Vol. 26 No. 3 September 2003 Journal of Pain and Symptom Management 827

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1 Vol. 26 No. 3 September 2003 Journal of Pain and Symptom Management 827 Original Article Impaired Communication Capacity and Agitated Delirium in the Final Week of Terminally Ill Cancer Patients: Prevalence and Identification of Research Focus Tatsuya Morita, MD, You Tei, MD, and Satoshi Inoue, MD Seirei Hospice, Seirei Mikatabara Hospital, Hamamatsu, Shizuoka, Japan Abstract The maintenance of intellectual activity is an important area in the good death concept. To clarify the communication capacity levels of terminally ill cancer patients in their final week, and to identify factors contributing to the development of communication capacity impairment and agitated delirium, a retrospective study was performed on 284 consecutive hospice inpatients. The data were collected by chart review, and two independent raters measured the degree of communication capacity and agitation in the last week, using multiple items from the Memorial Delirium Assessment Scale, the Communication Capacity Scale, and the Agitation Distress Scale. The percentages of patients who could achieve complex communication were 43%, 28%, and 13% at 5 days, 3 days, and 1 day before death, respectively. Agitated delirium was identified in 20%. Patients receiving opioids at a dose of 120 mg oral morphine equivalents/day one week before death were significantly unable to communicate clearly 3 days before death (0.48 [ ], P 0.011). Male gender and the presence of icterus were identified as significant contributors to the development of agitated delirium (odds ratios [95% C.I.] 2.6 [ ], P 0.01; 2.4 [ ], P 0.01). These findings demonstrate that communication capacity impairment and agitated delirium are frequently observed in terminally ill cancer patients, and are significantly correlated with a higher dose requirement of opioids and the presence of icterus. To explore the best management to maintain the intellectual activity of dying patients, research should focus on a homogeneous sample of patients receiving high-dose opioids and those with hepatic encephalopathy. In the meanwhile, clinicians should educate patients and family members about the nature of the dying process and help facilitate the completion of life purposes requiring complex mental activities before the latest stages of cancer. J Pain Symptom Manage 2003;26: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Palliative care, delirium, sedation, neoplasm, hepatic encephalopathy, opioid Address reprint requests to: Tatsuya Morita, MD, Seirei Hospice, Seirei Mikatabara Hospital, 3453 Mikatabaracho, Hamamatsu, Shizuoka, , Japan. Accepted for publication: January 14, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Introduction The maintenance of intellectual activity has recently been stressed as an important area in the good death concept. 1 3 A good death /03/$ see front matter doi: /s (03)

2 828 Morita et al. Vol. 26 No. 3 September 2003 survey from United States revealed that 92% of seriously ill patients regarded being mentally aware as important for a good death, while only 65% of physicians regarded it as important. 3 Relief from physical discomfort is undoubtedly a fundamental part of good death, but terminally ill patients have a range of needs beyond symptom alleviation: strengthening relationships with loved ones, achieving a sense of control, completing their life by resolving conflicts, relieving burdens, and contributing to others. 1 3 Maintained mental capacity is a basic requirement for these activities, and it has recently been stressed that the primary goal of end-oflife care should focus on achieving the maximum balance between symptom palliation and psychomimetic complications, rather than complete remission of physical distress. 4 6 Clinically, several observations in palliative care settings revealed that the percentages of alert patients ranged from 25 82% during the final week and the proportion decreased to 10 45% in the last 3 days; 7 9 in another study the percentage of patients who could speak lucidly in the last 3 days was 34%. 10 While these observations focused on global consciousness levels of patients, no studies have specifically investigated patient communication capacity that is a more specific requirement for completing interpersonal activities. Many empirical studies have revealed that agitated delirium is an important complication that impairs the mental capacity of terminally ill cancer patients: 7 29% of all cancer patients receive palliative sedation therapy for agitated delirium, 7 9,11 13 and % of terminal delirium requires the continuous administration of benzodiazepines Identifying which patients were likely to develop communication capacity impairment and agitated delirium is valuable for determining which groups of patients should be the principal focus of research to explore treatment strategies. This is particularly important because the pathophysiology of delirium varies among underlying etiologies and the heterogeneity of target populations limits the clinical applications of research findings. 