Association between polypharmacy and the persistence of delirium: a retrospective cohort study

doi:10.21203/rs.3.rs-46903/v2

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Association between polypharmacy and the persistence of delirium: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-46903/v2

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published 06 Oct, 2020

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Background: Although the association between polypharmacy and the occurrence of delirium has been well studied, the influence of polypharmacy on the persistence of delirium remains unclear. We aimed to explore the effect of polypharmacy on the persistence of delirium.

Methods: This retrospective cohort study was conducted at a tertiary hospital. The medical records of patients diagnosed with delirium who were referred to the Department of Psychosomatic Medicine were reviewed. Presentation with delirium on day 3 was set as the outcome in this study. We counted the number of drugs prescribed on the date of referral, excluding general infusion fluids, nutritional or electrolytic products, and psychotropics. To define polypharmacy, we developed a classification and regression tree (CART) model and drew a receiver operating characteristic (ROC) curve. The odds ratio (OR) of polypharmacy for the persistence of delirium on day 3 was calculated using a logistic regression model with the propensity score as a covariate.

Results: We reviewed the data of 113 patients. The CART model and ROC curve indicated an optimal polypharmacy cutoff of six drugs. Polypharmacy was significantly associated with the persistence of delirium both before [OR, 3.02; 95% confidence interval (CI), 1.39–6.81; P = 0.0062] and after (OR, 3.19; 95% CI, 1.32–8.03; P = 0.011) propensity score adjustment.

Conclusion: We discovered an association between polypharmacy and worsening courses of delirium and suggest that polypharmacy is a prognostic factor for delirium.

Pharmacodynamics

Neurology

classification and regression tree

delirium

polypharmacy

propensity score

receiver operating characteristic curve

Delirium is an acute psychiatric disorder but is caused by physiological or pharmacological factors. Therefore, the body-mind relationship is strongly associated with its pathology. Both psychiatric and physiological interventions are critical to their management [1].

Polypharmacy is a growing and social issue worldwide. Inappropriate prescribing practices mainly contribute to its occurrence [2,3]. It causes both physiological and psychological problems in patients with multiple morbidities [4,5].

The association between polypharmacy and the incidence of delirium has been well studied [6-10] and a guideline recommends drug reviews for delirium prevention [11]. However, the influence of polypharmacy on the persistence of delirium has yet to be examined thoroughly. One retrospective study investigated the effect of a drug review on the course of delirium treatment, but did not focus on the effect of the number of drugs [12].

Therefore, we aimed to explore the association between polypharmacy and the persistence of delirium.

Ethics consideration

The institutional review board of Yokohama Rosai Hospital approved the study (No. 31-42) and waived the requirement for informed consent owing to the retrospective design.

Medical record review

This retrospective cohort study was conducted at Yokohama Rosai Hospital, a tertiary medical center in Japan. We reviewed the medical records of patients (a) who were suspected to have any psychiatric disorder by physicians in departments other than the Department of Psychosomatic Medicine, (b) who were referred to the Department of Psychosomatic Medicine from March 2019 to October 2019, (c) who had been diagnosed with delirium by psychosomatic physicians, and (d) who were not under continuous sedation.

We defined the first 24 hours from 9:00 p.m. on the referral date as day 1, and every subsequent period of the following 24 hours as day N. We reviewed the medical charts to determine whether patients had presented with delirium on day 3, which was denoted as the outcome. Day 3 was selected because a previous study suggested that an outcome evaluation on this day could be used to estimate the treatment effectiveness [13], and this outcome has been widely adopted [14,15]. Patients were evaluated based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, 2013). Two authors (K.K. and M.D.) evaluated the outcomes independently, and any disagreements were resolved by discussion. The reproducibility of the evaluation was analyzed using the kappa statistic.

The number of drugs prescribed on the referral date was counted, excluding general infusion fluids, nutritional or electrolytic products, and psychotropic agents.

Statistical analysis

We used the t-test to compare the means of continuous variables, and Fisher’s exact test or the chi-squared test to compare the proportions of categorical variables in patients with and without delirium symptoms on day 3.

We performed the following analyses to determine the cutoff for polypharmacy [16,17]. First, we developed a classification and regression tree (CART) model in which the maximum tree depth was fixed at one and the Gini index was used as the splitting metric. We considered the splitting value of the root node to be the cutoff value. We also generated a receiver operating characteristic (ROC) curve and calculated the Youden index for each cutoff point. The cutoff that maximized the Youden index was considered the optimal cutoff value.

We calculated the odds ratio (OR) of polypharmacy for the persistence of delirium on day 3 using a logistic regression model with the propensity score as a covariate. Propensity scores were calculated using a logistic regression model based on the following variables: age, sex, the presence of 17 diseases in the updated Charlson comorbidity index (an index to predict mortality based on the presence of comorbid conditions) [18], the Karnofsky Performance Status (an index of physical performance ability) [19] score on admission, and psychotropics (five categories: antipsychotics, benzodiazepine or Z-drugs, ramelteon or suvorexant, antidepressants, and others). The Karnofsky Performance Status was used as an index of the severity of patients. Psychotropics were included because of their potential effects on delirium [1,20]. To confirm the sufficiency of the sample size, we performed a power analysis of the univariate logistic regression model.

All analyses were conducted using R version 4.0.0 (R Foundation for Statistical Computing, Vienna, Austria, 2019) with the packages ‘powerMeditation’ (version 0.3.2), ‘ROCR’ (version 1.0-11), ‘rpart’ (version 4.1-15), and ‘vcd’ (version 1.4-7). A P-value < 0.05 was considered statistically significant.

