International Journal of Critical Illness and Injury Science

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 12  |  Issue : 4  |  Page : 190--196

Early onset delirium incidence and risk factors in hematology oncology patients admitted to the intensive care unit: A retrospective cohort study


Rachel C Klosko1, Joshua R Arnold2, Claire V Murphy2, Jessica Brimmer2, Natalie Hagy3, Matthew C Exline4, Eric McLaughlin5, Jessica L Elefritz2,  
1 Department of Pharmacy Practice, Binghamton University School of Pharmacy and Pharmaceutical Sciences, Johnson City, NY, The United States of America
2 Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio, The United States of America
3 College of Pharmacy, The Ohio State University, Columbus, Ohio, The United States of America
4 Division of Pulmonary Diseases, Critical Care Medicine, and Sleep, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, The United States of America
5 Center for Biostatistics, The Ohio State University, Columbus, Ohio, The United States of America

Correspondence Address:
Dr. Jessica L Elefritz
410 W 10th Ave, 368 Doan Hall, Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH 43210
The United States of America

Abstract

Background: Delirium occurs frequently in intensive care unit (ICU) patients; however, there are limited data evaluating its impact on critically ill hematology-oncology patients. We aimed to determine the incidence and risk factors for early-onset delirium development in hematology-oncology patients admitted to the ICU. Methods: This single-center, retrospective cohort study evaluated the primary outcome of incident delirium within 7 days of ICU admission in adults admitted to the hematology-oncology medical or surgical ICU. Patients with delirium (DEL) were compared to those without (No-DEL) for evaluation of secondary endpoints including hospital mortality, ICU, and hospital length of stay (LOS). Multivariable logistic regression modeling was performed to identify independent risk factors for delirium. Results: Delirium occurred in 125 (51.2%) of 244 patients. Inhospital mortality was significantly higher in the DEL vs. No-DEL group (32.8% vs. 15.1%, P = 0.002). Median (1st and 3rd quartiles) ICU and hospital LOS were significantly longer in the delirium group, respectively (6 [4–10] days vs. 3 [2–5] days, P < 0.001, and 21 [14–36] days vs. 12 [8–22] days, P < 0.001). Higher Sequential Organ Failure Assessment score, high-dose corticosteroids, mechanical ventilation (MV), and brain metastases were each independently, associated with an increased delirium risk. Conclusion: Hematology-oncology patients admitted to the ICU frequently develop delirium. Consistent with literature in nonhematology-oncology critically ill patients, identified independent risk factors for delirium were MV and organ dysfunction. Risk factors unique to the critically ill hematology-oncology patient population include high-dose corticosteroids and brain metastases. Further research is needed to evaluate strategies to mitigate delirium development in this population based on risk assessment.



How to cite this article:
Klosko RC, Arnold JR, Murphy CV, Brimmer J, Hagy N, Exline MC, McLaughlin E, Elefritz JL. Early onset delirium incidence and risk factors in hematology oncology patients admitted to the intensive care unit: A retrospective cohort study.Int J Crit Illn Inj Sci 2022;12:190-196


How to cite this URL:
Klosko RC, Arnold JR, Murphy CV, Brimmer J, Hagy N, Exline MC, McLaughlin E, Elefritz JL. Early onset delirium incidence and risk factors in hematology oncology patients admitted to the intensive care unit: A retrospective cohort study. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Feb 4 ];12:190-196
Available from: https://www.ijciis.org/text.asp?2022/12/4/190/364741


Full Text



 Introduction



Delirium occurs frequently in critically ill patients with documented rates up to 48% and 87% in intensive care unit (ICU) and mechanically ventilated patients.[1],[2],[3],[4],[5] Delirium development is an independent predictor of mortality, increased ICU length of stay (LOS), and cognitive impairment, making prevention and treatment crucial in critically ill patients.[4],[6] Delirium is also the most common neuropsychiatric complication in cancer patients; however, few studies have evaluated delirium in this population, potentially leaving it under-recognized and under-treated.[7],[8],[9],[10] The objective of this study is to determine the incidence of early-onset delirium and risk factors for development in hematology-oncology patients admitted to the ICU.