17,18 To date, several observational studies have investigated the associations between the underlying etiologies of delirium and its symptom severity or reversibility, 15,19 but these study populations were highly selected. No studies have been performed on nonselected patients. The primary aims of this study were 1) to clarify the communication capacity levels of terminally ill cancer patients in their final stage of life using validated measurement instruments, and 2) to identify factors contributing to the development of communication capacity impairment and agitated delirium in nonselected patients. Methods This retrospective study was performed on consecutive terminally ill cancer patients admitted to our palliative care unit during two periods: from June 1996 to October 1997 and January 2000 to March These study periods were determined for another study to identify the factors contributing to midazolam tolerance. 20 Inclusion criteria for this study were: 1) patients who died at the Seirei Hospice after a stay of 7 days or more, 2) the absence of a medical history of schizophrenia and dementia, and 3) the absence of prior communication difficulties, such as aphasia and aphonia. For each patient, patient characteristics (age, gender, primary tumor sites, presence or absence of icterus), medical interventions in the last week, communication capacity, consciousness levels, and the degree of agitation were evaluated by chart review. Two raters from 3 attending physicians and 3 retired palliative care nurses independently completed the evaluations. We investigated the presence or absence of icterus as a potential contributing factor of agitated delirium because a previous study suggested icterus as a significant determinant of severe delirium requiring symptomatic sedation. 15 The presence of icterus was defined as total bilirubin 2.0 mg/dl, ammonia 80mg/dL, or overt icterus recorded. Other metabolic factors (e.g., dehydration and electrolyte imbalance) and organic factors (e.g., brain metastasis) that might influence mental capacity 15,19 were not examined, due to methodological difficulties in reliably diagnosing without laboratory or radiological examinations. We adopted this study design despite an apparent shortcoming of limited numbers of potential etiologies to be examined because we primarily intended to analyze a nonselected population.

3 Vol. 26 No. 3 September 2003 Impaired Communication Capacity and Agitated Delirium 829 The medical interventions investigated were daily hydration volume and daily doses of opioids, steroids, and all sedative medications in the final week. The available sedative drugs in these study periods were haloperidol, mianserin, hydroxyzine, midazolam, flunitrazepam, bromazepam, diazepam, chlorpromazine, levomepromazine, barbiturates, and propofol. We excluded oral benzodiazepines because a large number of patients could not take oral medication in their final week. Psychotropics used as antiemetics were included because patients often received them for multiple indications (e.g., nausea and delirium). Opioid dosage was converted to an oral morphine equivalent (OME) following a standard ratio. 21 Patients receiving no sedative medications were defined as those who received none of the sedative medications listed above. Patients receiving intermittent sedation and patients receiving continuous sedation were defined as those who received any of hydroxyzine, benzodiazepines, chlorpromazine, levomepromazine, barbiturates, or propofol intermittently or continuously on any day during the final week, respectively. 22 The degree of communication capacity impairment was assessed as the best condition each day, using the voluntary communication item (Item 4) from the Communication Capacity Scale. 23 This was originally a 5-item observerrating scale to quantify communication capacity in terminally ill patients with acceptable psychometric properties. 23 For this study, 1 item investigating to what degree patients could achieve voluntary communication was selected (0: clear and complex communication, 1: clear and simple communication, 2: slightly incoherent, and 3: obviously incoherent), because it was difficult to rate all items retrospectively. In addition, patient consciousness levels were evaluated with the Fainsinger consciousness score as the best condition each day, so that we could compare current results with the previous findings; 7 9 it categorizes patient consciousness levels as alert, drowsy, and unresponsive. The degree of agitation was evaluated as the most severe symptoms each day, using 3 grading methods: the psychomotor activity item (Item 9) from the Memorial Delirium Assessment Scale (MDAS) and the extent of motor anxiety and the contents of motor anxiety items (Item 2 and Item 3) from the Agitation Distress Scale. 