This study examined the characteristics and outcomes of advanced cancer patients with delirium who were admitted to the acute palliative care unit (APCU). Of 323 advanced cancer patients in the APCU who were diagnosed with delirium, 71% were diagnosed on APCU admission and 29% developed delirium after admission. Delirium was reversed in 26%. Patients diagnosed with delirium after APCU admission had a lower median overall survival rate and lower rate of delirium reversibility than those diagnosed on admission.
Keywords: Delirium, Terminal delirium, Palliative care, End-of-life symptoms
Abstract
Background.
Delirium is a common neuropsychiatric condition seen in patients with severe illness, such as advanced cancer. Few published studies are available of the frequency, course, and outcomes of standardized management of delirium in advanced cancer patients admitted to acute palliative care unit (APCU). In this study, we examined the frequency, characteristics, and outcomes of delirium in patients with advanced cancer admitted to an APCU.
Methods.
Medical records of 609 consecutive patients admitted to the APCU from January 2011 through December 2011 were reviewed. Data on patients’ demographics; Memorial Delirium Assessment Scale (MDAS) score; palliative care specialist (PCS) diagnosis of delirium; delirium etiology, subtype, and reversibility; late development of delirium; and discharge outcome were collected. Delirium was diagnosed with MDAS score ≥7 and by a PCS using Diagnostic and Statistical Manual, 4th edition, Text Revision criteria. All patients admitted to the APCU received standardized assessments and management of delirium per best practice guidelines in delirium management.
Results.
Of 556 patients in the APCU, 323 (58%) had a diagnosis of delirium. Of these, 229 (71%) had a delirium diagnosis on admission and 94 (29%) developed delirium after admission to the APCU. Delirium reversed in 85 of 323 episodes (26%). Half of patients with delirium (n = 162) died. Patients with the diagnosis of delirium had a lower median overall survival than those without delirium. Patients who developed delirium after admission to the APCU had poorer survival (p ≤ .0001) and a lower rate of delirium reversal (p = .03) compared with those admitted with delirium.
Conclusion.
More than half of the patients admitted to the APCU had delirium. Reversibility occurred in almost one-third of cases. Diagnosis of delirium was associated with poorer survival.
Implications for Practice:
Delirium is the most common neuropsychiatric condition in patients with severe medical illness and those at the end of life. It can be a source of distress for patients, their families, and the medical team. When missed, or if symptoms are misinterpreted, delirium may also lead to unnecessary interventions. This underlines the importance of diagnosis and detection of delirium in populations that are at increased risk. This study has important implications in practice, as it can assist clinicians in making decisions regarding other medical interventions, advance care planning, and communicating with families relating to end-of-life issues.
Introduction
Delirium is a common neuropsychiatric condition seen in patients with severe illness such as advanced cancer and is characterized by an acute disorder of cognition and attention, diminished level of consciousness, and inability to maintain focus and attention. This often occurs in the setting of an acute medical illness in vulnerable individuals [1, 2]. It is a source of significant suffering to patients and their families, as well as for the medical team delivering care for the patient [3, 4]. It is sometimes a source of conflict associated with misinterpretation of symptoms that can occur with cognitive dysfunction [5, 6]. The development of delirium is also associated with increased mortality and morbidity [7–9].
The incidence of delirium varies from 15% to 50% of elderly patients admitted to a general medical floor, to as high as 80% of patients who are near the end of life [10, 11]. Previous studies have shown that the prevalence of delirium at the time of admission to an acute palliative care unit ranged from 28% to 42% [12, 13]. The wide variation in the prevalence of delirium may be attributed to failure of recognition by the medical team and underuse of validated tools to screen for at-risk patients [14, 15]. Despite the implications of the presence of delirium on prognosis, few published studies are available on the frequency, course, and outcomes of standardized management of delirium in advanced cancer patients [2, 13, 16]. In this study, we examined the frequency, characteristics, and outcomes of delirium in patients with advanced cancer who were admitted to an APCU. This knowledge would assist clinicians in improving care for patients with advanced cancer.
Materials and Methods
We reviewed the electronic medical records of 609 consecutive patients admitted to the acute palliative care unit (APCU) at a major academic cancer center during the period of January 1, 2011, to December 31, 2011. This study was approved by the institutional review board of The University of Texas MD Anderson Cancer Center.
