Drug therapy for delirium in terminally ill adult patients (Review)

Jackson KC, Lipman AG

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 4 http://www.thecochranelibrary.com

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . PLAIN LANGUAGE SUMMARY . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . RESULTS . . . . . . . . . . DISCUSSION . . . . . . . . AUTHORS CONCLUSIONS . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . CHARACTERISTICS OF STUDIES DATA AND ANALYSES . . . . . APPENDICES . . . . . . . . WHATS NEW . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 4 7 7 8 8 9 13 13 13 13 14 14 14 14

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review]

Drug therapy for delirium in terminally ill adult patients

Kenneth C Jackson1 , Arthur G Lipman2
1 School of Pharmacy, Pacic University, Hillsboro, OR, USA. 2 Department of Pharmacotherapy and Pain Management Center, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Contact address: Kenneth C Jackson, School of Pharmacy, Pacic University, 222 SE 8the Avenue, Suite 451, Hillsboro, OR, 97123, USA. kenneth.jackson@pacicu.edu. (Editorial group: Cochrane Pain, Palliative and Supportive Care Group.) Cochrane Database of Systematic Reviews, Issue 4, 2009 (Status in this issue: Edited) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: 10.1002/14651858.CD004770 This version rst published online: 19 April 2004 in Issue 2, 2004. Re-published online with edits: 7 October 2009 in Issue 4, 2009. Last assessed as up-to-date: 17 February 2004. (Help document - Dates and Statuses explained) This record should be cited as: Jackson KC, Lipman AG. Drug therapy for delirium in terminally ill adult patients. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD004770. DOI: 10.1002/14651858.CD004770.

ABSTRACT Background Delirium is a common disorder that often complicates treatment in patients with life-limiting disease. Delirium is described using a variety of terms such as agitation, acute confusional states, encephalopathy, organic mental disorders, and terminal restlessness. Delirium may arise from any number of causes, and treatment should be directed at addressing these causes. In cases where this is not possible, or does not prove successful, the use of drug therapy may become necessary. Objectives The primary objective of this review was to identify and evaluate studies examining medications used to treat patients suffering from delirium during the terminal phases of disease. Search strategy We searched the following sources: MEDLINE (1966 to July 2003) , EMBASE 1980 to July 2003), CINAHL (1982 to July 2003), PSYCH LIT (1974 to July 2003), PSYCHINFO (1990 to July 2003) and The Cochrane Library Issue 2, 2003) for literature pertaining to this topic. Selection criteria Prospective trials with or without randomization and/or blinding involving the use of pharmacological agents for the treatment of delirium at the end of life were considered. Data collection and analysis Two review authors independently assessed trial quality using standardized methods and extracted data for evaluation. Outcomes related to both efcacy and adverse effects were collected. Main results Thirteen potential studies were identied by the search strategy. Of these, only one study met the criteria for inclusion in this review. This study evaluated 30 hospitalized AIDS patients receiving one of three different agents: chlorpromazine, haloperidol, and lorazepam. Analysis of this trial found chlorpromazine and haloperidol to be equally effective. Chlorpromazine was noted to slightly worsen cognitive function over time but this result was not signicant. The lorazepam arm of the study was stopped early as a consequence of excessive sedation.
Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1

Authors conclusions The data from one study of 30 participants would perhaps suggest that haloperidol is the most suitable drug therapy for the treatment of patients with delirium near the end of life. Chlorpromazine may be an acceptable alternative if a small risk of slight cognitive impairment is not a concern. However, there is insufcient evidence to draw any conclusions about the role of pharmacotherapy in terminally ill patients with delirium, and further research is essential.

PLAIN LANGUAGE SUMMARY Drug therapy for delirium in terminally ill adult patients There is limited evidence from clinical trials on the role of drug therapy for the treatment of delirium in terminally ill patients. Delirium occurs frequently in patients with terminal illness, and may be caused by the illness itself or as a side effect of drug treatments for symptom management at the end of life. A search of the international literature for randomized controlled trials of drug therapies for the treatment of delirium in patients with terminal illness yielded only one small study, and it was therefore not possible to assess the effectiveness of treatment options. It is hoped that this review will provide an incentive for further research.