23,24 The former assesses the psychomotor activities of delirium symptoms as 4 grades (0: normal psychomotor activity, 1: mild, 2: moderate, and 3: severe hyperactivity). 24 The latter was originally a 6-item observer-rating scale to quantify agitation-related distress in delirious terminal patients, and the inter-rater reliability, internal consistency, and concurrent validity were assessed in the validation study. 23 For this study, we selected 2 items that could be retrospectively rated: the extent of motor anxiety (0: no motor anxiety, 1: limited to the patient s extremities, 2: the patient tries to sit up in bed but does not leave the bed, and 3: the patient gets out of bed) and the contents of motor anxiety (0: no motor anxiety, 1: mild, 2: moderate, and 3: severe motor anxiety). Statistical Analyses First, to confirm inter-rater reliability for all the ratings completed, we calculated Cohen s kappa coefficients. The values were for the Communication Capacity Scale item, for Fainsinger s consciousness scale, for the MDAS item, and for the Agitation Distress Scale items. For statistical analyses, impaired communication capacity was defined as present when patients had a Communication Capacity Scale item of 2 or 3, that is, when patients could not achieve clear communication. Agitated delirium was defined as present when patients had scores of 2 or 3 on the psychomotor activity item of the MDAS any day during the final week. To quantify the degree of agitation, an ad hoc agitation score was defined as the maximum value of the total scores of the MDAS item and the Agitation Distress Scale items, because the internal consistency of these 3 items was notably high (Cronbach s alpha coefficient ). The possible range of the agitation score is thus 0 9, and higher scores indicate higher levels of agitation. To identify factors that contribute to the development of impaired communication capacity 3 days before death and agitated delirium, patient characteristics, medical treatments (hydration volume, opioid dose, and use of steroids one week before death) were screened by the Mann-Whitney U-test, the Chi square test, or Fisher s exact methods, where appropriate. To identify the independent determinants of agitated delirium, two multivariate analyses were

4 830 Morita et al. Vol. 26 No. 3 September 2003 conducted: a logistic regression analysis in which the patients who developed agitated delirium were compared with the others, and a linear multiple regression analysis in which the agitation score was continuously used as a dependent variable. In both analyses, all contributing factors revealed by univariate analyses (P 0.10) were entered into the equation in a backward elimination fashion. All analyses were performed using the Statistical Package for the Social Sciences (version 9.0). Results Of 363 patients admitted during these study periods, 79 patients (22%) were excluded based on the exclusion criteria. The characteristics of the 284 patients analyzed are summarized in Table 1. Opioids were administered to 209 patients (morphine to 198 patients and fentanyl to 54 patients), with median dose of 93 mg OME/ day (mean, mg OME/day; maximum, 2000 mg OME/day); 246 (87%) patients received nonsteroidal anti-inflammatory drugs (NSAIDs). In the final week, 107 patients (38%) received intravenous hydration of more than 500 ml/day. Steroids, psychostimulants, and other adjuvant analgesics (antidepressants, anticonvulsants, anti-arrhythmics, or ketamine) Table 1 Patient Characteristics Age n(%) Gender (male) Male 153 (54) Female 131 (46) Primary site Lung 55 (19) Stomach 51 (18) Colon 27 (9.5) Pancreas 22 (7.7) Rectum 18 (6.3) Breast 16 (5.6) Bile duct 12 (4.2) Esophagus 11 (3.9) Liver 11 (3.9) Uterus 10 (3.5) Soft tissue 10 (3.5) Prostate 8 (2.8) Ovary 8 (2.8) Unknown 6 (2.1) Neck 5 (1.8) Blood 4 (1.4) Bladder 4 (1.4) Kidney 3 (1.1) Small intestine 2 (0.7) Skin 1 (0.4) were prescribed for 196 patients (69%), 4 patients (1.4%), 53 patient (19%), respectively. Seven patients received an anesthesiologic procedure. The psychotropics administered were: haloperidol (45%, n 129), midazolam (22%, n 62), hydroxyzine (18%, n 50), rectal diazepam (12%, n 33), flunitrazepam (5.6%, n 16), rectal bromazepam (4.6%, n 13), chlorpromazine (2.5%, n 7), barbiturates (2.1%, n 6), mianserin (1.8%, n 5), propofol (0.7%, n 2), and levomepromazine (0.4%, n 1). Table 2 shows the changes of communication capacity levels during the final week. While more than 70% of all