Association between delirium superimposed on dementia and mortality in hospitalized older adults: A prospective cohort study

Background Hospitalized older adults with preexisting dementia have increased risk of having delirium, but little is known regarding the effect of delirium superimposed on dementia (DSD) on the outcomes of these patients. Our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in hospitalized older adults. Methods and findings This was a prospective cohort study completed in the geriatric ward of a university hospital in São Paulo, Brazil. We included 1,409 hospitalizations of acutely ill patients aged 60 y and over from January 2009 to June 2015. Main variables and measures included dementia and dementia severity (Informant Questionnaire on Cognitive Decline in the Elderly, Clinical Dementia Rating) and delirium (Confusion Assessment Method). Primary outcomes were time to death in the hospital and time to death in 12 mo (for the discharged sample). Comprehensive geriatric assessment was performed at admission, and additional clinical data were documented upon death or discharge. Cases were categorized into four groups (no delirium or dementia, dementia alone, delirium alone, and DSD). The no delirium/dementia group was defined as the referent category for comparisons, and multivariate analyses were performed using Cox proportional hazards models adjusted for possible confounders (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates). Overall, 61% were women and 39% had dementia, with a mean age of 80 y. Dementia alone was observed in 13% of the cases, with delirium alone in 21% and DSD in 26% of the cases. In-hospital mortality was 8% for patients without delirium or dementia, 12% for patients with dementia alone, 29% for patients with delirium alone, and 32% for DSD patients (Pearson Chi-square = 112, p < 0.001). DSD and delirium alone were independently associated with in-hospital mortality, with respective hazard ratios (HRs) of 2.14 (95% CI = 1.33–3.45, p = 0.002) and 2.72 (95% CI = 1.77–4.18, p < 0.001). Dementia alone did not have a significant statistical association with in-hospital mortality (HR = 1.69, 95% CI = 0.72–2.30, p = 0.385). Finally, while 24% of the patients died after discharge, 12-mo mortality was not associated with dementia or delirium in any of the diagnostic groups (DSD: HR = 1.15, 95% CI = 0.79–1.68, p = 0.463; delirium alone: HR = 1.05, 95% CI = 0.71–1.54, p = 0.810; dementia alone: HR = 1.19, 95% CI = 0.79–1.78, p = 0.399). Limitations to this study include not exploring the effects of the duration and severity of delirium on the outcomes. Conclusions DSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia.


Conclusions
DSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia.

Author summary
Why was this study done?
• Delirium is an acute disturbance of the mental state that frequently affects hospitalized patients, in particular older adults.
• Seriously ill older patients often have both delirium and dementia, but the prognostic effects of delirium superimposed on dementia (DSD) are still poorly understood.
What did the researchers do and find?
• We followed a cohort of hospitalizations of acutely ill older adults admitted to the geriatric ward of a tertiary university hospital in São Paulo, Brazil, from January 2009 to June 2015.
• We included 1,409 admissions of patients with a mean age of 80 years.
• We confirmed the elevated frequency of delirium, dementia, and their coexistence in the acute care setting. We also observed high mortality rates in patients with DSD and delirium alone, both in the hospital and after discharge.
• After adjusting our analyses to account for possible confounding factors (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates), we found that DSD and delirium alone were predictive of a worse prognosis in the hospital setting, but not in the 12 months following discharge.

What do these findings mean?
• Delirium is associated with poor short-term prognosis both in patients with and without preexisting dementia.

Introduction
Delirium is an acute disturbance of the mental state that has a fluctuating nature and is characterized by inattention and cognitive impairment. Its occurrence depends on an intricate relationship between predisposing and precipitating factors, which amount to more than 60 characteristics associated with delirium [1]. Older adults who have three or more of these characteristics have a 60% higher risk of developing delirium. Advanced age, preexisting dementia or cognitive impairment, functional dependence, and visual impairment are particularly relevant risk factors in this context [2]. Coexistence between delirium and dementia is highly frequent, and hospitalized patients with dementia are up to eight times more likely to have delirium [3]. Compared with isolated dementia, having both delirium and dementia is associated with higher costs, more pronounced functional decline, and increased mortality [4,5]. Fick et al. studied 139 older adults with dementia admitted to a community hospital; they found an incidence of delirium of 32% and demonstrated an increase in the length of hospital stay in these cases [4].
Despite the high prevalence of delirium and dementia in the hospital setting, evidence regarding the effects of their coexistence on outcomes in older adults is still limited and conflicting [3]. For instance, one study found that hospitalized patients with delirium superimposed on dementia (DSD) were two times as likely to die in their 2-y follow-up [6]. Conversely, another study reported that 12-mo mortality was highest in older adults with delirium and without dementia [7]. Therefore, our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in a large cohort of hospitalized older adults, with the hypothesis that DSD will be associated with increased mortality.