BACKGROUND
Delirium has been dened as, an aetiologically non-specic, global, cerebral dysfunction characterised by concurrent disturbances of level of consciousness, attention, thinking, perception, memory, psychomotor behaviour, emotion, and the sleep-wake cycle (Breitbart 1998). Disorientation, uctuation of the symptoms, and acute or abrupt onset of such disturbances are other features of delirium. Various terms are used to describe delirium in the palliative care setting, including agitation; acute confusional state; encephalopathy; organic mental disorder; and terminal restlessness. Delirium is common in patients with advanced cancer. In one study of terminally ill cancer patients, Massie 1987 reported that more than 75 per cent were suffering from delirium. Treatment is possible in patients with advanced illness, but delirium may not be reversible in the last 24 to 48 hours of life. (This is most likely due to the fact that irreversible processes such as multiple organ failure are occurring at this stage). Delirium occurring in the last days of life is frequently referred to as terminal restlessness or terminal agitation. Because delirium presents as impaired memory, impaired thinking and judgement, and disorientation, the condition is often confused with dementia. However, delirium differs from dementia in that delirium is more acute in presentation, often with a uctuating course, and may be reversed with treatment. It can therefore prove difcult to diagnose and manage either condition, particularly because delirium and dementia are not mutually exclusive: patients with dementia may also be predisposed to delirium. Attention to the underlying cause provides the best treatment approach for most patients but unfortunately this can be difcult to identify for clinicians unfamiliar with delirium. Delirium may arise from one or more factors including metabolic encephalopathy; electrolyte abnormalities; infection; haematological abnormalities; nutritional decits; paraneoplastic syndromes; brain tumors; central nervous system metastases; seizure disorders; hypoxia; and environmental factors. In addition, numerous drugs are known to give rise to delirium in the terminally ill. For example, opioids, anticholinergic agents, corticosteroids and antineoplastic agents can cause delirium, and combinations of agents can contribute to the confusion seen in these patients (Jackson 1999). Treatment of delirium may be limited because, even when the root cause is found, it may not be reversible (eg, brain metastases). In addition, the patients setting (for example if they are living at home) may preclude treatment: given that the patients comfort should be the priority, unpleasant or painful diagnostic procedures should be avoided if at all possible. Managing the root cause of the problem is therefore complex in this patient group and, if treatment is advocated because the symptoms are distressing to the patient or family, a pharmacological intervention to treat the delirium itself may be required. Medications useful for the management of delirium include neuroleptics (eg, haloperidol, thioridazine, chlorpromazine, and methotrimeprazine) and benzodiazepines (eg, lorazepam, and midazolam). Haloperidol is most often cited as the drug of choice for the treatment of delirium (Breitbart 2000; Ingham 1998; Roth 1996), but patients in their last days of life may be candidates for more intensive pharmacotherapy for this condition (de Stoutz 1995). The vast majority of literature pertaining to the treatment of delirium in terminal illness is provided in case reports and case series.
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Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A number of review articles has been published but to date no systematic review of the evidence has been undertaken (Bluestine 1994; Breitbart 1996b; Breitbart 2000; Caraceni 1995; de Stoutz 1995; Fainsinger 1993; Stiefel 1994).

in the terminally ill. Smith and colleagues published a valuable review describing those methods that have value in the trials associated with pharmacological treatments (Smith 1995). These instruments include the: Memorial Delirium Assessment Scale (MDAS). Delirium Rating Scale (DRS). Delirium Scale (D-Scale). Saskatoon Delirium Checklist (SDC). Delirium Symptom Interview (DSI). Extrapyramidal Symptom Rating Scale.

OBJECTIVES
The primary objective of this review is to identify and evaluate clinical studies examining pharmacotherapeutic modalities in the treatment of patients suffering from delirium during the terminal phases of disease.