patients achieved clear simple communication 5 days before death, the percentage of the patients who achieved complex communication was 43%. This further decreased to 28% 3 days before death. Even if the patients received no sedative medications, only 46%, 35%, and 15% achieved complex communication 5 days, 3 days, and 1 day before death, respectively. The percentages of alert/drowsy/unresponsive patients were 47/60/0.7%, 25/73/2.1%, and Table 2 Communication Capacity a Levels in the Final Days 5 Days 3 Days 1 Day Before Before Before Death Death Death All patients Complex communication 43% 28% 13% Clear simple communication 30% 20% 24% Slightly incoherent 18% 25% 27% Obviously incoherent 9.5% 17% 36% Patients receiving no sedation medication (n 72) Complex communication 46% 35% 15% Clear simple communication 26% 24% 28% Slightly incoherent 22% 29% 31% Obviously incoherent 5.6% 13% 26% Patients receiving intermittent sedation (n 107) Complex communication 39% 27% 14% Clear simple communication 31% 29% 23% Slightly incoherent 19% 27% 24% Obviously incoherent 11% 17% 38% Patients receiving continuous sedation (n 49) Complex communication 39% 18% 6.1% Clear simple communication 31% 33% 22% Slightly incoherent 18% 24% 24% Obviously incoherent 12% 24% 47% a Measured by the voluntary communication item from the Communication Capacity Scale.

5 Vol. 26 No. 3 September 2003 Impaired Communication Capacity and Agitated Delirium /78/12% 5 days, 3 days, and 1 day before death, respectively. Agitated delirium was identified in 58 patients (20%), and the mean agitation score was (median 0, range 0 9). Patients who received larger dose of opioids a week before death were significantly unable to communicate clearly 3 days before death (Table 3). The odds ratio of 120 mg OME/day or more opioid use for communication capacity impairment 3 days before death was 0.48 with 95% confidence intervals of (P 0.011). On the other hand, male and icteric patients were significantly likely to develop agitated delirium, and the agitation score was significantly higher in younger, male, and icteric patients than their counterparts (Table 3). There were no statistically significant influences of primary tumor sites on patient communication capacity and severity of agitated delirium. Multivariate analyses revealed that male gender and the presence of icterus were independently correlated with the development of agitated delirium and the agitation score (Table 4). Discussion One important finding of this study is clarification of prevalence of impaired communication capacity in the final one week of life. This study revealed that the percentages of patients who could achieve complex communication were 43%, 28%, and 13%, 5 days, 3 days, and 1 day before death, respectively. These results are similar to a previous observation in a Australian hospice that patients who could speak lucidly in the last 3 days were 34%. 10 Of special note is that, even in patients receiving no sedative medications, the patients able to achieve complex communication were 46% 5 days before death and 35% 3 days before death (Table 2). These findings show that, contrary to the general wish for clear intellectual activities in the terminal stage, 1 3 complete preservation of communication capacity is not easy in many patients, although the ability to communicate simple matters is maintained in 70% 5 days before death and 50% 3 days before death, even if receiving some sedative medications. Therefore, it is necessary for clinicians to educate Table 3 Contributing Factors to Impaired Communication Capacity and Agitated Delirium Hyperactive Lack of Clear Delirium b Communication a During the 3 Days Before Death Last Week Agitation (n 118) P (n 58) P Score c P Age 75 (n = 65) 46% (n = 30) % (n 8) (n 219) 40% (n 88) 23% (n 50) Gender Male (n 153) 42% (n 64) % (n 42) Female (n 131) 41% (n 54) 12% (n 16) Icterus Absence (n 194) 43% (n 84) % (n 30) Presence (n 90) 38% (n 34) 31% (n 28) Opioid dose 1 week before death 120 mgome/day (n 65) 55% (n 36) % (n 16) mgome/day (n 219) 37% (n 82) 19% (n 42) Hydration volume 1 week before death 500 ml/day (n 107) 42% (n 45) % (n 26) mL/day (n 177) 41% (n 73) 18% (n 32) Steroid use 1 week before death Presence (n 196) 43% (n 84) % (n 41) Absence (n 88) 39% (n 34) 19% (n 17) OME: oral morphine equivalent. a Defined as clear and complex communication or clear and simple communication on the voluntary communication item from the Communication Capacity Scale 3 days before death. b Defined as psychomotor activity item score 2 on the MDAS on any day during the last week. c Defined as the maximum value of the total scores of the psychomotor activity item from the MDAS and 2 items from the Agitation Distress Scale during the last week; possible range 0 9; higher scores indicate higher levels of agitation.

