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Geriatr Gerontol Int 2016; 16: 424–431

ORIGINAL ARTICLE: EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH

In geriatric patients, delirium symptoms are related to the anticholinergic burden Moustafa Naja,1,2 Jadwiga Zmudka,1 Sanaa Hannat,1 Sophie Liabeuf,2 Jean-Marie Serot1 and Pierre Jouanny1,3 1

Department of Geriatric Medicine, 2Clinical Research Center, Amiens University Medical Center, Amiens, and 3Department of Geriatric Medicine, Dijon University Medical Center, Dijon, France

Aim: Anticholinergic drugs are widely prescribed for elderly patients and could induce several neuropsychological disorders, especially delirium. The aim of the present study was to evaluate the relationship between anticholinergic burden and delirium symptoms. Methods: A total of 102 patients aged over 75 years (86.3 ± 5.8 years, 53 women and 49 men) hospitalized in a geriatric medicine department were included in this prospective study. Anticholinergic burden was assessed by classifying drug use into three levels (low, medium or high). An overall, weighted score was established. Delirium symptoms were measured with the Confusion Assessment Method on days 1, 3, 5, 8, 15 and 21. Covariates studied were comorbidities (Charlson), health status, activities of daily living, nutrition (albumin), cognition, length of stay and mortality. Results: A total of 51.6% of the patients were taking anticholinergic drugs at home (2.13 ± 1.34). Length of stay was 14.5 ± 9.9 days. Prevalence of delirium symptoms ranged on days between 34.8 and 60%. Anticholinergic burden was correlated with the appearance of delirium symptoms. Delirium symptoms were associated with greater mortality (16.1 and 3.7 % in patients with and without delirium symptoms; P = 0.049), a longer hospital stay (18.09 ± 11.34 vs 11.75 ± 7.80 days, P = 0.001), greater dependence on discharge (activities of daily living score: 1.57 ± 1.56 vs 3.41 ± 1.45, P < 0.0001) and worse health status on discharge (5.3 ± 2.7 vs 7.0 ± 1.7, P = 0.0008). Conclusion: Anticholinergic burden appears as a risk factor for both delirium symptoms and mortality. Prevention of delirium symptoms requires its reduction Geriatr Gerontol Int 2016; 16: 424–431. Keywords: adverse effect, anticholinergic burden, delirium, elderly patients, hospitalization.

Introduction In the elderly, the frequent presence of multiple chronic diseases leads to polypharmacy. Accordingly, the iatrogenic risk in this population is a public health problem.1 Aging weakens the cholinergic system and increases the permeability of the blood–brain barrier.2 In addition to these physiological changes, dementia (especially Alzheimer’s disease) and delirium are accompanied by a hypocholinergic state, which contributes to the neuropsychological manifestations often observed in elderly

Accepted for publication 10 February 2015. Correspondence: Professor Pierre Jouanny MD, MPh, Department of Geriatric Medicine, CHU de Dijon – Champmaillot, 2 rue Jules Violle – BP 87909, 21079 DIJON Cedex, France. Email: [email protected]

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doi: 10.1111/ggi.12485

patients on anticholinergic drugs.3 The neurotransmitter, acetylcholine (2-acetyloxy-trimethylammonium), has a widespread, important role in the central nervous system and is involved in several cognitive processes (such as memory, motor skills, learning, etc.).4 A cholinergic deficit is associated with Alzheimer’s disease.5 Delirium is an acute cognitive disorder. Its prevalence increases with age to reach 14% in people aged ≥80 years and 60–87% in elderly patients hospitalized in emergency.3,6 Delirium is characterized by a disturbance of consciousness, a change in cognition or development of a perceptual disturbance that cannot be accounted for by dementia.7,8 There is often evidence from the patient’s medical history, physical symptoms or laboratory results to suggest that delirium is caused by the physiological consequences of a general medical condition.7 Etiology of delirium is multifactorial, with both predisposing factors (especially dementia) and © 2015 Japan Geriatrics Society

Delirium and anticholinergic burden

precipitating factors (infection or hospitalization, and/or use of drugs with anticholinergic properties).9 Delirium leads to major cognitive impairments, prolongs hospitalization, increases the level of care required, and is associated with loss of autonomy and increasing mortality.10–12 Elderly patients frequently take more than six drugs, which generally include one or more with anticholinergic properties.13 Drug–drug interactions can amplify side-effects.2,14 The anticholinergic activity of a drug defines its capacity to inhibit cholinergic transmission. Several studies have shown that older persons exposed to anticholinergic burden (AB) have a decline in cognitive functioning.15,16 Because of the important role of cholinergic system impairment in cognitive pathologies, we aimed to study the role of AB in delirium, related to its potentially prevention. The primary objective of the present study was to establish whether or not AB is associated with delirium symptoms. Secondary objectives were to determine if delirium is associated with mortality, loss of independence, length of stay and health status, and to identify factors associated with AB (medical conditions, comprehensive geriatric assessment etc.).