METHODS

In addition, cognitive function assessments such as the Mini-Mental-Status Examination (MMSE) or Mini-Mental State Questionnaire (MMSQ) may be of value in evaluating clinical efcacy related to pharmacotherapy for delirium.

Criteria for considering studies for this review

Types of studies Prospective controlled trials and randomized controlled trials comparing any pharmacotherapeutic treatment for delirium with other treatments in patients with terminal disease. Trials could be conducted in any setting. Types of participants Terminally ill adult patients (18 years or older) who are diagnosed with delirium. Delirium may have been described by a variety of terms including agitation, confusional states, encephalopathy, organic mental disorders, and terminal restlessness. In all cases, the reviewers sought to verify that the disorder being treated qualied as a form of delirium as dened by the Diagnostic and Statistical Manual of Mental Disorders (APA 1995). Because the denition for terminal illness is often difcult to ascertain, studies for evaluation included subjects with life-limiting disease (e.g. advanced cancer, AIDS); who were receiving hospice or palliative care; or had end-stage disease. Types of interventions Studies were included if they compared any pharmacotherapy for the treatment of delirium with another pharmacological agent or non pharmacological approach. Specic known pharmacological agents include: benzodiazepines, chlorpromazine, haloperidol, methotrimeprazine, midazolam, olanzapine, propofol, risperidone and thioridazine. In addition, other agents identied during the search for eligible studies would have been considered. Types of outcome measures A variety of instruments are available in the evaluation of delirium in general populations, but none has been specically validated

Search methods for identication of studies

Electronic searches To identify studies for inclusion in this review, detailed search strategies were developed for each electronic database searched. These were based on the search strategy developed for MEDLINE but revised appropriately for each database. Please see Appendix 1 for the MEDLINE search strategy. The search strategy combined the subject search with phases 1 and 2 of the Cochrane Sensitive Search Strategy for RCTs (as published in Appendix 5c in the Cochrane Handbook) (Cochrane 2003).
Databases to be searched:

1. The Cochrane Pain, Palliative & Supportive Care Trials Register (July 2003) 2. The Cochrane Central Register of Controlled Trials (CENTRAL), in The Cochrane Library (Issue 1, 2003) 3. MEDLINE (1966 to July 2003) 4. EMBASE (1980 to July 2003) 5. CINAHL (1982 to July 2003) 6. PSYCHLIT (1974 to July 2003) 7. PSYCHINFO (1990 to July 2003) Searching other resources

Reference lists

The reference lists of review articles and studies included in this review were searched for additional studies and references.
Unpublished data

Unpublished studies were not sought.

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Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Language

The search strategy attempted to identify all relevant studies regardless of language of publication.

Was there a description of withdrawals and dropouts sufcient to determine the number of patients in each treatment group entering and completing the trial? (1 = yes; 0 = no). This scale allocates a score of between 0 and 5 (maximum). Higher scores indicate higher quality in the conduct and/or reporting of the trial. Inter-rater reliability of the quality assessments would have been calculated (using the Kappa coefcient) but unfortunately only one study met the inclusion criteria. Anaylsis It was planned to analyse continuous data to provide estimates of treatment effect (Weighted Mean Difference (WMD) with a xed effect model), using RevMan Analyses in RevMan 4.2.