6 832 Morita et al. Vol. 26 No. 3 September 2003 Table 4 Independent Determinants of Agitated Delirium (Multivariate Analyses) Hyperactive Delirium During the Agitation Last Week a P Score b P Gender 2.6 [ ] (male) Icterus 2.4 [ ] a Data are shown as odds ratios and 95% confidence intervals. Agitated delirium was defined as a psychomotor activity item score 2 on the MDAS on any day during the last week. b Data are shown as regression coefficients S.E.. F 9.56, R- square 6.4%. Agitation score was defined as the maximum value of the total scores of the psychomotor activity item from the MDAS and 2 items from the Agitation Distress Scale during the last week. Age ( 75 or not), gender, and presence/absence of icterus were entered into the models. the natural course of the dying process to patients and family members and to facilitate the completion of life purposes requiring complex mental activities before the latest stageof cancer. The second important finding is identification of factors contributing to communication capacity impairment and agitated delirium. High-dose opioid requirement was identified as a significant determinant of impaired communication capacity in this population. The medical strategies proposed to minimize opioid-induced cognitive dysfunction include psychostimulants, opioid rotation, hydration to increase metabolite clearance, and the use of nonopioid treatments (adjuvant medications and neurosurgical procedures). 25 We considered these strategies as treatment options for this study population as our usual clinical practice, but statistical analyses identified that high-dose opioids remained a significant stimulator of communication impairment. The possible interpretations of these results are 1) the adjuvant analgesics we used might have minimum benefits on the maintenance of communication capacity due to their psychomimetic effects, 2) as morphine and fentanyl were the only strong opioids available in Japan, we could not perform more aggressive opioid rotation, 3) as the psychostimulants were available only by oral medications, alargenumberofpatientscouldnottakethem in the final week, and 4) our efforts to initiate neurosurgical procedures might leave room for improvement. However, we believe that our medical treatments for opioid-induced cognitive dysfunction were appropriately performed following standard practice, because consciousness disturbance measured by Fainsinger s consciousness scale was no more frequent in our patients than in other palliative care units (alert patients, 40% vs %, 25% vs %, and 9.9% vs %, 5 days, 3 days, and 1 day before death, respectively), 7 9 and because our prescriptions of adjuvant analgesics are generally within the reported ranges. 26 We therefore stress the need to explore more effective strategies to maintain the communication capacity of terminally ill cancer patients requiring high-dose opioids for symptom control. Future research should focus on medical strategies that achieve both symptom control and the maintenance of intellectual activity, such as highly selective opioid agonists and/or adjuvant analgesics with minimum psychomimetic effects, and less invasive neurosurgical procedures such as intrathecal opioids using an implantable drug delivery system. 27 Agitated delirium was observed in 20% of our patients, and was significantly associated with the presence of icterus and male gender. These results correspond to previous studies that identified icterus as a significant determinant of developing severe delirium requiring symptomatic sedation, 15 and male gender as a predictor of delirium in hospitalized elderly patients. 28, 29 Hepatic encephalopathy is a common complication in advanced liver diseases, and nutritional management and reduction in the nitrogenous load arising from the gut through bowel cleansing, non-absorbable disaccharides, and antibiotics is effective in a large number of nonterminal patients. 30 However, refractory hepatic encephalopathy still remains a difficult and challenging problem, and the existing literature suggests that several medications that directly affect neurotransmission, such as bromocriptine and the benzodiazepine antagonist flumazenil, might be beneficial for selected patients. 31,32 In addition, because phenylalanine elevation and increased serotonin activity are suggested as being in part responsible for hepatic encephalopathy, 17,18 the newer neuroleptic agents, risperidone and olanzapine, could be pathophysiologically more reasonable medications for hepatic encephalopathy than haloperidol. 33,34 To date, nonetheless, no systematic studies have been performed to address the potential benefits of these specific treatments for hepatic encephalopathy for

