522105 research-article2014

PMJ0010.1177/0269216314522105Palliative MedicineZimmerman et al.

Original Article

Increasing anticholinergic burden and delirium in palliative care inpatients

Palliative Medicine 2014, Vol. 28(4) 335­–341 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269216314522105 pmj.sagepub.com

Kristin M Zimmerman1,2, Marci Salow2,3, L Michal Skarf3,4, Tia Kostas3,4,5, Allison Paquin2,3, Mark J Simone4,5 and James Rudolph3,4

Abstract Background: Delirium may complicate the hospital course and adversely impact remaining quality of life for palliative care inpatients. Medications with anticholinergic properties have been linked to delirium within elderly populations via serum anticholinergic assays. Aim: The aim of this study is to determine whether increasing anticholinergic burden, as measured using a clinical assessment tool, is associated with an increase in delirium among palliative care inpatients. Design: This study was completed as a retrospective, case-control study. Setting/participants: Veterans admitted to the Veterans Affairs Boston Healthcare System and consulted to the palliative care service were considered for inclusion. Increase in anticholinergic burden from admission through hospital day 14 was assessed using the Anticholinergic Risk Scale. Presence of delirium was determined by use of a validated chart review instrument. Results: A total of 217 patients were analyzed, with a mean age of 72.9 (±12.8) years. The overall delirium rate was 31% (n = 67). Patients with an increase in Anticholinergic Risk Scale (n = 72 (33%)) were 40% more likely to experience delirium (odds ratio = 1.44, 95% confidence interval = 1.07–1.94) compared to those without increase (n = 145 (67%)). After adjustment for age, brain metastasis, intensive care unit admission, illness severity, opiate use, and admission Anticholinergic Risk Scale using multivariable modeling, delirium risk remained significantly higher in patients with an Anticholinergic Risk Scale increase compared to those without increase (adjusted odds ratio = 1.43, 95% confidence interval = 1.04–1.94). Conclusion: An increase in Anticholinergic Risk Scale from admission was associated with delirium in palliative care inpatients. While additional study is needed, anticholinergic burden should be increased cautiously in palliative inpatients, and those with increases should be closely followed for delirium. Keywords Delirium, anticholinergic, palliative care, aged, psychopharmacology

What is already known about the topic? •• Delirium may complicate hospital course and impact remaining quality of life for palliative care inpatients, a high-risk group. •• Medications with anticholinergic properties are often used in palliative care and have been linked to delirium occurrence via serum assays. •• Correlations with clinical tools and measures of change in anticholinergic burden have not been made in the palliative care population. What this paper adds? •• This study demonstrates that an increase in anticholinergic burden as measured by a clinical tool, the Anticholinergic Risk Scale (ARS), was associated with a 40% greater likelihood for delirium among palliative care inpatients.


of Pharmacy Practice, Massachusetts College of Pharmacy & Health Sciences University, Boston, MA, USA 2Department of Pharmacy, Veterans Affairs (VA) Boston Healthcare System, Boston, MA, USA 3Division of Geriatrics and Palliative Care, Veterans Affairs (VA) Boston Healthcare System, Boston, MA, USA

4Division 5Division

of Aging, Harvard Medical School, Boston, MA, USA of Aging, Brigham and Women’s Hospital, Boston, MA, USA

Corresponding author: Kristin M Zimmerman, Massachusetts College of Pharmacy & Health Sciences University, 179 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]

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Palliative Medicine 28(4) •• This study quantified a 2-point increase on ARS to be associated with greater delirium likelihood and assessed chronology of approximately 2 days after peak ARS to delirium occurrence.

Implications for practice, theory, or policy •• Anticholinergic burden should be increased cautiously in palliative care inpatients. •• When an increase in anticholinergic burden is necessary, patients should be followed closely for the development of delirium. •• This work builds a foundation for clinical tools such as the ARS to be further evaluated for use in clinical care decisions and screening measures.