The electronic medical records were reviewed to obtain patient demographics, Eastern Cooperative Oncology Group (ECOG) status, Memorial Delirium Assessment Scale (MDAS) score [17], Edmonton Symptom Assessment Scale (ESAS) score [18], and discharge disposition. For those patients with delirium, information also was gathered on the use of psychoactive medications, possible underlying delirium etiology, delirium subtype, and delirium reversibility.
Patients are admitted to the APCU when there is severe symptom distress that precludes optimal management on the regular medical floors and those who are transitioning to end-of-life care. In most cases, patients have discontinued active therapy at the moment of admission to the APCU. None of the patients had any recent surgery. Patients admitted from the emergency department, intensive care unit, other medical floors, and the outpatient center often present with acute medical complications related to their malignancy.
Outcome Measures
Memorial Delirium Assessment Scale
The Memorial Delirium Assessment Scale (MDAS) is a clinician-rated, 10-item scale for assessing delirium and its severity, and it covers all delirium phenomenological areas. Each item is scored from 0 to 3 depending on its intensity and frequency (possible range: 0–30). The cutoff score of 7 has been validated in the advanced cancer population [17].
Diagnosis of Delirium
Patients were grouped into those with a diagnosis of delirium on admission and those with no delirium on admission. Diagnosis of delirium was made by a board-certified palliative care specialist (PCS) using the MDAS and Diagnostic and Statistical Manual (DSM), 4th edition, Text Revision criteria. Patients were diagnosed as having delirium if they scored 7 out of 30 on the MDAS. The MDAS is used routinely to screen for delirium and monitor severity. Delirium is noted to be reversed if the MDAS score is less than 7 out of 30, or if the PCS reports the delirium to be resolved in the progress notes for at least 2 consecutive days. Patients who were not initially determined to have delirium but subsequently develop delirium during their stay in the APCU were considered to be a different group. In all, there were three groups of patients that were analyzed: those with delirium from admission, those with no delirium on admission and who developed it during the course of the admission, and those who never developed delirium at any time during the hospitalization.
Precipitating Variables Associated With Delirium
Information on the potential precipitating factors for delirium were determined from PCS progress notes along with information on its management, which included those factors that targeted symptoms as well as those that treated the underlying medical condition thought to precipitate delirium. In the absence of a potential precipitating factor for the delirium, the investigator reviewed laboratory and other pertinent medical information to determine possible underlying medical issues causing the delirium. We adapted criteria that were similar to those used by Lawlor et al. to determine precipitating factors for delirium [19]. Each precipitating factor we considered was assessed using the following criteria: (a) evidence of a medical conditions present using specific clinical, laboratory, or radiological findings; (b) temporal association of the course of delirium and the potential precipitating factor; and (c) changes in delirium severity in association with changes of the potential precipitating factor.
Commonly identified causes of delirium include medications such as opioids or benzodiazepines, infection, organic brain lesions, electrolyte abnormalities, dehydration, and terminal delirium (when patients are actively dying). For the purposes of this study, the etiologies of delirium were classified into infection, medication, metabolic, multifactorial, and terminal, as these were the commonly cited etiologies on review of the medical records. For those patients for whom the etiology for delirium was not clearly identified, the investigators used the following criteria. Infection was considered a cause if the patient was receiving antibiotics, antivirals, or antifungals; had positive cultures; urinalysis results suggestive of a urinary tract infection; or imaging studies suggestive of infection (e.g., chest radiograph suggestive of pneumonia). Medications were considered a cause if drugs like opioids, benzodiazepines, anticholinergic drugs, corticosteroids, hypoglycemic agents, dopamine agonists, muscle relaxants, and other psychotropic medications were present and were subsequently discontinued, decreased, or, in the case of opioids, changed to a different one. Metabolic etiologies included medical conditions such as hypercalcemia, dehydration, electrolyte abnormalities, liver and renal failure, glucose abnormalities, hypoxia, and anemia. A multifactorial etiology was reported if there were more than three possible etiologies of delirium, including underlying advanced cancer. Terminal delirium was reported if the patient was imminently or actively dying and all other possible reversible etiologies of delirium had been addressed, and improvement in the condition was not observed.