Methods Participants The present prospective cohort study was carried out in the Geriatric Department at Amiens University Medical Center, Amiens, France. It was carried out for a period of approximately 6 months consecutively. It receives patients aged over 75 years admitted for various reasons (cardiorespiratory disorders, alterations in general health and/or cognitive impairment), often on an emergency basis. All patients admitted to one geriatric medicine unit (20 beds) were included. There were no exclusion criteria.

AB The AB for drugs given at home at baseline was calculated on the basis of an interview and the patient’s medical record. This burden was then calculated relative to drugs given on the day of admission (D0) and then weekly during the hospital stay. All medications given in hospital were logged using DxCare software (MedaSys, Gif-sur-Yvette, France). To assess AB, we used two anticholinergic drug scales. The Anticholinergic Cognitive Burden (ACB) list was developed by Boustani. A score of 1 is given to drugs with an anticholinergic effect in vitro or in animal studies but that have no clinically proven cognitive effects. A score of 2 or 3 is given to drugs that show a clinically proven anticholinergic effect.17,18 Carnahan established the Anticholinergic Drug Scale (ADS) after studying the © 2015 Japan Geriatrics Society

relationship with serum anticholinergic activity assay results.19 On the four-level ADS, a drug’s anticholinergic potential is scored as follows: level 0 = no known anticholinergic properties; level 1 = potentially anticholinergic, as evidenced by receptor binding studies; level 2 = anticholinergic adverse events sometimes noted, usually at excessive doses; level 3 = markedly anticholinergic. The AB was calculated here by combining the two scales. If a drug is present in the two scales with different scores, we have considered the highest score. The dose of each drug given was transcribed into a coefficient relative to the normal dose and then multiplied by the drug’s AB score. As an example, patient X was taking 20 mg of paroxetine, 80 mg of furosemide and 1 mg of alprazolam per day at home. The recommended doses for an elderly patient (France’s Vidal drug compendium) are 20 mg for paroxetine, 20–40 mg for furosemide and 1–2 mg of alprazolam. Hence, the doses of paroxetine and alprazolam taken by patient X were those recommended doses, and so a coefficient of 1 was noted. The dose of furosemide taken by this patient X was twice the recommended initial dose, and so a coefficient of 2 was noted. Paroxetine was scored as 3 on the ADS, with alprozolam and furosemide scored as 1. By calculating the AB as (coefficient × AB score for drug A) + (coefficient x AB score for drug B) + (coefficient × AB score for drug C), the final score for patient X was 6 (1 × 1 [for alprazolam] + 2 × 1 [for furosemide] + 1 × 3 [for paroxetine]).

Delirium symptoms To detect delirium, the Confusion Assessment Method (CAM) was administered on admission and throughout the inpatient stay (day 1 [D1], day 3 [D3], day 5 [D5], day 8 [D8], day 15 [D15] and day 21 [D21]). The CAM is a standardized delirium assessment tool with acceptable psychometric properties, and is recommended by national guidelines.20,21 The CAM score is determined by examining the patient for: (i) acute and fluctuating changes in mental status; (ii) inattention; (iii) disorganized or incoherent thinking; and (iv) altered level of consciousness.22 We evaluated the incidence of occurrence of one or more of delirium symptoms.

Covariates Predisposing and precipitating factors Major predisposing factors leading to delirium were assessed. Covariates were respectively: age and cognition (Mini-Mental State Examination [MMSE], which basically evaluates cognition) carried out soon after admission, the presence of sensory disturbances (severe blindness and deafness) and personal autonomy (activities of daily living [ADL] at home). | 425

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Precipitating factors assessed were comorbidity according to the Charlson Comorbidity Index (based on the information noted in hospital records and provided by the family physician, family members), the number of previous hospitalizations, creatinine clearance to detect kidney failure and serum albumin to detect malnutrition.6

Other covariates Other covariates assessed were sex, marital status (single, married, divorced, widowed), place of residence (with spouse or other family member, alone or in an institution), socioeconomic level before retirement and educational level (less/more than 10 years or high school diploma). Health status was measured before and immediately after hospitalization by asking the patient to score his/her perceived status on a numeric scale ranging from 0 (worst possible health status) to 10 (best possible health status). All the aforementioned measurements are recommended by the French National Authority for Health and routinely carried out in geriatric departments in France. Under French law, formal consent is not required in anonymous epidemiological studies of data collected during hospitalization without care practices modifications.