 Methods



Study design

A single-center, retrospective, cohort study from July 1, 2018, to June 30, 2019, was conducted to determine the incidence of early-onset delirium in hematology-oncology patients aged 18–89 years admitted to the medical ICU (MICU) or surgical ICU (SICU) at a large academic medical center with a national cancer institute-designated comprehensive cancer center. The comprehensive cancer center contains a 24-bed MICU and 12-bed SICU specifically for critically ill hematology-oncology patients. Patients were identified from ICU admission reports in the electronic medical record during the study period and randomly selected for screening using a random number generator. Patients who were pregnant, incarcerated, receiving active treatment for alcohol withdrawal or intravenous drug abuse, admitted to a neurology service, had documented coma (Richmond Agitation-Sedation Scale of − 4 or − 5) for more than 60% of the study time frame, had a history of dementia, had no history of malignancy or a benign hematologic disorder, or died within 24 h of ICU admission were excluded. Delirium was not assessed prior to the patient's ICU admission. For patients with multiple qualifying episodes, hospital encounters, or multiple admissions to the ICU during a single hospital encounter, only the first was included for evaluation. Patients were assessed for 7 days from ICU admission, or until ICU discharge, or death. The study was approved by the cancer clinical scientific review committee and the local institutional review board (IRB). A waiver for the consent process was obtained from the IRB. The manuscript adheres to the STROBE guideline.

Outcomes and risk factors

The primary outcome evaluated was the incidence of delirium within the first 7 days of ICU admission. Delirium was defined as two positive Confusion Assessment Method (CAM)-ICU assessments within a 24-h period. CAM-ICU assessments are performed by nursing staff at least once per 12-h shift. The secondary outcomes compared between patients with delirium (DEL) and those without (No-DEL) include hospital mortality, and among survivors, ICU and hospital LOS. Potential risk factors for delirium development were also compared between patients with and without delirium. Static risk factors included hospital LOS >1 day prior to ICU admission, MICU or SICU admission, hematologic or oncologic malignancy, presence of brain metastases, severe malnutrition, organ dysfunction per Sequential Organ Failure Assessment (SOFA) score at the time of ICU admission, and receipt of immunotherapy, cytotoxic chemotherapy, or chimeric antigen receptor T-Cell (CAR-T) therapy within 30 days of ICU admission. Dynamic risk factors included the receipt of invasive mechanical ventilation (MV) or shock within the 7-day study time frame, and medications and metabolic abnormalities occurring from 48 h prior to ICU admission through the 7-day study time frame.[11] Shock was defined according to the study investigators as the administration of continuous infusion vasopressors for a period of 6 h or more. Medications evaluated included the receipt of high-dose corticosteroids, benzodiazepines, and continuous neuromuscular blocking agents (NMBAs). Metabolic abnormalities included hyponatremia (serum sodium <130 mmol/L), hypernatremia (serum sodium >150 mmol/L), hypercalcemia (ionized calcium >5.6 mg/dL), uremia (BUN >100 mg/dL), and hyperammonemia (serum ammonia >47 umol/L). High-dose corticosteroids were defined as >1 mg/kg/day prednisone equivalents based on the patient's actual body weight. Benzodiazepine use was defined as receipt of >20 mg lorazepam equivalents in a 24-h period.[12] Dynamic risk factors were required to occur prior to the development of delirium among the delirium cohort. Severe malnutrition was defined according to the Academy of Nutrition and Dietetics (AND) and American Society for Parenteral and Enteral Nutrition 2012 malnutrition criteria and collected for patients with a documented evaluation by a registered dietitian.[13]

Data collection

Data were collected via retrospective chart review of Epic© (Epic Systems Corporation, Verona, WI, United States), the electronic medical record, and were managed using REDCap™ (Research Electronic Data Capture) electronic data capture tools hosted at The Ohio State University.[14],[15] REDCap™ (Vanderbilt University, Nashville, TN, United States) is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources.