Data collection and analysis

Study selection Titles and abstracts were screened by one review author (KCJ) to determine appropriateness for further evaluation. Full text copies of potentially relevant studies and review articles were assessed for inclusion in the review, and their bibliographies screened for other, potentially relevant studies. Studies previously evaluated in a prior literature review were re-evaluated (Jackson 1999). Any disagreements pertaining to study inclusion were resolved by discussion between the two review authors (KCJ and AGL). After a study was deemed appropriate for inclusion, the review authors assigned a grade for its methodological quality (see below). Study authors were contacted for any clarication required to determine study viability. A data extraction form was designed, and the following data items were collected independently by the two review authors (KCJ and AGL): 1. Publication details 2. Patient characteristics (number of patients included in the trial, age, gender, performance status, etc) and study setting (e.g. hospice) 3. Trial methodology 4. Description of pharmacological intervention 5. Description of instrument used to evaluate delirium 6. Results 7. Quality 8. Study withdrawals/patient attrition 9. Adverse effects Quality assessment The methodological quality of each study selected for inclusion in the review was assessed independently by two review authors (KCJ and AGL) using the Oxford Scale (Jadad 1996). This scale assesses randomization, blinding and study withdrawals, as follows: Was the study described as randomized? (1 = yes; 0 = no) Was the method of randomization well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate) Was the study described as double-blind? (1 = yes; 0 = no) Was the method of double-blinding well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate)

RESULTS

Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. Thirteen potential studies were identied by the search strategy. Of these, only one met the criteria for inclusion in this review ( Breitbart 1996a). The reasons for excluding the other 12 studies (Adams 1984; Adams 1986; Akechi 1996; Breitbart 2002; Burke 1991; Cobb 2000; Fainsinger 2000; Lawlor 2000; McIver 1994; Oliver 1985; Olofsson 1996; Pereira 1997; Stiefel 1992) are described in the Characteristics of excluded studies table. The included study (Breitbart 1996a) was a double blind, threedrug analysis of the effectiveness of chlorpromazine, haloperidol, and lorazepam in 30 hospitalized AIDS patients. The 30 patients evaluated in this study met DSM-III-R criteria for delirium, and scored 13 or greater on the Delirium Rating Scale (DRS). Of those patients with delirium, 23 were male and 7 female. The mean age was 39.2 years (SD 8.8, range 23 to 56 years). The mean Karnofsky Performance Score at baseline was 52.3 (SD 21.3, range 10 to 90). The Medical Status Prole showed patients to have an average of 12 medical conditions (SD 4.1, range 6 to 22). Data collection occurred over a 28-month period. A total of 244 participants were initially identied and invited to participate in the trial. In all cases patients were able to provide informed consent. Patients were subsequently followed for the onset of delirium. When delirium occurred, patients were randomized to one of the three drug treatments in a double-blind fashion. Once enrolled, patients received drug doses based on an approved drugdosing protocol. Using the protocol, patients received a study drug and were re-evaluated at the end of each hour. If the Delirium Rating Scale (DRS) score was 13 or greater, then the patient was
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given the drug dose at the next level. Once stabilization occurred, patients were given a maintenance dose on day two, and continued on the treatment for up to six days via the protocol. Stabilization was dened as asleep, calm, not hallucinating, or a score of 12 or less on the DRS. Maintenance doses were given such that half of the rst 24-hour dose requirement was given twice daily. Patient deaths: Five patients died within eight days of protocol initiation (two on chlorpromazine, two on haloperidol, and one on lorazepam), and four more died within seven days of completing the protocol (three on chlorpromazine and one on lorazepam). Seventeen patients lived beyond two weeks following protocol initiation (mean 183 days, range 19 days to 1305 days). An additional four patients were known to have lived a minimum of two to seven months but were lost to follow up. The dosing protocol is given in Table 1. Table 1. Dosing protocol Dose Level 1 2 3 4 5 6 7 8 9 Haloperidol 0.25 mg oral or 0.125 mg IM 0.5 mg oral or 0.5 mg IM 1.0 mg oral or 0.5 mg IM 2.0 mg oral or 1.0 mg IM 2.5 mg oral or 1.5 mg IM 2.5 mg oral or 1.5 mg IM 2.5 mg oral or 1.5 mg IM 5.0 mg oral or 3.0 mg IM 5.0 mg oral or 3.0 mg IM Chlorpromazine 10 mg oral or 5 mg IM 20 mg oral or 10 mg IM 40 mg oral or 20 mg IM 80 mg oral or 40 mg IM 100 mg oral or 50 mg IM 100 mg oral or 50 mg IM 100 mg oral or 50 mg IM 200 mg oral or 100 mg IM 200 mg oral or 100 mg IM Lorazepam 0.5 mg oral or 0.2 mg IM 1.0 mg oral or 0.5 mg IM 1.5 mg oral or 0.7 mg IM 2.0 mg oral or 1.0 mg IM 2.5 mg oral or 1.25 mg IM 2.5 mg oral or 1.25 mg IM 2.5 mg oral or 1.25 mg IM 4.0 mg oral or 2.0 mg IM 4.0 mg oral or 2.0 mg IM