Ethical considerations
This study was approved by the local institutional review board (Comissão de Ética para Análise de Projetos de Pesquisa do Hospital das Clínicas da Faculdade de Medicina de Universidade São Paulo). Written consent was obtained from participants, and principles expressed in the Declaration of Helsinki were respected. All patient-identifiable information was stored in locked cabinets and/or secure electronic servers.

Study design and population
We followed a cohort of acutely ill patients admitted to a geriatric ward of a tertiary university hospital in São Paulo, Brazil. The unit admits medical patients aged 60 y and over and is staffed with a multidisciplinary team that includes geriatricians, nurses, physiotherapists, speech therapists, social workers, psychologists, and nutritionists. A minimum age of 60 y is the only specific requirement for admittance in the ward, but older adults with high clinical complexity and vulnerability are preferentially referred for admission.
We included consecutive hospitalizations from January 2009 to June 2015 with the following criteria: (1) age of 60 y or over and (2) admission for acute illness (defined as disease of recent onset, or as recent complication of chronic disease, requiring hospitalization for clinical management). Cases were excluded based on the following criteria: (1) admission for end-oflife care, (2) incomplete data on the main variables, (2) length of stay shorter than 48 h, and (4) patient or caregiver refusal to authorize use of hospital data for research. examination data (comorbidities, visual and auditory deficits, vital signs, and admission diagnoses); functional status (six activities of daily living; each activity was scored on a scale ranging from 0 to 2 points, and a final score was generated from the total sum of the items; range = 0-12, 12 = best) [14]; nutritional status (Mini Nutritional Assessment) [15]; polypharmacy (defined as the chronic use of five or more medications) [16]; and laboratory tests (hemoglobin, total leukocytes, C-reactive protein, glomerular filtration rate [GFR], urea, sodium, potassium, sodium bicarbonate, albumin, and 25-hydroxyvitamin D).

Statistical analysis
The analysis plan for this study was developed as part of a doctorate thesis investigating prognostic factors in acutely ill older adults with delirium and was determined beforehand, during the designing stages of the study. The analysis did not differ from the original plan.
A descriptive analysis of demographic, clinical, and laboratory characteristics was performed using counts and proportions, means and standard deviations, and medians and interquartile ranges. Categorical variables were compared using the Chi-square test or Fisher's exact test as appropriate. Continuous variables were compared using one-way ANOVA or the Kruskal-Wallis test as appropriate.
We defined the date of the diagnosis of delirium as time zero for the survival analyses. Kaplan-Meier curves were used to represent unadjusted hospital survival and 12-mo survival according to delirium and dementia diagnosis, and log-rank tests to compare the groups. The association between DSD and time to death was analyzed using Cox proportional hazards models adjusted for the following preselected covariates: age, sex, marital status, referring unit, functional status (activities of daily living), nutritional status, comorbidities (hypertension, diabetes, heart failure, cerebrovascular disease, coronary disease, chronic obstructive pulmonary disease, and cancer), polypharmacy, vital signs (heart rate and mean arterial pressure), GFR, urea, albumin, total leucocytes, and C-reactive protein. A sensitivity analysis was performed grouping patients with mild dementia with those without dementia, based on the hypothesis that these patients might follow more similar clinical paths. The analyses were performed within patients, considering that each individual might have had more than one hospitalization during the study period. All statistical tests were two-tailed, and an alpha error of up to 5% was accepted. Statistical analyses were performed using Stata SE 14.1 (StataCorp).