Introduction Delirium is an acute fluctuation in cognition occurring with either a disturbance of consciousness or impairment in perception. Delirium occurs in 10%–30% of medically ill, hospital inpatients and is associated with increases in morbidity and mortality.1 Delirious patients are at increased risk of medical complications, prolonged hospitalizations, functional decline, and institutionalization.1 Palliative care patients are at high risk of delirium, where as many as 83% of terminally ill patients will develop delirium near death.1 In this population, delirium has been shown to contribute to patient, family, and caregiver stress.2,3 The ability to remain oriented to surroundings, with preserved cognitive function and ability to communicate, is important for patients and caregivers at the end of life.4–6 Disturbance in consciousness, changes in cognition, and impairments in perception associated with delirium may interfere with the experience of “dying well.”4–6 The causes of delirium in palliative care are typically multifactorial, including metabolic dysfunction, brain metastases, infections, and medications.7,8 Medications with anticholinergic properties are particularly concerning as serum anticholinergic activity has been correlated to delirium incidence and severity in elderly patient populations, with reductions linked to symptom improvement.9–12 Anticholinergics have also been linked to cumulative risk of cognitive impairment and mortality in such populations.13 Such links between serum anticholinergic levels and delirium have not been demonstrated within the palliative care population. Additionally, use of serum anticholinergic assays is impractical in the course of clinical care, and its associations with true medication load questioned.14 While clinical tools to quantify anticholinergic burden exist, they have not been utilized to predict or characterize delirium occurrence. Drugs with anticholinergic properties are often used in palliative care for end-of-life symptoms and management of comorbid conditions. Unfortunately, desired physiologic effects, such as anti-secretory, anti-emetic, and antidiarrheal, may be accompanied by deleterious cognitive effects. Examples of anticholinergic medications include

atropine, scopolamine, ipratropium, ranitidine, promethazine, and loperamide. In their study of palliative care outpatients in Australia, Agar et al.15 found that increases in anticholinergic burden are associated with decreases in functional measures and quality of life as patients approach death. Anticholinergic side effects found in their population included increased dry mouth and increased difficulty concentrating. However, there was no increase in confusion or hallucinations.15 Caring for palliative care patients at the end of life necessitates a judicious balance between the benefits of symptom management afforded by the use of anticholinergic medications and the significant risks of delirium from these medications. Since the clinical decision is often difficult, additional information regarding the overall risk of increasing anticholinergic burden would be helpful. In addition, the ability to predict the time course for the onset of delirium is also helpful in this population, particularly when patients may have a prognosis of days to weeks. Validated tools to clinically quantify this anticholinergic burden have been developed. The Anticholinergic Risk Scale (ARS) is a tool designed to estimate the extent to which an individual may be at risk of anticholinergic adverse effects that can lead to cognitive dysfunction and delirium (Figure 1). The scale ranks medications according to their anticholinergic potential on a 3-point scale (0 (no or low risk) to 3 (high anticholinergic potential)).16 The total risk is equal to the sum of the points for all medications. Higher ARS scores were significantly associated with increased risk of anticholinergic adverse effects in geriatric outpatient populations.16 It remains unknown how anticholinergic medications may contribute to delirium in the palliative care population. While presence or absence of anticholinergic burden, as measured by serum anticholinergic assays, has been associated with delirium in geriatric populations, correlations with clinical measures of anticholinergic burden have not been made within the palliative care population. To our knowledge, only two investigations have utilized clinical tools for the assessment of delirium within older inpatients.17,18 Han et al.17 utilized the Summers’ Drug Risk Scale to associate delirium severity with anticholinergic medications in

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Zimmerman et al. 1 Point

2 Points

3 Points

Carbidopa-levodopa Entacapone Haloperidol Methocarbamol Metoclopramide Mirtazapine Paroxetine Pramipexole Quetiapine Ranitidine Risperidone Selegiline Trazodone Ziprasidone

Amantadine Baclofen Cetirizine Cimetidine Clozapine Cyclobenzaprine Desipramine Loperamide Loratadine Nortriptyline Olanzapine Prochlorperazine Pseudoephedrine Tolterodine