Eligible patients

Of the 113 reviewed patients, 64 (57%) did not have symptoms of delirium on day 3. The kappa statistic for a delirium evaluation was 0.66 (95% confidence interval [CI] = 0.53–0.80), which showed a substantial degree of reproducibility. The descriptive data are shown in Table 1. Only the Karnofsky Performance Status score differed significantly between patients with and without symptoms of delirium on day 3.

Number of drugs and persistence of delirium

The splitting value of the root node in the CART model was six, and this number also maximized the Youden index in the ROC curve (Figure 1). Therefore, we defined polypharmacy as the use of six or more drugs. Sixty-four (57%) patients in the cohort met this definition of polypharmacy.

As shown in Table 2, polypharmacy was significantly associated with the persistence of delirium on day 3 in the absence (OR, 3.02; 95% CI, 1.39–6.81; P = 0.0062) and presence of the propensity score as a covariate (OR, 3.19; 95% CI, 1.32–8.03; P = 0.011). The C-statistic of the propensity score model was 0.767. The power of the significance of polypharmacy in the univariate model was 0.808, suggesting that the sample size was sufficient for the study.

The present study assessed the association between polypharmacy and the persistence of delirium and showed that the use of six or more drugs was associated with the persistence of delirium.

The results suggest that polypharmacy may not only induce delirium, as it is known to [6-8], but may also worsen the course of delirium treatment. As delirium occurs due to body-mind relationship and polypharmacy is a social issue, the results showed an example of the bio-psycho-social pathology [21]. The results support the claims of a previous study that reported the effectiveness of a drug review on the course of delirium treatment [12].

Additionally, the cutoff of six drugs, which was calculated based on the ROC curve and CART model, was congruent with the values reported by previous studies for the association of polypharmacy with adverse effects [5-10]. The incidence of drug–drug interactions, which is considered to be associated with delirium [22], may increase drastically when the number of drugs exceeds six.

This study had certain limitations. First, the outcome was evaluated based on a retrospective review, and therefore its accuracy could not be fully validated. Second, the propensity score model did not include the severity of delirium (e.g., severity score measured using the Delirium Rating Scale, Revised-98), comorbid diseases that were not listed in the Charlson comorbidity index [18], or laboratory test data. Third, the contents of the drugs were not considered in the analyses. Finally, the present study only included patients who were suspected to have any psychiatric disorder by non-expert medical staff. As the rate of undetected delirium is extremely high [23], the generalizability of the results might be limited.

We identified an association between polypharmacy and a worsening course of delirium in this pilot study. Therefore, we suggest that polypharmacy is a prognostic factor for delirium.

CART, classification and regression tree; ROC, receiver operating characteristic; OR, odds ratio; CI, confidence interval

Ethics approval and consent to participate: The institutional review board of Yokohama Rosai Hospital approved the study (No. 31-42) and waived the requirement for informed consent owing to the retrospective design.

Consent for publication: Not applicable.

Availability of data and methods: The datasets and source codes are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no conflicts of interest.

Funding: None.

Author contributions: All authors conceived the study concept and design. KK and DM collected the data. KK performed the statistical analyses. KY supervised the research project. All authors participated in the interpretation of the results and writing of the report and approved the final version of the manuscript.

Acknowledgments: We thank Dr. Kosuke Inoue for his helpful advice regarding the statistical analysis.

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Table 1. Patient characteristics (N=113)

	Delirium (n=49)	No delirium (n=64)	P-value
Age (years), mean (SD)	80.76 (11.90)	81.81 (8.25)	0.60^‡
Male sex, n (%)	28 (57)	34 (53)	0.81^*
Charlson comorbidity index, mean (SD)	3.14 (2.02)	2.92 (2.35)	0.59^‡
Karnofsky Performance Status, mean (SD)	39.59 (20.61)	48.44 (25.02)	0.04^‡
Number of drugs, mean (SD)	7.04 (3.26)	6.14 (3.95)	0.19^‡
Number of drugs with psychotropics, mean (SD)	10.02 (3.78)	8.66 (4.11)	0.07^‡
Psychotropics use, n (%)
Antipsychotics	33 (67)	39 (61)	0.61^*
Benzodiazepine or Z-drugs	12 (24)	13 (20)	0.76^*
Ramelteon or suvorexant	41 (84)	55 (86)	0.95^*
Antidepressant	3 (6)	2 (3)	0.65^†
Other drugs	19 (39)	18 (28)	0.32^*

*, Chi-squared test; †, Fisher’s exact test; ‡, Student’s t-test.

Other drugs included anti-dementia drugs, valproic acid, Yokukansan.

Table 2. Odds ratios of polypharmacy for the persistence of delirium on day 3

	OR	95% CI	P-value
Without propensity score	3.02	1.39–6.81	0.0062
With propensity score as a covariate	3.19	1.32–8.03	0.011

OR, odds ratio; CI, confidence interval

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Review #2 received at journal
21 Aug, 2020
Editorial decision: Major revision
21 Aug, 2020
Reviewer #2 agreed at journal
12 Aug, 2020
Review #1 received at journal
09 Aug, 2020
Reviewer #1 agreed at journal
05 Aug, 2020
Reviewers invited by journal
31 Jul, 2020
Editor assigned by journal
30 Jul, 2020
Submission checks completed at journal
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Editor invited by journal
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Association between polypharmacy and the persistence of delirium: a retrospective cohort study

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