Factors for a Timely Identification of Possible Occurrence of Delirium in Palliative Care: A Prospective Observational Study

Delirium occurs in 50-80% of end-of-life patients but it is often misdiagnosed. Identification of clinical factors potentially associated with delirium onset can lead to a correct early diagnosis. To this aim, we conducted an observational prospective study on patients from an Italian Palliative Care Unit (PCU) in 2018-2019 and evaluated the presence of clinical factors at patients’ admission. We then compared their presence in patients who developed delirium and in those who did not during follow-up. On 503 enrolled patients, 95 (18.9%) developed delirium. In univariate analyses, factors significantly more frequent in patients with delirium were advanced age, care in hospice, very compromised performance status, hypoxia, high number of simultaneous clinical factors, presence of breathlessness, poor well-being, severe drowsiness, and background therapy with haloperidol and drugs acting on CNS. In multivariate analyses, setting of care (odds ratio, OR, 1.68 for hospice versus home care, 95% confidence interval, CI 1.02-2.75; p=0.040), and administration of psychiatric drugs (OR 1.74 for administration versus no administration, 95% CI 1.08-2.81; p=0.023) were significantly associated with the risk of developing delirium, while the associations with age (OR 1.82 for > 80 years versus ≤ 70 years, 95% CI=0.98-3.36; p=0.046) and presence of breathlessness (OR 1.70, 95%, CI 0.99-2.89, p=0.053) were of borderline significance. The study indicates that some clinical factors are associated with the probability of delirium onset. Their evaluation in PC patients could help the healthcare professionals to timely identify the development of delirium in those patients.


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The study protocol was approved by the Ethics Committee of the ASST of Vimercate (MB), Italy in June 18, 2018 (project n. 2824). Written informed consent for participation in the study and processing personal data were collected from all recruited patients before any study-related activity was carried out.

Statistical analysis
Descriptive statistics were used to summarize the patients' demographic and clinical characteristics.
Sociodemographic factors, and prevalence of potential risk factors, symptoms and drug use were compared between patients who developed delirium and those who did not develop it, to understand which of them were significantly related to the development of delirium. Differences between patients with and without delirium were analyzed using the t test and chi-square test, respectively for continuous and categorical variables. We then run univariate and multivariate logistic regression models to estimate the odds ratios (ORs) of delirium for various exposure factors and their corresponding 95% confidence intervals (CIs). For all statistical analyses, we used the software SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 3.4.1 (R Development Core Team, 2017)..

Results
After a median follow-up time of 16 days (interquartile range, IQR, 6-39), 95 (18.9%) patients developed delirium. a Differences between the two groups were tested using chi-square or t tests. Table 2 presents the distribution of comorbidities included in the CIRS and the KPS, overall and according to the presence of delirium. Prevalence of comorbidities was not significantly different between patients with and without delirium; moreover, no significant difference was found according to levels of the CIRS score, although values of CIRS ≥ 8 were found more frequently in patients who developed delirium (20.0%) than in those who did not develop it (13.5%).
Conversely, general conditions were significantly more severe in patients with delirium than in those without delirium (KPS ≤3 0 in 33.7% and in 24.5% of patients, respectively). a Differences between the two groups were tested using chi-square tests. b During the last 10 years.
The prevalence of clinical factors in all patients and in the two sub-groups of patients who developed and did not develop delirium is given in Table 3. No significant differences were found for most clinical factors; however, the presence of hypoxia and the total number of simultaneously present clinical factors were significantly more frequent in patients who developed delirium than in those who did not develop it (24.2% versus 14.7% respectively with hypoxia, and 58.9% and 47.5% respectively with ≥ 2 clinical factors). Only 17.7% of patients (12.6% of those with delirium and 18.9% of those without delirium) had no clinical factors (Data not shown). In relation to symptoms, the presence of poor well being and breathlessness was significantly higher in patients who developed delirium (79.0% and 63.2%, respectively) than in those who did not develop it (64.5% and 46.1%; Table   4). Conversely, for other symptoms, such as pain, fatigue, anxiety and depression the prevalence was similar in patients with and without delirium. a Differences between the two groups were tested using chi-square tests.
The relationship between the severity of symptoms (measured by ESAS) and risk of developing delirium was shown in Table 5. For most symptoms, the severity was similar in patients who developed and in those who did not develop delirium. Only for drowsiness, poor well-being, and breathlessness, the presence of moderate/severe degree symptoms was higher in the former (17.9%, 26.3%, and 17.9 %, respectively) than the latter group (9.6%, 18.4%, and 12.0%, respectively). a Differences between the two groups were tested using chi-square tests for trend.