Amitriptyline Atropine products Benztropine Carisoprodol Chlorpheniramine Chlorpromazine Cyproheptadine Dicyclomine Diphenhydramine Fluphenazine Hydroxyzine Hyoscyamine products Imipramine Meclizine Oxybutynin Perphenazine Promethazine Thioridazine Thiothixene Tizanidine Trifluoperazine

Figure 1.  Anticholinergic Risk Scale. Total patient Anticholinergic Risk Scale score is defined as the sum of points for all medications.

already delirious older medical inpatients. Lafortune et al.18 utilized the ARS to associate increased values with delirium in cognitively impaired older inpatients. Furthermore, the effect of an increase in anticholinergic burden on delirium occurrence, timing, and modification has not been studied. Given that anticholinergic medications may alleviate many end-of-life symptoms, it is critical to have a more in-depth understanding of anticholinergic medications’ relationship to delirium in palliative care patients to allow providers to weigh the risks and benefits of using these medications as death approaches. Use of clinical tools such as the ARS to characterize this relationship can have significant clinical impact to reduce delirium by better encouraging use of alternative agents and delirium reduction measures at burden thresholds. This study aimed to determine whether an increase in anticholinergic burden throughout admission, as measured using a clinical tool, the ARS, was associated with increased odds of delirium in palliative care patients. Secondarily, we aimed to characterize the temporal relationship between increases in anticholinergic burden and delirium onset. To achieve this, we retrospectively reviewed palliative care inpatients and assessed changes in ARS scores throughout hospitalization to assess for impact on odds of delirium.

Materials and methods Sample This study retrospectively reviewed patients admitted to the Veterans Affairs (VA) Boston Healthcare System. Patients admitted between 1 July 2008 and 1 January 2010 and evaluated by the palliative care team during their admission were considered for inclusion. Patients were excluded from the study if the use of antipsychotics prior to admission was documented within the patient’s medication list in the computerized patient record system (CPRS) or in the history and physical admission note. Patients with evidence of delirium or mental status changes documented in history and physical or nursing admission notes were also excluded. The protocol was approved by the VA Boston Healthcare System’s Institutional Review Board.

Data collection Data were collected from the time of hospital admission (hospital day 0) through index date (no later than hospital day 14) from the electronic medical record. Index date was defined as the date of outcome occurrence (development of delirium) if outcome occurred prior to day 14 of admission. If no outcome occurred prior to day 14 of admission,

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Palliative Medicine 28(4)

Statistical analysis

Figure 2.  Study protocol. Peak Anticholinergic Risk Scale (ARS) score values were assessed prior to index date and were compared with ARS values at admission.

the index date defaulted to day 14. If the patient died prior to day 14, the index date defaulted to the date of death. If multiple outcomes occurred, only the first outcome was labeled as the index date and included in analysis.

Exposure Exposure was defined as the change in anticholinergic burden from admission to index date and was quantified using the ARS (see Figure 2). ARS scores were calculated manually from data contained within the electronic medical record, utilizing the outpatient prescription record and history and physical examination notes for calculation of admission ARS and utilizing the computerized medication administration record (MAR) for calculation of peak ARS. The peak ARS was defined as the highest total calculated value of administered anticholinergic medications at any time prior to the index date. If medications were administered on an asneeded basis, the MAR was queried to verify administration. Cases were defined as patients who had an increase in the ARS from admission to index date, whereas controls included those who had no change or a decrease in ARS.

Outcome Records were reviewed for delirium using a validated chart-based instrument developed by Inouye et al.19 This chart-based instrument prompts reviewers to search for and locate key terms and descriptors for identification of delirium. A positive result is indicated by the presence of these key terms and descriptors in addition to evidence of acute onset or acute change in symptoms.19

Covariates Additional data collected included basic demographics, such as age and gender. Consistent with previous delirium literature, data to complete an Acute Physiology and Chronic Health Evaluation–III (APACHE-III) score on all subjects were collected to account for potentially confounding variables.20 Additional data collected included presence of brain metastasis, comorbid dementing illnesses, and evidence of metabolic dysfunction or infection.