Statistical analysis

Descriptive statistics were used to detail the overall study cohort. The DEL and No-DEL cohorts were compared with categorical variables presented as frequency (percent) for categorical variables and analyzed using Fisher's exact test. Continuous variables are summarized using mean (standard deviation) for normally distributed variables or median (1st and 3rd quartiles [Q1-Q3]) for nonnormally distributed variables and analyzed using the Student's t-test or Mann–Whitney U-test, as appropriate.

Multivariable logistic regression was used to determine a set of predictive risk factors for delirium. Variables with P < 0.2 in univariate analysis were considered in the multivariable analysis. Due to receipt of benzodiazepines and use of MV being known confounding factors in this cohort, they were selected a priori for inclusion in the multivariable model regardless of significance. A backward variable selection method was used to build the model with P < 0.05 as the cutoff for inclusion, and model fit was assessed by the Akaike information criterion (AIC). Adjusted odds ratios with 95% confidence intervals for variables in the final model were reported. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, USA)

 Results



A total of 331 patients were screened for inclusion with 244 included in the final study analysis. The most common reasons for exclusion were no history of malignancy, coma for more than 60% of the study time, no documented CAM-ICU assessments, death within 24 h of ICU admission, and admission to a neurology service [Figure 1]. For the entire cohort, the median age was 64.0 (55.0–71.0) years and the majority were male 146 (59.8%). There were 168 (68.9%) patients with an oncologic malignancy, and 81 (33.2%) with a hematologic malignancy. Five patients had both hematologic and oncologic malignancies. The majority of patients (93.9%) had active malignancy at the time of ICU admission. There were 190 (77.9%) patients admitted to the MICU, and 57 (23.4%) patients admitted to the SICU. There were three patients who were admitted to both the MICU and SICU during their first 7 days in the ICU [Table 1]. The median Charlson Comorbidity Index was 6.0 (5.0–8.0).{Figure 1}{Table 1}

The primary outcome of delirium within 7 days of ICU admission occurred in 125 (51.2%) patients. In the DEL cohort, the median percentage of positive CAM-ICU assessments was 60.0% (24.4%–91.7%). A median of 4.5 (3.6–5.4) CAM-ICU assessments were documented per patient per day in the ICU.

Baseline characteristics for the DEL and No-DEL cohorts are summarized in [Table 1]. The median SOFA score was significantly higher in the DEL cohort although Charlson Comorbidity Index was similar. More patients in the DEL group had at least 1 day of hospital admission before ICU admission, and LOS prior to ICU admission was significantly longer in patients in the DEL group compared to the No-DEL group (3 [1–10] vs. 1 [0–5] days, P < 0.001). Patients in the DEL group were more likely to have received MV, high-dose corticosteroids, benzodiazepines, cytotoxic chemotherapy, immunotherapy, and CAR-T cell therapy. Patients in the DEL group were also more likely to have had a hematologic malignancy, brain metastases, and shock during their 7-day ICU admission compared to the No-DEL group. Few patients received CAR-T cell therapy, but all patients who did had delirium. No patients in either group received continuous NMBAs. Metabolic and electrolyte abnormalities were assessed between cohorts including the development of hyponatremia (median lowest serum sodium DEL 126 [125–128] mmol/L vs. No-DEL 128 [126–129] mmol/L, n = 47), hypernatremia (median highest serum sodium DEL 153.5 [151–156] mmol/L vs. No-DEL 155 mmol/L, n = 3), hypercalcemia (median highest ionized calcium DEL 6.49 [6.12–6.81] mg/dL vs. No-DEL 6.29 [6.02–6.56] mg/dl, n = 6), uremia (median highest blood urea nitrogen DEL 123.5 [116–131] mg/dL vs. No-DEL 108 [107–112] mg/dL, n = 7), and hyperammonemia (median highest serum ammonia DEL 76 [60–91] umol/L vs. No-DEL 60 [51–85] umol/L, n = 21). Occurrences of these abnormalities were not significantly different between groups.