Also included in the etiologic criteria were treatment strategies and discharge outcome. Treatment for underlying medical cause included antibiotics, hydration, electrolyte replacements, and medication changes (e.g., opioid rotation, discontinuation of drugs). Medications targeting symptoms of delirium include antipsychotics (e.g., haloperidol, chlorpromazine, and olanzapine) and benzodiazepines (lorazepam) as a single agent or in combination. Nonpharmacologic interventions are routinely provided to patients and families when delirium is diagnosed and include family education on delirium, a sitter at the bedside when appropriate, minimal nursing intervention and stimulation, and orientation techniques. A patient’s discharge disposition was designated as either discharged to home, hospice, or hospital death.
Process of Standardized Delirium Management in APCU
The APCU is an acute care, 12-bed unit dedicated to patients with severe symptom burden and those who are near the end of life. The APCU staff is composed of a trained palliative care physician, a nurse practitioner, a palliative care fellow, a chaplain, a social worker, counselors, a case manager, occupational and physical therapists, and specially trained palliative care bedside nurses. ECOG, MDAS, and ESAS are assessment tools that are routinely used by the PCS on initial consult and follow-up visits. MDAS and other formal assessments are done at the time of admission and on a daily basis by the PCS. It is routinely assessed at least once during the day, and more frequently if the situation requires it. For those patients who were unresponsive, a diagnosis of delirium was made by a PCS. Cognitive assessment is universally done using the MDAS. For those patients with borderline MDAS scores and older patients with increased risk factors for cognitive impairment, further assessment using the DSM-V criteria for dementia is conducted.
Statistical Analysis
Data were first summarized using standard descriptive statistics and contingency tables. Association between categorical variables was examined by chi-square test or Fisher exact test. The Wilcoxon-Mann-Whitney test was used to examine the difference on continuous variables between or among groups. Univariate and multivariate logistic regression models were applied to assess the effect of variables of interest on presence of delirium at admission and resolution of delirium. Overall survival (OS) was estimated using the Kaplan-Meier method and the comparison between or among patient characteristics groups was evaluated by log-rank test. Univariate and multivariate Cox regression models were applied to assess the effect of variables of interest on OS.
Results
A total of 609 patients were admitted to the APCU during the time period of interest. However, for 44 patients who had multiple admissions, a random sampling was done to select for only 1 admission to be analyzed in the study. A total of 556 patients were included in the analysis. Figure 1 shows the distribution of the different patient groups. Of the remaining 556 patients, 323 (58%) had delirium during their admission to the APCU, with 229 of the 556 (41%) having the diagnosis at the time of APCU admission. The median age was 58 years (range: 19–91 years; mean age: 56.51 years [SD: ± 13.85 years]). Table 1 summarizes the patient characteristics of the three groups of patients: those with delirium on admission, those who developed delirium after admission to the APCU, and those without delirium throughout the admission. Patients with poor ECOG status were more likely to have a diagnosis of delirium. When we compared ECOG status by cancer diagnosis, we found that of the 73 patients with hematologic malignancy, 4 (5%) had ECOG status 1 or 2, 14 (19%) had ECOG status 3, and 55 (75%) had ECOG status 4; of those with solid tumors (n = 481), 38 (8%) had ECOG 1 or 2, 204 (42%) had ECOG status 3, and 235 (49%) had ECOG status 4 (p < .0001).
Figure 1.
Distribution of patients admitted to the APCU with reference to the diagnosis of delirium.
Abbreviation: APCU, acute palliative care unit.
Table 1.
Admission characteristics of patients admitted to the acute palliative care unit
A summary of the delirium characteristics of patients admitted with delirium versus those who developed delirium after admission to the APCU are summarized in Table 2. Mixed delirium was the most frequent type of delirium (112 of 246 patients; 45%), followed by hypoactive (73 of 246; 30%) and hyperactive (61 of 246; 25%) types. Haloperidol was the most commonly used single-agent medication to treat symptoms of delirium (211 of 322 patients; 66%) followed by chlorpromazine (10 of 323; 3%). The use of olanzapine, lorazepam, and other antipsychotics was minimal. Other single interventions included opioid rotation (66 of 176 patients; 38%), hydration (18 of 176; 10%), and antibiotics (14 of 176; 8%). Most interventions were a combination of various treatment strategies. Counseling of the caregivers and patient, when indicated, was performed in all cases. Delirium after admission to the APCU occurred in approximately 17% of total APCU admissions (94 of 556 patients). The median length of stay for patients with delirium was 6 days, and 5 days for those without delirium (p = .0015). The median time to develop delirium for patients with late delirium in the APCU was 2 days after admission. No difference in the two groups was found with regard to age, sex, race, primary cancer diagnosis, ECOG status, delirium subtype, medication use, etiology, and use of other medical management. However, the data showed that patients admitted to the APCU with delirium had a higher rate of resolution of delirium symptoms compared with those who developed delirium after admission to the APCU. Increased death rate was associated with developing delirium after APCU admission.