Bivariable analysis compared the characteristics of patients with and without an increase in ARS from time of admission to index date. Bivariable associations used a t-test for continuous variables and a chi-square test for dichotomous variables. For adjusted analyses, logistic regression was used to determine the odds for developing delirium. All variables with a p < 0.20 in bivariable analysis were entered into the model. Additionally, age and APACHE-III were included in the model, because of their known associations with delirium.18 Odds ratios (ORs) for delirium are reported with 95% confidence intervals (CIs). Additionally, we examined trends for delirium based on the change in ARS according to categories (reduction, no change, increase of 1–2 points, and increase of ≥3 points). This trend was examined with a chi-square for trend test. All statistical analyses were conducted using STATA 11.0 (STATA, Inc., College Station, TX, USA).

Results The 217 patients included in this study had a mean age of 72.9 (±12.8) years, and 97% were male. Of the initial palliative care consults, 50% were excluded due to presence of antipsychotic use or mental status change at the time of admission. The overall rate of delirium in this cohort was 31% (n = 67). Table 1 compares characteristics of patients with and without an increase in ARS. The exposure groups did not differ significantly with regard to gender, dementia diagnosis, APACHE-III scores, or opiate use. Those with an increase in ARS were significantly more likely to be admitted to the intensive care unit (ICU) during their admission. Occurrence of delirium was significantly more common in patients with an increase in ARS (n = 72) compared to those with no increase (n = 145): 42% versus 26%, p = 0.01. Patients with an increase in ARS had a lower ARS score at admission of 0.8 ± 1.7 compared to 1.2 ± 1.7 in those with no increase (p = 0.10). Patients with an increase in ARS had the highest peak mean ARS value throughout admission: 3.0 ± 2.1 compared to 0.8 ± 1.4 in those with no increase in ARS. In patients with an increase in ARS, peak occurred on hospital day 4.2 ± 3.2, and magnitude of change was 2.2 ± 1.2. Within this group, delirium occurred on hospital day 6.5 ± 3.4, 2.3 ± 3.2 days after the peak in ARS. As shown in Table 2, any increase in the ARS significantly increased the odds of delirium (OR = 1.4, 95% CI = 1.1–1.9) in bivariable analysis. After multivariable adjustment, an increase in ARS remained significantly associated with increased odds of developing delirium (adjusted OR = 1.4, 95% CI = 1.0–1.9). Table 3 illustrates the association of delirium with increasing magnitude of ARS changes. Overall, there was a trend toward increased delirium with magnitude of increase in ARS (chi-square = 5.8; p = 0.02).

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Zimmerman et al. Table 1.  Characteristics of exposure groups. Characteristic

No increase in ARS (n = 145)

Increase in ARS (n = 72)

p value

Age, mean (±SD) APACHE-III, mean (±SD) Admission ARS, mean (±SD) Male, % (n) Brain metastasis, % (n) Dementia, % (n) ICU admission, % (n) Opiates on admission, % (n) Change in opiates, % (n)

74 (11) 45 (12) 1.2 (1.7) 97% (141) 5% (6) 3% (6) 25% (37) 34% (49) 49% (68)

70 (15) 43 (13) 0.8 (1.7) 96% (69) 1% (1) 3% (2) 42% (30) 29% (21) 55% (38)

0.04 0.37 0.10 0.58 0.15 0.61 0.04 0.69 0.40

SD: standard deviation; APACHE-III: Acute Physiology and Chronic Health Evaluation–III score at admission; admission ARS: Anticholinergic Risk Scale at admission; dementia: presence of International Classification of Diseases (ICD-9) code consistent with dementia diagnosis; ICU admission: intensive care unit visit prior to index date; opiates on admission: use of opiates documented in medication lists or history and physical at admission; change in opiates: change in prescribed opiate regimen throughout admission.