Results
We included 1,409 hospitalizations, representing 1,204 patients (Fig 1). Participants were predominantly very old, female, and from middle-to low-income groups ( Table 1). Most admissions were referred from the emergency department, and nearly half of these cases waited at least 48 h before being transferred to our unit. Median length of hospital stay was of 15 d (interquartile range [IQR] = 9; 26). The median Charlson Comorbidity Index score was 3 (IQR = 1; 5).
Only 15% of the patients could be classified as having normal nutritional status according to the Mini Nutritional Assessment (median score = 8; IQR = 5; 11). Other common geriatric syndromes in our sample were depression, urinary incontinence, falls, sensory deficits, and pressure ulcers. In the initial laboratory assessment, the mean value of serum albumin was low (32 ± 06 g/l), and the median value of C-reactive protein was high (352 nmol/l; IQR = 105; 838). Mean hemoglobin level at admission was 110 (± 23) g/l, and mean GFR was 67 (± 39) ml/min.
A total of 265 (19%) older adults died in the hospital, and an additional 272 died in the follow-up period after discharge. Examining hospital mortality according to delirium and dementia diagnosis, we found that mortality was 8%, 12%, 29%, and 32% for the no delirium/ dementia, dementia alone, delirium alone, and DSD groups, respectively (Pearson Chisquare = 112, p < 0.001). After discharge, 12-mo mortality was 37% in the DSD group, compared to 16% in the group without delirium or dementia, 26% in the dementia alone group, and 26% in the delirium alone group (Pearson Chi-square = 41, p < 0.001). We found the differences between the unadjusted mortality probabilities according to delirium and dementia diagnosis to be statistically significant (log-rank tests, p < 0.001) (Fig 2). Delirium superimposed on dementia and prognosis Compared with no delirium/dementia, delirium alone and DSD were associated with greater risk for hospital mortality after adjustment for several possible confounders (age, sex, marital status, referring unit, functional status, nutritional status, comorbidities, polypharmacy, vital signs, GFR, urea, albumin, total leucocytes, and C-reactive protein; Table 2). We did not observe a statistically significant association between dementia alone and hospital mortality. Delirium alone was particularly predictive of in-hospital death, with a hazard ratio (HR) of 2.72 (95% CI = 1.77-4.18, p < 0.001), compared to 2.14 (95% CI = 1.33-3.45, p = 0.002) for DSD and 1.29 (95% CI = 0.72-2.30, p = 0.385) for dementia alone. In \the adjusted analyses, we could not demonstrate an independent association between delirium, dementia, or DSD and 12-mo mortality (Table 3).

