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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1223-1231 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9079 Impact of Delirium on Cognition, Distress, and Health-Related Quality of Life After Hematopoietic Stem-Cell Transplantation
From the Departments of Biobehavioral Sciences and Public Health Sciences, Fred Hutchinson Cancer Research Center; Departments of Psychiatry and Behavioral Sciences, Epidemiology, and Health Services Research, University of Washington, Seattle, WA; College of Public Health and Comprehensive Cancer Center, Ohio State University, Columbus, OH; and Arizona Medical Psychology, Scottsdale, AZ Address reprint requests to Jesse R. Fann, MD, MPH, Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington, 1959 NE Pacific St, Seattle, WA 98195-6560; e-mail: fann{at}u.washington.edu
Purpose: To determine the impact of delirium during the acute phase of myeloablative hematopoietic stem-cell transplantation (HSCT) on health-related quality of life (HRQOL), distress, and neurocognitive functioning 30 and 80 days after transplantation. Patients and Methods: Ninety patients completed a battery assessing HRQOL, distress, and neuropsychological functioning before receiving their first HSCT. Delirium was assessed three times per week using the Delirium Rating Scale and the Memorial Delirium Assessment Scale from 7 days before transplantation through 30 days after transplantation. At 30 days after transplantation, distress and neurocognitive functioning were assessed. At 80 days after transplantation, HRQOL, distress, and neuropsychological functioning were re-evaluated. Results: After adjusting for confounding factors, patients who experienced a delirium episode, versus patients who did not, reported significantly worse depression, anxiety, and fatigue symptoms at 30 days (linear regression ßs = 0.2, 0.3, and 0.5, respectively; P < .04). At 80 days, patients with a delirium episode had significantly worse executive functioning (ß = –1.1; P < .02), attention and processing speed (ßs = –4.7 and –5.4, respectively; P < .03), mental health on the Medical Outcomes Study Health Survey, 12-item short form (ß = –6.5; P < .02), and anxiety, fatigue, and cancer and treatment distress symptoms (ßs = 0.4, 0.6, and 0.3, respectively; P < .03). Conclusion: Patients with a malignancy who experience delirium during myeloablative HSCT showed impaired neurocognitive abilities and persistent distress 80 days after transplantation. Effective prevention or treatment of delirium during HSCT may improve both cognitive and psychological outcomes.
Delirium occurs in 25% to 40% of patients with cancer1-3 and 45% to 85% of patients with advanced cancer.4-7 Delirium in patients with cancer has been associated with adverse outcomes, including decreased performance status,8 increased pain and use of breakthrough analgesia,9,10 longer length of hospital stay,11,12 increased distress for the patient and his or her spouse, caregivers, and nurses,13,14 and decreased survival.7,8 However, much of this evaluation has been conducted in samples of patients with advanced disease or in palliative care settings with limited follow-up. Although cognitive impairment,15-18 anxiety, and depression19,20 have been found in studies of delirium in noncancer populations, studies have not focused on these outcomes after delirium during cancer treatment. Delirium may represent a diminished brain reserve capacity impacting several domains of cognitive, affective, and global functioning. The pathophysiology of delirium and its potential cognitive and emotional sequelae are likely multifactorial and include physiologic disruption caused by altered neurotransmission (eg, acetylcholine, dopamine, serotonin, norepinephrine, glutamate, gamma-aminobutyric acid, and melatonin), inflammation, and chronic stress.21-28 The evidence suggests that, although the overt symptoms of delirium may be short lived, there may be a lasting impact of delirium on cognition, distress, and health-related quality of life (HRQOL). However, studies have not evaluated the impact of delirium in patients undergoing high-dose conditioning followed by hematopoietic stem-cell transplantation (HSCT) for malignancy. Patients treated with HSCT have unique pathophysiologic, treatment, psychosocial, and environmental demands that may influence their neuropsychiatric condition. Our previous work has found that 50% of patients receiving myeloablative regimens experience a delirium episode during the 4 weeks after transplantation that is often accompanied by increased distress, fatigue, and pain.29,30 Although the effects of delirium on neurocognitive, psychiatric, or HRQOL outcomes may be more pronounced in this high-risk group, the limited data available have only linked delirium with potentially increased length of hospital stay.31 This prospective study investigated the impact of delirium during the acute phase of HSCT on 30- and 80-day cognitive, distress, and HRQOL outcomes. We were particularly interested in the neurocognitive domain of executive functioning, given our previous finding that pretransplantation executive functioning was associated with incident delirium.29 Consistent with research in general hospitalized samples, we hypothesized that patients who experienced a delirium episode after HSCT would demonstrate decreased cognitive functioning, increased distress, and diminished HRQOL at 30 and 80 days compared with patients who did not experience a delirium episode and that outcomes would be worse for patients with more severe delirium.