Table 2.  Adjusted ORs for delirium. Bivariable associations with delirium

Multivariable associations with delirium


95% CI

Adjusted OR

95% CI

Age (per year) Brain metastasis APACHE-III (per point) ICU admission Increase in ARS

1.01 0.3 1.01 1.5 1.4

0.99–1.03 0.03–2.2 0.99–1.04 0.8–2.8 1.1–1.9

1.01 0.3 1.0 1.4 1.4

0.99–1.04 0.04–2.9 0.98–1.04 0.7–2.6 1.0–1.9

OR: odds ratio; CI: confidence interval; brain metastasis: presence of brain metastasis documented in admission history and physical; APACHE-III: Acute Physiology and Chronic Health Evaluation–III score at admission; ICU admission: intensive care unit visit prior to index date; increase in ARS: change in Anticholinergic Risk Scale score from admission.

Table 3.  Delirium with ARS increase. ARS change category (n)

Degree of ARS change

Delirium, n (%)

Decrease (27) No change (118) Increase = 1–2 points (43) Increase ≥ 3 points (29)

−1.9 (±0.7) 0 (±0) 1.3 (±0.5)

6 (22) 31 (26) 17 (40)

3.4 (±0.8)

13 (45)

ARS: Anticholinergic Risk Scale. Patients were divided into ARS change category depending on the decrease, absence of change, or increase by 1–2 or ≥3 points on the ARS. Degree of ARS change reflects the mean change in ARS for each patient group.

Discussion This retrospective study sought to determine whether an increase in anticholinergic burden, as measured by the ARS, was associated with an increase in delirium in palliative care inpatients. These findings demonstrate that an increase in ARS was associated with statistically significant increased odds of delirium in this population. Compared to those with no increase, those with an increase

in ARS after hospital admission were associated with a 40% increase in odds of delirium. While these findings demonstrate an association, our study design prevents causal attribution. Increases were equivalent in magnitude to approximately 2 points on the ARS—similar in value to the addition of medications such as loratadine or loperamide—and peaked approximately 2 days prior to delirium occurrence. In patients experiencing delirium, the peak ARS values and the degree of ARS change were significantly higher than those who did not experience delirium. By quantifying and characterizing the increased odds of delirium, these findings highlight the need for greater attention to, and judicious use of, anticholinergic medications at the time of prescription. This study also showcases the use of a practical clinical tool, the ARS, for such assessment. The association of delirium and anticholinergic load found in this study is consistent with prior work.9–12,17,18 As anticholinergic assays used in prior studies may be difficult to obtain and clinically interpret, the utilization of a validated tool within this study may have practical implications as noted above. These findings validate concern for deliriogenic potential of anticholinergic medications in

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Palliative Medicine 28(4)

this population and support a temporal, potentially predictable and additive relationship between increasing anticholinergic load and delirium. There have been studies with findings contrary to these. However, these studies had important differences that may explain the disparate findings. One study by Campbell et al.21 of older, cognitively impaired, hospitalized adults did not find an association with anticholinergic medications and delirium. This study, however, quantified anticholinergic burden utilizing an alternate scale, the Anticholinergic Cognitive Burden Scale. In addition, Gaudreau et al.’s22 study of hospitalized oncology patients also failed to find an association between anticholinergic medications and delirium. The study by Gaudreau et al. did not use a validated tool for anticholinergic assessment. Neither study assessed for the impact that changes in anticholinergic exposure may have on delirium. Finally, van Munster et al.23 found that predisposing factors for delirium co-occur with serum anticholinergic assays and may neutralize the associations between anticholinergics and delirium. However, as with many medications, these pharmacokinetic and pharmacodynamic changes, including inflammation, may result in enhanced anticholinergic impact at similar assay levels.23 The comprehensive assessment of exposure is a strength of this study. The CPRS allowed access to pointof-care MARs and nursing assessments. Utilization of this system allowed for the inclusion of important covariates, including confounding medications, laboratory and assessment values, and the accounting of administration and measurement timing. This system permitted the complete assessment of otherwise difficult-to-measure data. Challenges to this work remain. The multifactorial nature of delirium, its under-recognition, and the inability to completely control for confounders may be viewed as limitations. For example, 55% of the control group developed delirium despite no change, or even a decrease, in ARS. The APACHE-III score is used to limit this confounding within the delirium literature and was included in our analysis. The APACHE-III assessment for disease severity accounts for the delirium risk factors of age, illness, and infection severity. Opioids were the only potentially confounding medications assessed in this study. Limitations to delirium assessment are inherent in this study’s widely male population and retrospective, observational nature. The ORs used in this case-control study can only approximate the relative risk for delirium with anticholinergic medication use. The sensitivity and specificity of case and control identification rely on that of the chart review tool, which is subject to interpretation bias; however, the tool designed by Inouye et al.19 was validated with a sensitivity of 74% and a specificity of 83%. Finally, the effect of the exposure may be underestimated by the inability to account for delirium occurrence after the index date.