Discussion
In our cohort of acutely ill hospitalized older adults, we observed that DSD occurred in 26% of admissions. Approximately one in three of these admissions resulted in death during hospitalization, with a cumulative mortality of 57% at 12 mo. The high frequency of delirium and dementia and the elevated mortality rates are consistent with data reported in the literature [2,17]. We found that delirium in the absence of dementia and DSD were both associated with increased hospital mortality compared to those with no delirium/dementia. In contrast, we did not find statistically significant associations between delirium, dementia, or DSD and 12-mo mortality after adjustment for confounding factors. Other factors demonstrated to have prognostic importance in our cohort were age, admission from an emergency department or intensive care unit, functional dependency, malnutrition, cancer, reduced GFR, and hypoalbuminemia.
Our results confirm that overlap between delirium and dementia is common. Dementia represents an important risk factor for delirium, and delirium has been increasingly linked  Delirium superimposed on dementia and prognosis with long-term cognitive decline [2]. However, evidence on how the combined effects of these conditions influence clinical outcomes is conflicting. In a prospective cohort of hospitalized older adults, McCusker et al. reported that the occurrence of delirium was an independent predictor of mortality that was particularly strong among individuals without preexisting dementia (HR = 3.77, 95% CI = 1.39-10.20) [7]. Yet they did not find a statistically significant association between delirium and mortality in individuals with dementia (HR = 1.96, 95% CI = 0.76-5.05). In a sample of 425 patients aged 70 y or more from geriatric wards and long-term institutions, Laurila et al. also showed lower survival rates at 12 mo for the group with delirium and without dementia (HR = 2.10, 95% CI = 1.16-3.77) but not for the group with DSD (HR = 1.24, 95% CI = 0.64-2.42) [18]. The analysis was adjusted for age, sex, comorbidities, and dementia severity, but it should be noted that it was not planned in the original study design [19]. Delirium superimposed on dementia and prognosis In contrast, Francis and Kapoor studied 229 patients aged 70 y or more admitted to a general hospital and concluded that the higher mortality observed in older patients with delirium was largely explained by the existence of previous functional and cognitive impairment [6]. The authors cited as limitations of their findings that the sample included only 46 cases of delirium and that institutionalized patients and those with advanced dementia were excluded. Similar results were published by Bellelli et al., who compared four paired groups of 47 older patients admitted to a rehabilitation center (without delirium or dementia, dementia alone, delirium alone, and DSD) and found that DSD cases had a significantly higher risk of death in 12 mo than any of the other three groups [20]. Still, the sample size and specificity of the study setting were potential limitations of the work. In a subsequent study in the same center, Morandi et al. confirmed the association between DSD and an increased risk of mortality over 12 mo (odds ratio = 1.8, 95% CI = 1.1-2.8) [5]. Delirium superimposed on dementia and prognosis We found that delirium was associated with a greater risk of hospital mortality in the presence of dementia, but was exceptionally so in the absence of preexisting cognitive decline. As we have seen, this finding is consistent with descriptions of other studies, but it is still controversial. Delirium has been largely accepted as a predictor of mortality in hospitalized older adults [2], but the reasons behind diverging results when dementia comes into play remain to be explained.
One possible explanation for the discrepancy is that it may be more difficult to diagnose delirium in the context of dementia [21], resulting in misclassifications and errors in analysis. This might explain why, in our sensitivity analysis, we found an association between moderate and severe dementia and 12-mo mortality but not between DSD and the same outcome. Presuming that it is more difficult to diagnose delirium in these stages of dementia, one must accept the possibility that in some cases behavioral symptoms of dementia might have been wrongly defined as delirium, and vice versa, generating biases in the results.
Another possibility is that the prognostic significance of delirium in the presence of dementia is indeed different. It could be argued, for example, that the intensity of insult needed to trigger delirium in patients with impaired cognitive reserve is less than that required among those who do not have a cognitive deficit. Consequently, delirium might represent a less severe clinical complication in patients with dementia [7]. This could explain why we found that those with delirium alone had the greatest risk of hospital mortality, and why some studies did not demonstrate an association of DSD with worse prognosis.
Our study had limitations. It was conducted in a single center, in a unit specialized in the care of geriatric patients with high clinical complexity and vulnerability. Although many of our results are consistent with those described by other groups, these aspects of the study may have decreased its external validity. The prolonged hospital stays and elevated mortality are of note, but it is likely that these are the product not only of a specialized setting, but also of a health care system inefficient in providing high-quality primary care and effective post-hospital rehabilitation. The elevated hospital mortality we observed also raises the concern of immortal time bias in this study. If a substantial number of patients died before having the chance of developing delirium, its association with our outcomes might have been weakened.
We examined the association of the occurrence of delirium and dementia with mortality, adjusting our analysis for numerous clinical variables that have rarely been controlled for in the context of hospitalized older adults. Nevertheless, it is reasonable to assume that there are predictors of mortality in this population that were not measured or contemplated. The duration of delirium episodes and dementia etiologies are some of the aspects we did not investigate. We also did not explore the effect of the overall severity of delirium symptoms on prognosis, though DSD cases had higher Delirium Index scores upon delirium diagnosis.
It is possible that a greater proportion of non-respondents in the 12-mo follow-up had delirium and/or dementia as compared to respondents, which would introduce bias into the analyses, pulling the results towards the null. However, we believe that because the number of dropouts in the study was small (less than 8% in all four groups), this effect on our findings should have been minimum. Finally, the involvement of multiple geriatric fellows as study examiners may have affected our measures. Although we did not establish inter-rater reliability estimates, we point out that the examiners were routinely trained by the same investigator and supervised by the same clinicians to confer consistency to the method.
Our work also had several positive aspects. This is one of the largest cohorts ever to be analyzed to investigate the effects of DSD on the mortality of acutely ill older adults. Data were recorded prospectively and systematically, following a standardized model of comprehensive geriatric assessment, which allowed for a detailed view of the health of the study participants. In addition, our routines ensured a horizontal follow-up of all admitted patients, with daily discussions with experienced geriatricians, reducing the risk of non-detection of delirium, dementia, or other geriatric syndromes.
In summary, delirium was associated with poor prognosis in patients both with and without preexisting dementia in our cohort of acutely ill older adults. However, it is possible that DSD has different outcome implications compared to delirium alone, and that strategies to prevent and treat delirium in persons with dementia might need specific approaches. Inouye et al., in their classic study on a multicomponent intervention to prevent delirium in hospitalized older patients, found that those with dementia were possibly more responsive to measures such as orientation, therapeutic activities, mobility activities, and avoidance of psychotropic medications [22]. The same can be said of the clinical and prognostic meaning of delirium in the absence of previous cognitive impairment. Clinicians should be aware of the repercussions of this diagnosis and use it as one of the foundations from which to discuss prognosis with patients and families/caregivers. Future studies should focus on individualized preventive and treatment strategies to fight the impact of delirium and DSD on the health of older adults.