Risk of bias in included studies

The one study that met inclusion criteria (Breitbart 1996a) received a score of ve on the Oxford quality scale, which is the highest value achievable.

fects. In this three drug study (chlorpromazine n = 13; haloperidol n = 11; lorazepam n = 6), a dose level protocol was utilized as described in Table 1. Mean drug doses during the rst 24 hours were as follows: haloperidol 2.8 mg (SD 2.4, range 0.8 to 6.3). chlorpromazine 50 mg (SD 23.1, range 10 to 70). lorazepam 3 mg (SD 3.6, range 0.5 to 10). Average maintenance doses were: haloperidol 1.4 mg (SD 1.2, range 0.4 to 3.6). chlorpromazine 36 mg (SD 18.4, range 10 to 80).
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Effects of interventions
In the one evaluable study by Breitbart 1996a, the analyses indicated that both chlorpromazine and haloperidol were of benet in the treatment of delirium in hospitalized AIDS patients. The lorazepam arm of this study was stopped early due to adverse ef-

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

 lorazepam 4.6 mg (SD 4.7, range 1.3 to 7.9). Maintenance doses were given beginning on day two for up to six days in total. Patients were given the maintenance doses on a twice daily basis. No information was provided on the average length of therapy, nor was information provided as to the criteria used for discontinuing pharmacotherapy. Efcacy as measured by the Delirium Rating Scale (DRS) was noted with both chlorpromazine and haloperidol. In both cases, scores on the DRS improved for chlorpromazine and haloperidol during the rst 24 hours of treatment. Further improvements were not seen past this time frame (see Table 2). Table 2. Delirium rating scale (DRS) scores DRS scores All (n=30 patients) Chlorpromazine (n=13) Haloperidol (n=11) Lorazepam (n=6) Baseline 20.1 (SD 3.5, range 14 to 28) 20.62 (SD 3.88) 20.45 (SD 3.45) 18.33 (SD 2.58) Day 2 13.3 (SD 6.1, range 3 to 26) 12.08 (SD 6.5) 12.45 (SD 5.87) 17.33 (SD 4.18) End of therapy 12.8 (SD 6.4, range 3 to 26) 11.85 (SD 6.74) 11.64 (SD 6.1) 17.0 (SD 4.98)

Cognitive status Cognitive status, measured using the Mini-Mental State Examination, improved for chlorpromazine and haloperidol during the rst day of treatment. However, only the statistic for chlorpromazine reached statistical signicance. Patients receiving lorazepam showed an increase in cognitive impairment. In the chlorpromazine arm, patients were noted to have a signicant decrease in cognitive function from day two to the end of treatment. This is not surprising given the anticholinergic properties of this agent. See Table 3 for MMSE scores. Table 3. Mini-Mental-State-Examination (MMSE) scores

MMSE scores Chlorpromazine patients)

Baseline (n=13 10.92 (SD 8.87)

Day 2 18.31 (SD 10.61)

End of therapy 15.08 (SD 10.43)

Haloperidol (n=11 patients)

13.45 (SD 6.95)

17.27 (SD 8.87)

17.18 (SD 12.12)

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Table 3. Mini-Mental-State-Examination (MMSE) scores

(Continued)

Lorazepam (n=6 patients

15.17 (SD 5.31)

12.67 (SD 10.23)

11.5 (SD 8.69)