7 Vol. 26 No. 3 September 2003 Impaired Communication Capacity and Agitated Delirium 833 symptom alleviation in terminally ill cancer patients. As pathophysiology in delirium is assumed to be different according to each underlying etiology, 17,18 the target population of future research should be a homogeneous sample of delirious patients with hepatic failure. This study has several limitations. First, the inter-rater reliability was acceptable but relatively low, and the retrospective nature of this study can decrease the reliability of data collected. Second, this study could not investigate all the variables in the development of cognitive dysfunction, due to our intentions to analyze a nonselected population. In particular, we could not assess dehydration, which commonly occurs in the terminal phase, due to the difficulty in reliably diagnosing this condition without laboratory examinations. Third, due to the lack of direct assessment of patient distress, we cannot conclude whether impaired communication capacity actually contributed to patient discomfort or not. Fourth, we cannot differentiate the effects of opioids and those of underlying diseases on patient communication capacity due to complex etiologic nature in the terminal periods. Finally, as we did not exclude depressed patients, cognitive impairment from depression might confound the results. In conclusion, impaired communication capacity and agitated delirium is frequently observed in terminally ill cancer patients. Impaired communication capacity is significantly associated with a higher dose requirement of opioids, and agitated delirium is significantly correlated with the presence of icterus and male gender. Future research to explore better strategies to maintain intellectual activity should focus on a homogeneous sample of patients receiving high-dose opioids and those with hepatic encephalopathy. In the meanwhile, clinicians should discuss the natural course of the dying process with patients and family members, and facilitate the completion of life purposes requiring complex mental activities before the latest stage of cancer. Acknowledgments The authors would like to acknowledge Masae Fujita, RN, Izumi Sato, RN, Yuki Morishita, RN, for their assistance in data collection. References 1. Singer PA, Martin DK, Kelner M. Quality endof-life care. Patients perspectives. JAMA 1999;281: Steinhauser KE, Clipp EC, McNeilly M, et al. In search of a good death: observations of patients, families, and providers. Ann Intern Med 2000;132: Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA 2000;284: Daeninck PJ, Bruera E. Opioid use in cancer pain. Is a more liberal approach enhancing toxicity? Acta Anaesthesiol Scand 1999;43: Sjøgren P. Psychomotor and cognitive functioning in cancer patients. Acta Anaesthesiol Scand 1997; 41: Weiss SC, Emanuel LL, Fairclough DL, et al. Understanding the experience of pain in terminally ill patients. Lancet 2001;357: Fainsinger R, Miller MJ, Bruera E, et al. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991;7(1): Fainsinger R, Landman W, Hoskings M, et al. Sedation for uncontrolled symptoms in a South African hospice. J Pain Symptom Manage 1998;16: Fainsinger RL, Waller A, Bercovici M, et al. A multicentre international study of sedation for uncontrolled symptoms in terminally ill patients. Palliat Med 2000;14: Turner K, Chye R, Aggarwal G, et al. Dignity in dying: a preliminary study of patients in the last three days of life. J Palliat Care 1996;12(2): Morita T, Inoue S, Chihara S. Sedation for symptom control in Japan: the importance of intermittent use and communication with family members. J Pain Symptom Manage 1996;12: Stone P, Phillips C, Spruyt O, et al. A comparison of the use of sedatives in a hospital support team and in a hospice. Palliat Med 1997;11: Ventafridda V, Ripamonti C, De Connno F, et al. Symptom prevalence and control during cancer patients last days of life. J Palliat Care 1990;6(3): Fainsinger R, de Moissac D, Mancini I, et al. Sedation for delirium and other symptoms in terminally ill patients in Edmonton. J Palliat Care 2000;16(2): Morita T, Tei Y, Tsunoda J, et al. Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 2001;22: Stiefel F, Fainsinger R, Bruera E. Acute confusional states in patients with advanced cancer. J Pain Symptom Manage 1992;7:94 98.

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