More patients in the DEL group received any corticosteroids (55.2% vs. 25.2%) and high-dose steroids [Table 1] compared to the No-DEL group. Overall, patients in the DEL group received numerically higher total corticosteroid doses compared to the No-DEL group (213 [113–425] vs. 141 [53–253] mg prednisone equivalents [P = 0.03]). Benzodiazepines were more common among the DEL group compared to the No-DEL group (59.2% vs. 40.3%), and while few patients received high-dose benzodiazepines, all who did were in the DEL group [Table 1]. Among patients who received any dose of a benzodiazepine, the total benzodiazepine dose was similar between the DEL and No-DEL groups (3.13 [1.50–7.75] vs. 3.25 [1.00–7.25] mg lorazepam equivalents). In patients who developed delirium, 75 (0–163) mg prednisone equivalents were received prior to the development of delirium and continued for a median duration of 5 (2–7) days, and 1 (0–3) mg lorazepam equivalents were received prior to the development of delirium and continued for a median duration of 1 (1–3) days.

Risk factors that met criteria for inclusion in the multivariable logistic regression were shock, high-dose corticosteroids, benzodiazepines, MV, brain metastases, hematologic malignancy, oncologic malignancy, cytotoxic chemotherapy, immunotherapy, CAR-T cell therapy, SOFA score, sex, obesity, and LOS >1 day prior to ICU admission. Receipt of CAR-T cell therapy and receipt of benzodiazepines met criteria, but could not be included in the multivariable modeling due to the small number of patients in each group. Hematologic malignancy was not included due to high collinearity with oncologic malignancy variable (all patients had at least one of the two malignancy types, but could also have both types). The following variables were removed during the backward selection: shock (P = 0.94), obesity (P = 0.49), oncologic malignancy (P = 0.29), cytotoxic chemotherapy (P = 0.34), LOS >1 day prior to ICU admission (P = 0.23), immunotherapy (P = 0.15), and sex (P = 0.06). SOFA score, high-dose corticosteroids, MV, and brain metastases were included in the final model, and were each associated with increased odds of delirium [Table 2]. The AIC of the final model was 251.6, compared to an AIC of 340.1 in the intercept-only model.{Table 2}

The secondary outcomes compared between the DEL and No-DEL groups are summarized in [Table 3]. The rate of inhospital mortality was significantly higher in the DEL group compared to the No-DEL group (P = 0.002). Among survivors, ICU (P < 0.001) and hospital LOS (P < 0.001) were also significantly longer in the DEL group.{Table 3}

 Discussion



This study reports a rate of early-onset delirium of 51.2% in adult hematology-oncology patients admitted to the MICU or SICU. Consistent with previous literature, higher SOFA score and MV were associated with an increased risk of delirium.[1],[3],[5],[16],[17],[18] Risk factors for delirium that were unique to the critically ill hematology-oncology patient population included high-dose corticosteroids and brain metastases. It is well known that ICU delirium is associated with poor patient outcomes including increased inpatient LOS, ICU LOS, and increased mortality, which was observed in this study as well.[4],[6] With the lack of effective pharmacologic treatment options for delirium, current guidelines recommend management focused largely on identification of patients at risk for delirium and utilizing targeted preventive strategies, such as performance of ABCDEF bundle elements to improve outcomes.[19],[20]

With improved survival of hematology-oncology patients and the rapid development of novel treatment options over the past decade, care of hematology-oncology patients in the ICU has escalated.[21] This further emphasizes the need for hematology-oncology-specific data to guide the assessment, prevention, and management of ICU delirium in this complex patient population. There are currently two published studies in which delirium has been evaluated in hematology-oncology ICU patients, with vastly differing rates of delirium.[17],[18] Almeida et al. prospectively evaluated the incidence of mortality and delirium in 170 patients with cancer who were admitted to the ICU and mechanically ventilated for >48 h. Delirium, defined as one positive CAM-ICU assessment by study personnel daily, was only able to be evaluated in 126 patients of whom 117 (92.8%) developed delirium. The rate of delirium reported by Almeida et al. is higher than the 52.1% delirium rate found in the present study, but this can likely be attributed to the fact that all the patients were mechanically ventilated which is a known independent risk factor for ICU delirium.[1],[4] In a single-center study, Sánchez-Hurtado et al. demonstrated an incidence of delirium of 22.9%.[18] The low incidence of ICU delirium could be a consequence of infrequent CAM-ICU assessments, as assessments were only completed once daily in this study. With more frequent CAM-ICU assessments and a more specific delirium definition, the present study likely reflected a more accurate rate of delirium in this patient population.