Table 2.
Summary of patient and clinical characteristics of patients admitted with delirium vs. patients who developed delirium after admission to the acute palliative care unit
Table 3 summarizes the univariate regression model of comparing patients admitted with delirium and those who developed delirium after admission to the APCU. The multivariate model showed that male patients (OR: 1.55; 95% confidence interval [CI]: 1.03–2.35); p = .0365) and ECOG status (ECOG status 1 and 2 vs. 4, OR: 0.17 [95% CI: 0.08–0.39; p < .0001]; 3 vs. 4, OR: 0.35 [95% CI: 0.24–0.52, p < .0001]) were the independent covariates significantly associated with the presence of delirium at admission. For those patients who developed delirium in the APCU, the median time to develop delirium was 2 days after admission to the APCU. The median time to resolution of delirium was 6 days. Patients with ECOG status 2 had a 5 times higher chance of delirium resolution (95% CI: 1.52–16.42; p = .0082) compared with patients with ECOG status 4.
Table 3.
Summary of univariate logistic regression analysis of patients admitted with delirium vs. patients who developed delirium after admission to the acute palliative care unit
A total of 180 of the 556 patients (32%) died in the APCU and the median time of overall survival was 12 days (95% CI: 9–15). The result of the multivariate Cox regression model for overall survival is presented in Table 4 and shows that cancer diagnosis (hematologic vs. solid tumor, hazard ratio [HR]: 1.7; 95% CI: 1.17–2.48; p = .0057), ECOG status (3 vs. 4, HR: 0.56; 95% CI: 0.38–0.83; p = .0041), and development of delirium on admission and during the stay in APCU (HR: 5.42; 95% CI: 3.30–8.90; p < .0001) are independent covariates that are significantly associated with overall survival. There were only 4 patients who had a reported ECOG status of 1 and 42 who had ECOG status 2. With such a low frequency, it became difficult to compare with those with ECOG status 3 (n = 218) and 4 (n = 290) and, therefore, the comparison was not included in the univariate and multivariate models. The Kaplan-Meier curve of overall survival in patients who had delirium or developed it later versus those with no delirium is also shown in Figure 2.
Table 4.
Multivariate Cox regression model for survival in patients with delirium vs. those without
Figure 2.
Kaplan-Meier curve of overall survival in patients with delirium on and after admission versus those who did not develop delirium.
A subgroup of patients who did not have a diagnosis of terminal delirium was analyzed. After removing patients with the diagnosis of terminal delirium, resolution of delirium was observed in 83 of 273 patients (30%; p = .0786) and was not significantly different among patients with delirium on admission and those with late delirium. Median time of overall survival was 15 days (95% CI: 12–26). Patients who were alive at discharge were censored. Patients who developed delirium after admission to the APCU also had a higher rate of death and were less likely to be discharged to home than those admitted with delirium (death: 39 [54%] vs. 84 [42%]; home: 3 [4%] vs. 27 [13%]; hospice: 30 [42%] vs. 91 [45%]; p = .0471). In addition, there was no significant difference among patients with delirium on admission and those with late delirium for any of the variables.
Discussion
We found a higher frequency of delirium among patients admitted to our APCU in comparison with that of other studies in advanced cancer patients [12, 16, 20]. Almost 60% of patients admitted to the APCU had delirium either at the time admission or at any time during the course of their hospital stay. This is similar to that shown in the study by Lawlor et al. [19]. When present, delirium interferes with effective communication and reporting of symptoms, and can also lead to inappropriate interventions [5, 21]. In fact, a previous study conducted by our group showed that approximately 60% of cases of delirium in patients with advanced cancer can be missed by the primary referring team [22]. This finding highlights one of the important roles that APCUs have in managing these challenging patients and is reflected in the admissions to the APCU from the primary oncology team. Delirium is a highly distressing condition that requires prompt recognition and control of symptoms that can be addressed best in the APCU where the PCS is much more familiar with symptom management, bedside nurses are trained to respond to patient and family distress, and where an interdisciplinary team can provide support and a uniform message of care goals.
