CDR score (HR = 1.81, CI: 1.47–2.23, p = 0.01), lower level of IADLs (HR = 0.95, CI: 0.89–0.99, p = 0.04) and higher exposure to anticholinergic and sedative medications (HR = 1.61, CI:1.07–2.42, p = 0.02) were found to be independent risk factors for delirium in patients with dementia. The omnibus test confirmed that the crude model of exposure to DBI was significant (− 2LL = 1846.263, χ²(2) = 6.772, p = 0.03).

In the multivariate analysis with Cox regression, a higher CDR score remained strongly associated with delirium after adjusting for possible covariates (HR = 3.71, CI: 2.24–6.15, p = 0.01). In addition, high exposure to anticholinergic and sedative medications increased the risk of delirium 4.09-fold compared to the group with no exposure (HR = 4.09, CI: 1.63–10.27, p = 0.01). The omnibus test confirmed that the Model was highly significant (− 2LL = 410.708, χ²(2) = 42.623, p < 0.01). The adjusted cumulative hazard curves for DSD based on exposure to anticholinergics and sedatives are shown in Fig. 1.

Sensitivity Analysis

A sensitivity analysis grouping cases of possible Alzheimer's dementia did not produce different results from the main analysis. There was still a statistically significant association between high medication exposure and episodes of delirium (HR = 4.77, CI: 1.58–14.44, p = 0.006).

Discussion

In the current study, more than two-thirds (72.2%) of the community-dwelling older adults with dementia were exposed to at least one sedative or anticholinergic. A significant majority of these (38.1%) had high exposure to these medications. In addition, the prevalence of delirium (up to 33.2%) showed a significant upward trend with increased exposure. Moreover, the most common delirium subtype was hyperactive delirium in both the low- and high-exposure groups. One of the most striking findings of the current analysis was the significant association of high DBI levels with DSD, even after adjusting for potential covariates. To our knowledge, this is the first study to show that high exposure to these drugs increases the risk of delirium four-fold in this population.

In addition, a previous study showed that people with dementia have a higher anticholinergic burden than those without dementia [35]. Moreover, high anticholinergic burden is an independent risk factor for delirium and is associated with worsening cognitive and physical function in patients with DSD [36, 37]. However, studies investigating the association between delirium and anticholinergic burden have neglected sedative load as a potential mediator. Recently, it was shown that increasing sedative load with minimal anticholinergic burden at baseline was associated with a higher incidence of delirium in community-dwelling older adults with dementia [11]. Consistent with these findings, our results showed that the total anticholinergic and sedative components of DBI increased the overall risk of delirium in patients with dementia. A previous population-based cross-sectional study of 2087 participants showed that the use of these drugs increases the risk of frailty [38]. However, this study did not evaluate delirium as an outcome. Our findings on the association between delirium and exposure to anticholinergics and sedatives are unique.

One possible explanation for these findings, as a neurotransmitter hypothesis, is the deterioration of cholinergic neurotransmission and expansion of neuroinflammation due to activation of microglial cells in patients with dementia [39, 40]. Because of these pathological changes, patients may be more susceptible to the possible adverse effects of drugs. In addition, the cholinergic system plays an important role in inflammation and oxidative stress [41]. Accordingly, high exposure to anticholinergics and sedatives may exacerbate systemic inflammatory status in this vulnerable population. Furthermore, high exposure results in significantly more drug-induced deterioration than low exposure when considered together with variables contributing to a complex clinical condition [42]. We speculated that cumulative high exposure to anticholinergics and sedatives may have a more detrimental effect via these possible changes. Therefore, these underlying inflammatory mechanisms may shed light on the possible relationship between drug exposure and DSD pathogenesis [41].

Although older adults with dementia are more susceptible to adverse effects of anticholinergics and sedatives, these medications are commonly prescribed in clinical practice. This is consistent with recent reports that the prevalence of taking at least one anticholinergic or sedative drug was 10–60% of patients with dementia in a different clinical setting [35, 43–46, 11]. In our study, the higher percentage (72.2%) of patients who were exposed to these medications reflected the greater ability of the DBI to detect anticholinergic and/or sedative medications.

Despite increasing attempts to identify modifiable risk factors, age, gender, educational level, comorbidity, and severity of illness have been significantly and independently associated with delirium in community-dwelling older adults with dementia [4, 47, 48]. For example, a recent study showed that the severity of dementia according to the CDR score increased the risk of delirium after adjusting for age, gender, and education level [49]. Accordingly, these results are consistent with the findings of the present study that the CDR score is one of the most important risk factors for delirium after adjusting for relevant confounders.

This study has certain limitations. Although the baseline risk of high drug exposure was established on admission, this study did not examine the association between changes in the DBI and the risk of delirium over time. However, recent evidence from animal studies suggests that ingestion of drugs with anticholinergic or sedative properties may alter the brain structure [50]. Therefore, the cumulative effects of these drugs may persist over a long period, even when these drugs are discontinued or switched. Although we carefully accounted for several covariates, such as age, gender, CCI score, Lawton-Brody IADL score, CDR score, and polypharmacy; residual confounding remains possible.