Adverse effects Extrapyramidal effects are often a limitation with a variety of agents used in the treatment of delirium. In this analysis none of the agents produced overt extrapyramidal side effects, namely dystonic or dyskinetic symptoms. A non-signicant increase was noted in extrapyramidal side effects only in the Parkinsonism sub scale of the Extrapyramidal Symptom Rating Scale and was attributed to the side effects seen in the lorazepam arm. The authors of this study (Breitbart 1996a) suggest that these data are difcult to analyze given the small numbers (six patients) in the lorazepam arm. See Table 4 for Extrapyramidal Symptom Rating Scale scores. Table 4. Extrapyramidal Symptom Rating Scale scores ESRS score Chlorpromazine (n=13 patients) Haloperidol (n=11 patients) Lorazepam (n=6 patients) Baseline 7.42 (SD 8.08) 7.0 (SD 6.8) 7.6 (SD 10.11) End of therapy 5.08 (SD 4.48) 5.54 (SD 6.76) 12.2 (SD 8.93) Breitbart 1996a). The third arm using lorazepam as a single entity was stopped early due to adverse effects, including increased confusion. The authors do not specically state that these patients maintained a particular subtype, but it seems rational to consider that the reason for lorazepams poor outcome might be explained by administration to hypoactive delirium or mixed presentation subjects. Both chlorpromazine and haloperidol appeared to yield positive outcomes with respect to symptoms measured by the Delirium Rating Scale (DRS). However, over time chlorpromazine produced a decrease in cognitive function as measured by the MMSE. This is not unexpected, given chlorpromazines pharmacology, e.g. anticholinergic pharmacology.

DISCUSSION
The American College of Critical Care Medicine has stated that haloperidol should be considered the preferred agent for treating critically ill adults with delirium (Shapiro 1995). While this statement may not seem congruent with palliative care, it should be noted that there are similarities between the two populations. As such this statement may prove advantageous in palliative care. Haloperidol is considered the pharmacotherapy of choice in the treatment of delirium near the end of life by a number of reviews and case reports (Bluestine 1994; Breitbart 1996b; Breitbart 2000; Caraceni 1995; de Stoutz 1995; Fainsinger 1992; Fainsinger 1993; Massie 1987; Roth 1996; Stiefel 1992; Stiefel 1994). It is important to consider the issue of disease presentation in relation to medication selection, i.e. hyperactive, hypoactive, or uctuating. Unfortunately, few prospective clinical trial data are available to guide clinicians. Breitbart and colleagues reported in their prospective, randomized, double blind trial that both haloperidol and chlorpromazine improved delirium symptoms in 30 hospitalized AIDS patients, as measured by the Delirium Rating Scale (

AUTHORS CONCLUSIONS Implications for practice

The evidence for using pharmacotherapy in the palliative care population is scarce. Selection of chlorpromazine versus haloperidol for the treatment of delirium in terminally ill patients is primarily based on anecdote. The one controlled clinical trial evaluated in this review shows these medications to be equally efcacious, however this
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Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

trial had a sample size of only 30 patients (Breitbart 1996a). In this trial, it was noted that chlorpromazine did lead to slight cognitive impairment over time as measured by the MMSE. The signicance of this modest impairment is debatable, considering the small change and small population. In addition, it should be noted that this study was conducted in an AIDS population. To date no randomized, placebo-controlled trials have been conducted in patients with advanced cancer or other terminal disease states. In general, factors to be considered when selecting therapy include the subtype of delirium, route of administration, and side effect prole. Haloperidol appears to have many advantages with regard to these factors. Haloperidol is viable for patients with hyperactive, hypoactive, or uctuating delirium and is available for both enteral and parenteral administration. Side effects are common with all the medications considered in the treatment of delirium, and medication selection should be predicated on patient-specic characteristics, such that toxicity can be minimized. The severity of symptoms and the patients life expectancy (days versus weeks versus months) will inuence therapy. Studies of atypical antipsychotics medications, such as olanzapine or risperidone, may provide further insights into the management of delirium in palliative care (Passik 1999).

cluding nursing interventions, and pharmacotherapy be more effective than either therapy alone for the treatment of delirium in palliative care Would assessment of delirium subtype impact on the outcomes associated with pharmacotherapeutic selections Would higher doses or combination regimens be more effective than those studied? How do other concurrent psychiatric disorders impact on delirium in palliative care, i.e. would subset analyses reveal additional data? Do organic or functional causes of delirium impact on the relative efcacy of commonly used agents or other interventions? What is the role of sedation in the management of delirium? Is there a role for atypical antipsychotics (e.g. olanzapine, risperidone) for managing delirium in palliative care?