Patients Ninety patients, who were ages 22 to 62 years and treated at the Fred Hutchinson Cancer Research Center, were recruited before their first myeloablative allogeneic or autologous marrow or peripheral-blood HSCT from 1997 to 1999. A broad range of cancer diagnoses and conditioning regimens were represented (Table 1).
Procedures Study procedures are detailed in a previous publication from this cohort.29 All procedures were approved by the institutional review board, and study patients signed written informed consent to participate before beginning transplantation conditioning. Before conditioning, patients completed a comprehensive battery assessing HRQOL, distress, and neuropsychological functioning. A subset of assessments was administered at 30 days after transplantation, and the full battery was repeated at 80 days after transplantation. At 7 days before transplantation, during conditioning, and through day 30 after transplantation, trained research nurses or investigators assessed patients with a brief delirium (diagnosis and severity), distress, and pain assessment battery three times per week targeted to the same time each day (Monday, Wednesday, and Friday).29 Patients with delirium were able to provide outcome data, except in the most severe cases.
Independent Variables Memorial Delirium Assessment Scale. The Memorial Delirium Assessment Scale (MDAS)35 is a 10-item clinician-rated scale that assesses delirium severity (score range, 0 to 30) and has been validated in cancer populations.36,37 Delirium severity for each patient was measured as the mean of the patient's peak post-transplantation MDAS score and the score for the assessments before and after the peak MDAS score.
Dependent Variables
Distress
Neurocognitive Testing The Digit Symbol subtest of the Wechsler Adult Intelligence Scale-Revised49 is a highly sensitive measure of visuomotor coordination skill, visual scanning, sustained attention, and response speed. Trailmaking A47 measures visual conceptual and visuomotor tracking. The Hopkins Verbal Learning Test-Revised50 measures immediate (total words recalled over three tries) and delayed (total words recalled after 20 minutes) memory and learning ability. The Modified Memory Questionnaire51 is a 35-item self-report assessment (higher scores = greater memory dysfunction). Verbal fluency was measured by the Controlled Oral Word Association Test (COWAT).52 The Mini-Mental State Examination53 is a brief measure of cognitive impairment extensively used in medical populations; it was administered at baseline and 30 and 80 days.
Potential Confounders
Statistical Analyses We graphed differences between the delirium groups from before transplantation to 30 and 80 and days after transplantation for the three domains that were available at all time points and that were found to be significant. To better visually depict the results, we constructed the 95% CIs around the difference in adjusted means between the delirium groups and centered on the adjusted delirium mean. In this manner, statistical significance is depicted when the confidence bounds do not reach the estimate for the nondelirium group. Analyses were conducted using SPSS version 13.0 (SPSS Inc, Chicago, IL; significance level, P < .05). Graphs were produced using STATA version 8.0 (STATA Corp, College Station, TX).
Patient Characteristics and Attrition Characteristics of the 90 patients are listed in Table 1. As reported previously,29 age was the only demographic variable that distinguished between patients with a delirium episode and patients without a delirium episode (P = .04). At 30 days after transplantation, 80 patients remained in the study. Of the 10 patients missing, five had a delirium episode, four were deceased by 30 days, and six could not participate as a result of severe illness (five of six died shortly after 30 days). By 80 days after transplantation, 59 patients remained in the study. Of the 31 patients missing, 17 had a delirium episode, 10 had been lost by 30 days, three more died between 30 and 80 days, and 18 could not participate as a result of severe illness (10 of 18 died shortly after 80 days). Logistic regression results predicting attrition at 80 days showed that delirium did not influence the likelihood of being missing from study at 80 days (odds ratio = 0.74; P = .5). As reported previously,29,30 50% of the patients experienced a delirium episode during the 4 weeks after transplantation. Mean delirium episode duration was approximately 10 days, and 86% of episode assessments with a psychomotor disturbance were of the hypoactive subtype. The mean peak MDAS delirium severity score after transplantation was 6.6 (standard deviation [SD], 4.0). At 30 days after transplantation, eight patients (10%) had current delirium (DRS scores > 12), and the mean MDAS severity score was 2.2 (SD, 1.5). At 80 days, only one patient (2%) had delirium, and the mean MDAS score was 2.1 (SD, 1.5).