The present study has several strengths. Subjects underwent a comprehensive geriatric assessment and were concurrently assessed with the DBI at enrollment, eliminating potential selection bias. In addition, we were able to account for the duration (at least one month) and the dosage of anticholinergic and sedative medications. This study had a large sample size, and a validated scale was used to objectively calculate drug exposure. In addition, the subtypes of dementia and delirium, and the possible etiology of delirium according to the drug exposure level are described in detail. Our study extends the findings of previous studies that reported an association with anticholinergic or sedative drugs and shows that total cumulative dose-related medication exposure should be considered in patients with dementia.

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Tables

Table 1. Characteristics of patients with dementia stratified by drug burden index.

Variables	Total (n=721)	Drug burden index			p value
		Drug burden index
		None (n=200)	Low exposure (n=246)	High exposure (n=275)
		None (n=200)	Low exposure (n=246)	High exposure (n=275)
Demographic and clinical data
Age (years), mean±SD	78.4±6.7	79.0±7.2	77.8±6.4	78.5±6.7	0.14
Gender (Female), n (%)	466 (64.6)	128 (64.0)	153 (62.2)	185 (67.3)	0.47
Education (years), median (min-max)	5 (0-22)	5 (0-22)	5 (0-18)	5 (0-20)	0.56
D-CCI score, median (min-max)	1 (0-9)	1 (0-6)	1 (0-8)	1 (0-9)	0.30
Polypharmacy (yes), n (%)	329 (45.6)	45 (23.1)	98 (39.8)	186 (68.1)	0.01
Lawton-Brody IADL, median (min-max)	8 (0-17)	8 (0-17)	8 (0-17)	3 (0-17)	0.01
CDR score, mean±SD	1.8±0.7	1.7±0.7	1.7±0.7	1.8±0.6	0.68
DBI score, mean±SD	0.71±0.6	-	0.56±0.1	1.36±0.4	0.01
Dementia subtypes, n (%)
Alzheimer	513 (71.2)	147 (73.5)	182 (74.0)	184 (66.9)	0.18
Vascular	148 (20.5)	31 (15.5)	46 (18.7)	71 (25.8)
Frontotemporal	10 (1.4)	2 (1.0)	3 (1.2)	5 (1.8)
Mixed or other dementia	50 (6.9)	20 (10.0)	15 (6.1)	15 (5.5)
Delirium (Yes), n (%)	195 (27.0)	42 (21.0)	61 (24.8)	92 (33.2)	0.01
Delirium subtypes, n (%)
Hyperactive	106 (14.7)	23 (11.6)	30 (12.2)	53 (19.3)	0.06
Hypoactive	47 (6.5)	9 (4.5)	15 (6.1)	23 (8.4)
Mixed	42 (5.8)	10 (5.0)	16 (6.5)	16 (5.8)
Delirium etiology, n (%)
Infection	73 (10.1)	12 (6.0)	25 (10.2)	36 (13.1)	0.04
Metabolic and endocrine disorders	48 (6.7)	12 (6.0)	11 (4.5)	25 (9.1)
Cerebrovascular disorders	17 (2.4)	7 (3.5)	4 (1.6)	6 (2.2)
Other illness	57 (7.9)	11 (5.5)	21 (8.5)	25 (9.1)
Abbreviations: CDR, clinical dementia rating; DBI, Drug burden index; D-CCI, Deyo–Charlson comorbidity index; IADL, instrumental activities of daily living scale.
Values given in bold indicate statistically significant results (p<0.05).

Table 2. Predictors of delirium in patients with dementia.

Variables	Delirium superimposed dementia


	Crude Model HR (95% CI)	p value	Model HR (95% CI)	p value


Age, years	1.06 (1.03-1.08)	0.01	1.02 (0.97-1.07)	0.42
Gender (Female)	0.94 (0.69-1.29)	0.71	0.61 (0.32-1.16)	0.13
D-CCI score	1.01 (0.93-1.10)	0.79	1.15 (0.90-1.47)	0.27
Lawton-Brody IADL score	0.95 (0.89-0.99)	0.04	1.04 (0.99-1.10)	0.12
CDR score	1.81 (1.47-2.23)	0.01	3.71 (2.24-6.15)	0.01
Polypharmacy	1.02 (0.75-1.39)	0.92	1.16 (0.55-2.42)	0.70
Drug burden index
None	reference		reference
Low exposure	1.15 (0.75-1.79)	0.52	1.62 (0.61-4.36)	0.34
High exposure	1.61 (1.07-2.42)	0.02	4.09 (1.63-10.27)	0.01
Abbreviations: CDR, clinical dementia rating; CI, Confidence Interval; D-CCI, Deyo–Charlson comorbidity index; IADL, instrumental activities of daily living scale; HR, hazard ratio.