Statistical analysis A descriptive analysis was carried out by calculating the mean ± SD for quantitative variables and the frequency distribution for categorical variables. Secondarily, an inferential analysis was used to look for factors (including the AB) that were significantly correlated with the occurrence of one of more delirium symptoms. Student’s t-test and the χ2-test were applied when assessing quantitative variables and categorical variables, respectively. The threshold for statistical significance was set to P < 0.05. Third, multivariate logistic regression was carried out to assess the respective impacts of the covariates. All statistical analyses were carried out with Statview software (Abacus Concepts, Berkeley, CA, USA).

Results A total of 102 elderly patients (mean ± SD age 86.3 ± 5.8; 48.0% males) were monitored during the study. There were no deaths before D2. The study group’s baseline characteristics are summarized in Table 1. A total of 86 of the 102 patients were taking medications at home. Of these, 54 (52.9 %) were taking anticholinergic drugs (Table 2). The prevalence and the 426 |

Table 1 Baseline characteristics of study participants Characteristics

Study participants (n = 102)

Age (mean ± SD) Male, n (%) Marital status, n (%) Single Married Divorced/separated Widowed Place of residence, n (%) With spouse With family Institution Alone with family nearby Alone without family nearby Education level, n (%) 10 years High school diploma Social class before retirement, n (%) Farmer Employee Housewife Worker Other No. hospitalizations (mean ± SD) Charlson Index (mean ± SD) Severe sensory disorders, n (%) Creatinine clearance (mean ± SD) Albumin (mean ± SD) MMSE score (mean ± SD) Basic ADL (mean ± SD) IADL (mean ± SD)

86.3 ± 5.8 49 (48.0) 7 (7.2) 33 (34.0) 2 (2.1) 55 (56.7) 33 (33.7) 15 (15.3) 10 (10.2) 27 (27.6) 13 (13.3) 39 (57.4) 24 (35.3) 5 (7.4) 13 (35.9) 23 (22.5) 2 (3.1) 22 (34.4) 4 (6.3) 3.1 ± 1.5 7.5 ± 2.6 12 (11.8) 63.4 ± 33.9 30.7 ± 4.7 18.4 ± 6.2 3.9 ± 1.9 2.7 ± 0.3

ADL, activities of daily living; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination.

mean number of drugs given to patients were analyzed, together with the corresponding level in AB list (Table 3). The mean AB was 2.13 ± 1.34 at home and increased to 2.50 ± 2.01 at D8. The prevalence of anticholinergic drug administration increased from 52.9% at home to 75.0% during the second week of hospitalization (D15). Overall AB increased slightly during the hospital stay, relative to the burden at home (Table 3). The prevalence of one or more of delirium symptoms increased during the hospital stay, and reached a value of 51.7% at D15. The mean number of delirium symptoms per patient first decreased and then slightly increased during hospitalization; after two weeks, the number was close to D1 value (Table 4). AB at home was significantly correlated with the presence of delirium symptoms, especially during the first © 2015 Japan Geriatrics Society

Delirium and anticholinergic burden

Table 2 Anticholinergic drugs taken by the study patients Score of 3

Score of 2

Score of 1

Amitriptyline Hydroxyzine Oxybutynin Paroxetine

Loxapine

Atenolol Diazepam Digoxin Fentanyl

Furosemide Lorazepam Midazolam Oxazepam

Oxycodone Tramadol Vancomycin Warfarin

Table 3 Anticholinergic burden and delirium symptoms during hospitalization

No. patients Prevalence of anticholinergic drugs Prevalence of anticholinergic drugs for each score level Mean no. drugs administered Mean burden Mean dose-related burden Prevalence of delirium symptoms

At home

D1

D8

D15

102 52.9% 1 2 3 61% 0% 14% 1 2 3 0.88 0 0.13 1.31 ± 1.25 2.13 ± 1.34

92 47.3% 1 2 3 42% 1% 7% 1 2 3 0.56 0.01 0.09 0.90 ± 1.42 2.11 ± 2.09 D1 D3 43.1% 36.9% D1 D3 1.89 1.65

49 72.8% 1 2 3 69% 1% 13% 1 2 3 1.11 0.01 0.13 1.58 ± 1.63 2.50 ± 2.01 D5 D8 34.8% 45.1% D5 D8 1.67 1.54

29 75.0% 1 2 3 71% 2% 8% 1 2 3 1.10 0.02 0.10 1.43 ± 1.45 2.27 ± 1.5 D15 51.7% D15 1.73

No. delirium symptoms D1, day 1; D8, day 8; D15, day 15.