Delirium is common in palliative care patients, yet can be reversed up to 50% of the time.9,24 This study highlights the association of delirium and increasing anticholinergic burden in palliative care inpatients. The association of increased delirium odds with ARS increases of approximately 2 points underscores the importance of judicious anticholinergic prescribing in this vulnerable patient population. As prior studies have demonstrated that delirium is often under-recognized and detected late in the course, the finding that peak ARS precedes clinical delirium by approximately 2 days may justify preemptive anticholinergic medication screening and assessment, and emphasize cautionary anticholinergic prescribing and minimization of other delirium risk factors in this population.1 In patients with symptoms warranting anticholinergic medication but with preexisting high ARS scores, delirium risk can be minimized by decreasing other deliriogenic medications, including opioids, and benzodiazepines, and by providing nonpharmacologic treatments such as hypnosis and behavioral therapies, which can be effective for the treatment of nausea and insomnia, or by using anticholinergic medications with a lower anticholinergic burden such as glycopyrrolate, haldol, or trazodone, or in lower doses. In addition, frequency of screening for delirium can be increased in patients with high ARS scores. Finally, using the ARS score to predict delirium allows clinicians to prepare families for the difficulty this will cause. This study builds a foundation for use of the ARS, in addition to the assessment of other important delirium risk factors, in clinical care decisions and screening measures to support the early screening, identification, and possible prevention of delirium. Future use may include systemslevel calculations of ARS to target high-risk patients. Further prospective study is needed to confirm a causal relationship.

Conclusion In this retrospective review, we found that an increase in anticholinergic risk scores after hospital admission was associated with a 40% increase in odds of delirium among palliative care inpatients. This observed link between anticholinergic burden and delirium warrants future investigation in a prospective study in order to further understand the true cause and effect relationship. Increase in ARS (18% vs 13%, p = 0.31) or occurrence of delirium (22% vs 13%, p = 0.09) was not significantly associated with an increase in death within 14 days. In an effort to minimize delirium, use of clinical tools such as the ARS may be used to weigh risks and benefits associated with anticholinergic medications in this vulnerable cohort. Future work linking ARS and delirium may prove useful in the prediction, prevention, and early intervention of delirium.

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Zimmerman et al. Acknowledgements We are grateful to the Veterans and Staff of the Veterans Affairs (VA) Boston Healthcare System and to Houman Javedan, MD, for his clinical expertise and review. Dr Zimmerman, Salow, Skarf, Paquin, Rudolph, and Kostas are Department of Veterans Affairs employees.

Declaration of conflicting interests Dr Kostas has published a geriatrics pocketcard and may receive royalties in the future (none yet received). The authors retained control of the data and reporting.

Funding Dr Rudolph is funded by a Veterans Affairs (VA) Rehabilitation Research Career Development Award and a T21 Alternatives to Institutional Long Term Care grant. Dr Kostas is funded by a VA T21 Alternatives to Institutional Long Term Care grant and is also the recipient of a John A. Hartford Center of Excellence Award which supports a portion of her salary. Dr Simone is funded by a Health Resources and Service Administration (HRSA) Geriatric Academic Career Award.

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Increasing anticholinergic burden and delirium in palliative care inpatients.

Delirium may complicate the hospital course and adversely impact remaining quality of life for palliative care inpatients. Medications with anticholin...
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