Implications for research

The paucity of controlled trials regarding the management of delirium in terminally ill patients presents many important research questions. These include the following: Would concurrent cognitive-behavioural therapy, in-

ACKNOWLEDGEMENTS
The review authors acknowledge and thank Phil Wiffen and Yvonne Roy of the Cochrane Pain, Palliative and Supportive Care Review Group, for their assistance in the preparation of this review.

REFERENCES

References to studies included in this review

Breitbart 1996a {published data only} Breitbart W, Rocco M, Platt M, Weissman H, Derevenco M, Grau C, et al.A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. American Journal of Psychiatry 1996;153(2):2317.

Akechi 1996 {published data only} Akechi T, Uchitomi Y, Okamura H, Fukue M, Kagaya A, Nishida A, et al.Usage of haloperidol for delirium in cancer patients. Supportive Care in Cancer Cancer 1996;4:3902. Breitbart 2002 {published data only} Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 2002;43(3):17582. Burke 1991 {published data only} Burke AL, Diamond PL, Hulbert J, Yeatman J, Farr EA. Terminal restlessness - its management and the role of midazolam. The Medical Journal of Australia 1991;155:4857. Cobb 2000 {published data only} Cobb JL, Glantz MJ, Nicholas PK, Martin EW, Paul-Simon A, Cole BF, et al.Delirium in patients with cancer at the end of life. Cancer Practice 2000;8(4):1727. Fainsinger 2000 {published data only} Fainsinger RL, De Moissac D, Mancini I, Oneschuk D. Sedation for
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References to studies excluded from this review

Adams 1984 {published data only} Adams F. Neuropsychiatric evaluation and treatment of delirium in the critically ill cancer patient. The Cancer Bulletin 1984;36(3):156 60. Adams 1986 {published data only} Adams F, Fernandez F, Andersson BS. Emergency pharmacotherapy of delirium in the critically ill cancer patient. Psychosomatics 1986; 27(1):338.

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

delirium and other symptoms in terminally ill patients in Edmonton. Journal of Palliative Care 2000;16(2):510. Lawlor 2000 {published data only} Lawlor PG, Gagnon B, Mancini IL, Pereira JL, Hanson J, SuarezAlmazor ME, et al.Occurrence, causes, and outcome of delirium in patients with advanced cancer. Archives of Internal Medicine 2000; 160:78694. McIver 1994 {published data only} McIver B, Walsh D, Nelson K. The use of chlorpromazine for symptom control in dying cancer patients. Journal of Pain and Symptom Management 1994;9(5):3415. Oliver 1985 {published data only} Oliver DJ. The use of methotrimeprazine in terminal care. The British Journal of Clinical Practice 1985;39(9):33940. Olofsson 1996 {published data only} Olofsson SM, Weitzner MA, Valentine AD, Baile WF, Meyers CA. A retrospective study of the psychiatric management and outcome of delirium in the cancer patient. Supportive Care in Cancer 1996;4: 3517. Pereira 1997 {published data only} Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997; 79:83542. Stiefel 1992 {published data only} Stiefel F, Fainsinger R, Bruera E. Acute confusional states in patients with advanced cancer. Journal of Pain and Symptom Management 1992;7(2):948.