30- and 80-Day Outcomes by Delirium Episode
At 80 days after transplantation, after adjusting for confounding, patients who had experienced a delirium episode reported significantly worse mental health functioning and more severe anxiety, fatigue, and cancer and treatment distress compared with patients who did not experience a delirium episode. Patients who had a delirium episode also demonstrated significantly worse executive/frontal functioning on the Behavioral Dyscontrol Scale (the difference reported on the Neurobehavioral Rating Scale was nearly significant, P = .05) and worse attention and processing speed. Rates of cognitive impairment (T score < 40)55,58 were significantly greater for the delirium group versus the no delirium group in attention and processing speed (Digit Symbol, P = .02; Trailmaking A, P = .04). Analyses testing the relationships between delirium severity on the MDAS and 30- and 80-day outcomes showed nearly identical results to the analyses of delirium episode (ie, the same outcome domains were found to be significantly associated with delirium severity) and are not presented here. Exceptions included no relationship between delirium severity and either 30-day fatigue or the 80-day Mental Component summary of the Medical Outcomes Study Health Survey, 12-item short form and a significant positive relationship between delirium severity and 80-day depression symptoms.
Outcomes Over Time by Delirium Episode
Patients who had experienced a delirium episode during myeloablative HSCT reported significantly more severe depression, anxiety, and fatigue at 30 days and worse mental health functioning, more severe anxiety, fatigue, and cancer and treatment distress, and worse executive/frontal lobe functioning and attention and processing speed at 80 days compared with patients who had not experienced a delirium episode, partially supporting our hypotheses. These effects were not a result of persistent delirium. We also found that delirium rating severity was associated with similar outcomes. Regardless of delirium status, patients showed decreased executive/frontal functioning at 30 days; however, by 80 days, patients who did not experience a delirium episode improved to above pretransplantation levels, whereas those who experienced a delirium episode continued to have decreased executive/frontal neurobehavioral functioning. The decreased executive/frontal functioning, attention, and processing speed in patients who experienced a delirium episode are consistent with prior work in general hospitalized cohorts linking delirium to cognitive impairment after discharge.15,16,18 Executive/frontal functioning, which includes ability to exhibit and control purposeful behavior, elements of motor planning, and go/no-go responses,45 can significantly impact a person's ability to resume fully independent function. Furthermore, impaired attention and processing speed can disrupt sustained attention, multitasking, and the acquisition phase of new learning and adversely affect stamina, thus impacting compliance with post-transplantation self-care and ability to adapt to new challenges. We did not find delirium to be associated with decreased verbal fluency and memory after adjustment for confounders. Anxiety and fatigue increased at 30 and 80 days in the delirium episode group; whereas, they decreased in the no delirium group. Increased distress in patients who experienced a delirium episode is consistent with prior studies in general hospitalized samples that have shown increased anxiety and depressed mood in patients with delirium.19,20 Prior work by Breitbart et al13 also found that delirium itself is later recalled as distressing to patients. However, the recall of delirium alone is unlikely to be responsible for the increased anxiety, fatigue, and cancer and treatment distress in these patients. Contrary to prior work in general hospitalized cohorts that linked delirium to functional decline59,60 or poor functional recovery,61 we did not find delirium to be associated with decreased physical HRQOL. Many other factors contribute to impaired physical function in these patients months and years after transplantation, thus likely overwhelming the influence of delirium episodes.43,62-67 Use of anticholinergic medications may cause cholinergic deficiency, which has been associated with delirium and cognitive impairment. Increased blood levels of cytokines such as interferon alfa, interleukin-2, interleukin-6, and tumor necrosis factor alpha in HSCT patients as a consequence of the malignancy or the treatment may alter neurotransmission and increase permeability of the blood-brain barrier, thus contributing to delirium.28,68-70 Cytokines have also been linked to depression, anxiety, fatigue, cognitive impairment, pain, and insomnia71-75 and, thus, perhaps also play a role in the adverse outcomes found in this study. Chronic stress states, including cancer, have been shown to increase cytokine and cortisol levels, in turn increasing the risk of delirium and depression.28,76,77 There is evidence that the brain can influence other systemic organs during severe illness through its own inflammatory response.78-80 