Only one previously published study evaluated risk factors for ICU delirium in hematology-oncology patients. Sánchez-Hurtado et al. observed that duration of MV, older age, and presence of metastases were associated with delirium in univariate analysis; however, MV was the only risk factor that remained significant on multivariate analysis. In the present study, two known risk factors (organ dysfunction based on SOFA score and use of MV) and two novel risk factors unique to the hematology-oncology population (receipt of high-dose steroids, and known brain metastases) were found to be significantly associated with an increased risk of delirium.

Corticosteroids are known to cause psychiatric reactions in patients ranging from mood changes to psychosis. Due to their effects on the hypothalamic–pituitary–adrenal axis, hippocampus, and dopaminergic system, corticosteroids may increase the risk of delirium by hindering attention and memory function.[22] Studies have shown mixed results on the rate of delirium in ICU patients receiving corticosteroids.[23],[24] In both of these studies, the majority of patients received <50 mg of prednisone equivalents daily. The hematology-oncology patient population may require corticosteroid doses >1 mg/kg/day of prednisone equivalents for a number of indications including immunotherapy-mediated toxicities, elevated intracranial pressure and edema secondary to brain metastases, proapoptotic chemotherapy regimen components, or a treatment of critical illness.[25],[26],[27] As the current study identified high-dose corticosteroids as a risk factor for development of early-onset delirium, the critically-ill hematology-oncology population requiring corticosteroid administration will be at high risk for delirium development.

In addition, brain metastases are known to occur in up to 30% of cancer patients, and 45.8% of patients were reported to display cognitive changes with brain metastases in one retrospective review.[26],[28] While the study conducted by Sanchez-Huartado et al. evaluated metastases, in general, as a potential risk factor for delirium, the present study is the first to demonstrate that brain metastases specifically increased the risk of ICU delirium in this patient population.

To our knowledge, this is the largest study to date evaluating delirium in the hematology-oncology ICU population, which allowed for a more robust risk factor analysis than previously published studies. Although this was a single-center, retrospective study, frequent assessment and documentation of CAM-ICU results in the electronic medical record allowed delirium to be accurately captured. Delirium was assessed approximately four times per day per patient which is much more frequent than previously published studies.

Although this study possessed many strengths, there are some limitations that should be considered. As evaluation of delirium was limited to the first 7 days of ICU admission, we were unable to assess if delirium developed prior to ICU admission, or after the 7-day study period in those who did not develop delirium within 7 days. This limits our patient population to specifically early-onset delirium patients. No patients received continuous NMBAs, and few patients CAR-T cell therapy, and therefore, no conclusions regarding the risk of delirium with these factors can be made. The high total daily dose cutoff of 20 mg of lorazepam equivalents resulted in few patients categorized as receiving high-dose benzodiazepines, which may limit an accurate assessment of delirium risk associated with benzodiazepines.[12] All patients who received high-dose benzodiazepines, however, subsequently developed delirium. Finally, severity of delirium is not routinely assessed, and therefore was unable to be collected retrospectively to characterize delirium in this study.

 Conclusion



The incidence of early-onset delirium in critically ill hematology-oncology patients observed was comparable to that shown in a general ICU population, and similarly, early-onset delirium was associated with increased hospital mortality, and increased LOS among survivors. Four independent risk factors for delirium were identified: two that have been previously reported in the general ICU population (MV and severity of illness based on SOFA score) and two that are unique to critically ill hematology-oncology patients (high-dose corticosteroids and brain metastases). Future studies should focus on evaluating strategies to mitigate delirium based on identified risk factors in this unique patient population.

Research quality and ethics section

This study was approved by the Institutional Review Board / Ethics Committee at Ohio State University Wexner Medical Center (Approval # 2019C0192). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the STROBE guideline, during the conduct of this research project.

Acknowledgements

This work was supported by the National Center for Advancing Translational Sciences, Grant UL1TR002733.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

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