Our study has shown that those patients with poor ECOG status are more likely to develop delirium, have a lower rate of reversibility, and a higher rate of death. Patients admitted to the APCU may be sicker and more frail, and, therefore, more at risk of developing delirium. This is consistent with studies in geriatric and other vulnerable patient populations that report an association between patient vulnerability factors and risk for delirium [23]. Hematologic malignancy was associated with a higher rate of delirium likely because these patients had worse ECOG status, were more frail, and possibly at increased risk of developing delirium. The high percentage of terminal delirium that was observed could indicate that those admitted to the APCU were closer to the end of life in their disease trajectory.
It is important to note the difference between those admitted with delirium and those who developed delirium during the APCU admission. Those admitted with delirium had higher rates of reversibility and lower mortality rates than those that developed delirium during the APCU admission. This finding suggests that in those patients with some adjustments in medications and correction of identifiable causes, delirium can be reversed. The percentage, however, is still lower than that presented in previous studies. For those with delirium on admission, reversibility was still only approximately 30% (68 of 229 patients).
Once patients are admitted to the APCU, efforts are made to modify potential factors that can cause delirium, such as medications, electrolyte abnormalities, and other metabolic issues. Despite these measures, delirium was still shown to occur in almost one-fifth of total APCU admissions. Development of delirium in the APCU may be considered an ominous sign. In fact, of patients who developed delirium while admitted in the APCU, approximately one-third had terminal delirium, a higher rate than that of patients with delirium on admission.
The results of this study also highlight important findings in the literature [24, 25]. Haloperidol is still the most commonly used single agent for the treatment of delirium. There were a few patients who required rotation to a different antipsychotic or were given additional antipsychotics for control of symptoms. The mixed type of delirium was found to be the most common subtype, followed by hypoactive delirium.
About one-half the patients who developed delirium died during their stay in the APCU. Mortality was high and reversibility was lower than previously described in the literature. Education provided to health-care providers and to patients’ families and caregivers about the poor prognosis associated with the development of delirium cannot be overemphasized.
The retrospective nature of our study lends it to a number of limitations, including missing data that are not recorded in the medical record (e.g., ESAS entries and presence of baseline cognitive impairments). Although we had a priori defined criteria for the diagnosis of delirium, underlying etiologies, delirium subtype, reversibility, and medical management, there were still some missing entries. Doing daily formal assessments for delirium may result in having a missed diagnosis of delirium, given its fluctuating nature. Prospective studies would be more ideal to capture such information with more accuracy.
Conclusion
More than half of the patients admitted to the APCU had delirium. Diagnosis of delirium was associated with poorer survival. Reversibility occurred in only one-third of patients despite active measures to reverse delirium by addressing underlying etiology and controlling symptoms. Educating medical staff, and patients’ families and caregivers is critical in the management of these patients. Further research is warranted to better understand its course, vulnerability features, factors for reversibility, and management.
This article is available for continuing medical education credit at CME.TheOncologist.com.
Author Contributions
Conception/Design: Maxine de la Cruz, Diane Liu, Akhila Reddy, Marvin Delgado-Guay, Eduardo Bruera
Provision of study material or patients: Maxine de la Cruz, Sriram Yennu, Eduardo Bruera
Collection and/or assembly of data: Maxine de la Cruz, Viraj Ransing, Eduardo Bruera
Data analysis and interpretation: Maxine de la Cruz, Sriram Yennu, Jimin Wu, Diane Liu, Akhila Reddy, Eduardo Bruera
Manuscript writing: Maxine de la Cruz, Viraj Ransing, Sriram Yennu, Akhila Reddy, Marvin Delgado-Guay, Eduardo Bruera
Final approval of manuscript: Maxine de la Cruz, Viraj Ransing, Sriram Yennu, Jimin Wu, Diane Liu, Akhila Reddy, Marvin Delgado-Guay, Eduardo Bruera
Disclosures
The authors indicated no financial relationships.
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