Finally, thalamic dysfunction and hypoxia may play a role in the pathogenesis of delirium in some patients,81-83 particularly in patients with CNS and pulmonary complications, which are problems common in the HSCT setting. Epidemiologic studies have documented long-term cognitive decline in patients with delirium, although the mechanism is not well understood.16 This added influence of delirium may be particularly salient in the HSCT population, where many patients demonstrate mild to moderate cognitive dysfunction and significant distress before transplantation.55,84-87 Executive dysfunction, which has been found to be a risk factor for delirium,29 has also been implicated as a risk factor for depression occurrence and persistence.88-90 Prior studies have documented high levels of distress and cognitive dysfunction in the months after myeloablative HSCT.31,43,55,85,91-95 Our findings suggest that preventing or treating delirium and its underlying etiologies and risk factors,29 such as renal and physical impairment, alcohol abuse, and excessive sedative or opioid use, in this population may be important in minimizing morbidity and maximizing recovery after HSCT. Our findings also underscore the importance of detecting hypoactive delirium, a psychomotor subtype that is often undetected and untreated. Although delirium prevention and randomized treatment studies have not been conducted in cancer patients, studies in other medical settings have found delirium to be potentially preventable96,97 and treatable.98,99 Some of the limitations of the study include the possibility of delirium status misclassification as a result of lack of daily assessments, confounding as a result of treatment effects, and information bias from missed assessments caused by severe medical illness or death.29 We also do not have delirium data between the 30-day and 80-day assessments. Furthermore, responses to distress assessments may have been subject to response shifts, whereby delirium status may influence ability to self-report symptoms. Some of the etiologic factors contributing to delirium, such as medications, anemia, or infection, may also contribute to the presentation of distress and neurocognitive symptoms. Delirium treatment effects would conservatively bias the impact of delirium toward better outcomes. By adjusting for confounding in the linear regression models, we were able to reveal significant group differences that were obscured by confounding in the unadjusted analyses. However, effects of certain patient vulnerability factors (eg, personality traits, decreased physical and emotional reserve, cerebral atherosclerosis) and precipitating factors (eg, long-term effects of anticholinergic medications) that could not be measured and accounted for in the analysis may have been associated with residual confounding in the 30- and 80-day outcome analyses. Our findings add to the growing evidence that delirium, although typically transient, is associated with adverse outcomes. Delirium has been found to be independently associated with higher mortality in cancer patients.7,8 Future research should examine whether delirium is associated with other long-term outcomes such as cognitive impairment, as has been found in noncancer populations, and whether specific patient or medical factors and delirium characteristics are associated with differential outcomes. Economic and societal costs associated with delirium have rarely been studied and should be incorporated into outcome studies. With the increased use of reduced-intensity conditioning regimens, delirium rates may be an important outcome that distinguishes HSCT treatment types. Finally, researchers should examine whether efforts to prevent and treat delirium can positively impact short- and long-term outcomes of HSCT.
The authors indicated no potential conflicts of interest.
Conception and design: Jesse R. Fann, Catherine M. Alfano, Sari Roth-Roemer, Wayne J. Katon, Karen L. Syrjala Financial support: Jesse R. Fann, Karen L. Syrjala Administrative support: Jesse R. Fann, Karen L. Syrjala Provision of study materials or patients: Jesse R. Fann, Karen L. Syrjala Collection and assembly of data: Jesse R. Fann, Sari Roth-Roemer Data analysis and interpretation: Jesse R. Fann, Catherine M. Alfano, Sari Roth-Roemer, Karen L. Syrjala Manuscript writing: Jesse R. Fann, Catherine M. Alfano, Sari Roth-Roemer, Wayne J. Katon, Karen L. Syrjala Final approval of manuscript: Jesse R. Fann, Catherine M. Alfano, Sari Roth-Roemer, Wayne J. Katon, Karen L. Syrjala
We thank Bart Burington, MS, and Ming-Yu Fan, PhD, for statistical assistance, Mary Pepping, PhD, for assistance with interpreting neuropsychological test data, and Kathy Beach, RN, and Wendy Brown, RN, for their invaluable assistance in carrying out the study.
Supported by Grant No. RPG-97-035-01-PBR from the American Cancer Society and by a grant from the University of Washington Royalty Research Fund. Also supported by Grant No. CA92408 from the National Cancer Institute (C.M.A.) and, in part, by Grants No. CA63030, CA78990, and CA112631 from the National Cancer Institute (K.L.S.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
10% to 15%.