Discussion
Delirium is often undetected or misdiagnosed. In one study, nursing staff anticipated delirium onset in only 31% of patients that subsequently manifested it [22]. Other studies confirmed these difficulties in making a timely diagnosis of delirium [23,24]. These difficulties are likely due to the limited experience and lack of specific skills of the healthcare professionals to diagnose this syndrome and to make a differential diagnosis from other neuropsychiatric conditions.
For this reason, we tried to identify a priori relevant clinical factors which can anticipate delirium onset and help the healthcare workers to timely make a diagnosis of this condition.
Investigating various clinical factors in all enrolled patients, we found that some of them were significantly more frequent in patients who subsequently developed delirium than in those who did not. In particular, ten factors were significantly related in univariate analyses, i.e., advanced age, care in hospice, very compromised performance status, hypoxia, high Among demographic aspects, only age seems to be a relevant predictor for delirium diagnosis: our data indicate in fact a progressive increase in the prevalence of delirium for increasing age of the patients. This is consistent with what has been reported in previous studies [3,25]. In particular, a review of the literature described a four-fold increased risk of developing delirium in hospitalized patients aged 75 years or more, when compared to younger individuals [3].
Our data indicate that the risk of developing delirium is higher in patients in hospice than those cared at home, suggesting that the relevant factor seems to be the hospitalization. This is consistent with previous studies which reported that old patients requiring hospital admission have a prevalence of delirium between 18% and 35% [3,15,16,26]. The sudden departure from their own habitat to a different environment plays an important role in delirium onset, especially in elderly patients with serious health conditions.
As already reported [26], we also observed that respiratory activity is important in predicting delirium: patients with breathlessness had an approximately two-fold risk of developing delirium. Furthermore, we found an increase of more than 70% in the risk of delirium onset in patients who used CNS acting drugs administered as background therapy.
This is not surprising, since the role of CNS active drugs in inducing delirium has been often debated in recent years.
Anticholinergics, antidopaminergics, sedative/hypnotics, antipsychotics, opioids, relaxants, in particular, have been considered as drugs that may cause delirium [26]. It should be also noticed that haloperidol, considered for years as the golden treatment in case of delirium [27][28][29], in univariate analysis was associated with an about 90% increased risk of delirium onset when prescribed as around the clock therapy, though the increase was only by 30%, not significant, in the multivariate analysis.
In our study, no association was found between level of education or marital status and risk of delirium, this suggests that delirium is related to the severe patients' clinical condition at the end-of-life -able to trigger delirium pathogenetic mechanisms -rather than the patients' cultural and socio-familial background. Moreover, the role of the primary pathology and concomitant diseases was not relevant for the onset of delirium. However, it should be considered that in this study the population of the patients was quite clinically homogeneous, since 90% of them had a diagnosis of neoplasm.
Although various risk factors for the onset of delirium have previously been investigated [14][15][16], most studies considered retrospectively these factors in patients who already presented an episode of delirium. In this study, we investigated a number of possible risk factors at the time of admission to the PCU, when the delirium episode had not yet happened, allowing us to identify potentially "delirium predisposing factors".
Recent data have shown the importance of physical activity on the well-being of palliative care patients [30]. It would be interesting to explore whether this would also the appearance of delirium, and this might be the topic for a future research on those difficult and fragile patients.
However, this study presents some limitations. In particular, we did not achieve the expected sample size calculated at the moment of planning the project, due to some difficulties in conducting the study in the setting of terminally ill patients. Moreover, the proportion of patients with delirium in our study was lower (about 19%) compared with previous study populations [11][12][13].This is probably due to the fact that patients enrolled in our study were at a very advanced stage of disease with a short survival time (average 18 days), reflecting the Italian situation where the delay in sending terminal patients to PC is very frequent [31]. Consequently, for some clinical factors, the association with delirium occurrence did not reach the statistical significance, even in the presence of high OR.

Conclusions
In conclusion, the study identified some factors which are relevant for the onset of delirium in terminally ill patients treated in a PCU. The identification of specific delirium predisposing factors may bring an advantage to patients, caregivers and healthcare professionals. Additional data and a future active sharing experience with other PCUs would be worthwhile to confirm these finding and usefulness in the clinical practice.