Table 4 Prevalence of delirium and delirium symptoms CAM

D1

D3

D5

D8

D15

Patients (n) Acute changes, n (%) Inattention, n (%) Disorganized thinking, n (%) Altered consciousness, n (%) Delirium, n (%)

102 9 (8.8) 29 (28.4) 32 (31.4) 13 (12.7) 8 (7.8)

92 5 (4.9) 16 (17.4) 26 (28.3) 9 (9.8) 8 (8.7)

76 4 (5.2) 15 (19.7) 17 (22.3) 10 (13.2) 6 (7.9)

49 3 (6.1) 8 (16.3) 17 (34.7) 6 (12.2) 4 (8.2)

29 2 (6.9) 8 (27.6) 9 (31.0) 7 (24.1) 4 (13.8)

CAM, Confusion Assessment Method.

few days (D3). Furthermore, the anticholinergic burden on D1 was associated with the presence of one or more of delirium symptoms on D1, D3 and D15. AB at D8 was found to be significantly associated with the presence of one or more delirium symptoms at D8 and D15. However, there was no obvious relationship between AB at D15 and the presence of one or more of delirium symptoms. The overall correlation between AB and confirmed delirium syndrome was not statistically significant. It was not possible to test the correlation between CAM and AB at D21 because of the low number of patients still in the study at this time-point (11 patients). The presence of one or more of delirium symptoms was associated with greater mortality by D3 (16.1% and 3.7% in patients with and without delirium symptoms, © 2015 Japan Geriatrics Society

respectively; P = 0.049); a longer mean length of stay (18.09 ± 11.34 vs 11.75 ± 7.80 days, respectively; P = 0.001), lower autonomy on discharge (ADL 1.57 ± 1.56 vs 3.41 ± 1.45, respectively; P < 0.0001) and worse health status on discharge (5.3 ± 2.7 vs 7.0 ± 1.7, respectively; P = 0.0008). High anticholinergic burden was correlated with the presence of delirium symptoms (burden 1.5 ± 2.3 vs 0.6 ± 1.1 in patients with and without delirium symptoms, respectively; P = 0.017) and with high mortality (anticholinergic burden at D1 2.0 ± 2.2 in deceased patients vs 0.7 ± 1.1 in living patients; P = 0.012). Patients with delirium symptoms were more dependent than non-delirious patients were on D1 (ADL 3.1 ± 2.1 vs 4.4 ± 1.4, respectively; P = 0.03) and other days (P = 0.01 to 0.0001). Furthermore, these patients had a worse health status on | 427

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discharge than non-delirious patients did (P = 0.0001). Scores for basic ADL and instrumental ADL were related to good health status on admission (P = 0.0002 and 0.04, respectively) and on discharge (P = 0.0001 and 0.002, respectively). Sensory disturbances were significantly associated with the presence of delirium symptoms on all days (P = 0.01 to 0.0001), and a poor health status degraded on discharge. Sensory disturbances were associated with poor scores for basic ADL (P = 0.0001) and instrumental ADL (P = 0.002). The presence of delirium symptoms during hospitalization was associated with a low MMSE score (13.6 ± 4.8 vs 20.8 ± 5.3; P = 0.0001). The Charlson comorbidity score was significantly correlated with age (P = 0.03), and was inversely correlated with the number of hospitalizations (P = 0.04). Age was associated with higher mortality (P = 0.04), the presence of sensory disturbances (blindness and/or deafness, P = 0.04) and poor health status on admission (P = 0.02). The health status on discharge was correlated with the health status on admission (P = 0.0001) and mortality (P = 0.01). No significant correlation was found between creatinine clearance, serum albumin level and delirium symptoms or other factors. In multivariate analysis, only two parameters were found to be independently associated with the presence of one or more delirium symptoms: MMSE and AB (Table 5).

Discussion The present study had some weaknesses. First, it was a single-center study. In non-speaking patients, it was difficult to collect some items of personal data (educational level, profession, basic and instrumental ADL) and to assess the presence of adverse events (xerostomia, visual disturbances etc.). Furthermore, the prevalence of confusion symptoms (attention disorders and disorganized thinking, in particular) was probably underestimated by clinical examination. Therefore, we considered that all non-speaking patients presented symptoms of confusion. Another study limitation relates to the fact that few patients were hospitalized for more than 2 weeks – meaning that reliable analyses were difficult to carry out after this time-point. The present study also had a number of strengths. The research was carried out on a continuous series of acute geriatric older adult inpatients; no patients were excluded and all hospitalized patients were evaluated, meaning that there was no selection bias. The study was carried out under “real life” conditions on geriatric patients with multiple, chronic diseases: no Charlson scores

In geriatric patients, delirium symptoms are related to the anticholinergic burden.

Anticholinergic drugs are widely prescribed for elderly patients and could induce several neuropsychological disorders, especially delirium. The aim o...
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