Cochrane 2003 Mulrow CD, Oxman AD, editors. The Cochrane Reviewers Handbook [updated February 2003]. In: The Cochrane Library [database on CDROM]. The Cochrane Collaboration. Oxford: Update Software; 2003, Issue 2. de Stoutz 1995 de Stoutz ND, Tapper M, Fainsinger RL. Reversible delirium in terminally ill patients. Journal of Pain and Symptom Management 1995;10:24953. Fainsinger 1992 Fainsinger R, Bruera E. Treatment of delirium in terminally ill patients. Journal of Pain and Symptom Management 1992;7:546. Fainsinger 1993 Fainsinger RL, Tapper M, Bruera E. A perspective on the management of delirium in terminally ill patients on a palliative care unit. Journal of Palliative Care 1993;9:48. Ingham 1998 Ingham JM, Caraceni AT. Delirium. In: Berger AM, Portenoy RK, Weissman DE editor(s). Principles and Practices of Supportive Oncology. Philadelphia, PA: Lippincott-Raven, 1998:47796. Jackson 1999 Jackson KC, Lipman AG. Delirium in palliative care patients. J Pharm Care Pain Sympt Cont 1999;7(4):5970. Jadad 1996 Jadad AR, Moore RA, Carroll D, et al.Assessing the quality of reports of randomized clinical trials: is blinding necessary. Controlled Clinical Trials 1996;17(1):112. Massie 1987 Massie MJ, Holland JC. The cancer patient with pain: psychiatric complications and their management. Medical Clinics of North America 1987;71:24358. Passik 1999 Passik SK, Cooper M. Complicated delirium in a cancer patient successfully treated with olanzapine. Journal of Pain and Symptom Management 1999;17(3):21923. Roth 1996 Roth AJ, Breitbart W. Psychiatric emergencies in terminally ill cancer patients. Pain and Palliat Care 1996;10:23559. Shapiro 1995 Shapiro BA, Warren J, Egol AB, et al.Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Critical Care Medicine 1995;23:1596 600. Smith 1995 Smith MJ, Breitbart WS, Platt MM. A critique of instruments and methods used to detect, diagnose, and rate delirium. Journal of Pain and Symptom Management 1995;10:3577. Stiefel 1994 Stiefel F, Razavi. Common psychiatric disorders in cancer patients II. Anxiety and acute confusional states. Supportive Care in Cancer 1994;2:2337. Indicates the major publication for the study

Additional references
APA 1995 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th Edition. Arlington, VA: American Psychiatric Publishing, Inc, 1995. Bluestine 1994 Bluestine S, Lesko L. Psychotropic medications in oncology and in AIDS patients. Advances in Psychosomatic Medicine 1994;21:107 37. Breitbart 1996b Breitbart W, Jacobsen PB. Psychiatric symptom management in terminal care. Clinics in Geriatric Medicine 1996;12:32947. Breitbart 1998 Breitbart W, Chochinov HM, Passik SD. Psychiatric aspects of palliative care. In: Doyle D, Hanks GWC, MacDonald N editor(s). Oxford Textbook of Palliative Medicine. 2nd Edition. New Yord: Oxford University Press, 1998:93356. Breitbart 2000 Breitbart W, Strout D. Delirium in the terminally ill. Clinics in Geriatric Medicine 2000;16(2):35772. Caraceni 1995 Caraceni A. Delirium in palliative care. European Journal of Palliative Care 1995;2:627.

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Breitbart 1996a Methods Randomized Double-blind Controlled trial of haloperidol vs. chlorpromazine vs. lorazepam Hospitalized AIDS patients (n = 30, 23 male 7 female) Mean age 39.2 years (SD 8.8, range 23 to 56). All met DSM-III-R criteria for delirium and scored 13 or greater on the Delirium Rating Scale (DRS). Mean Karnofsky Performance Score at baseline was 52.3 (SD 21.3, range 10-90). The Medical Status Prole showed patients to have a mean of 12.57 medical conditions (SD 4.1, range 6-22). Three drug study utilizing dose level protocol. Assessment done every hour until stabilization. Mean drug doses during the rst 24 hours: haloperidol 2.8 mg (SD = 2.4) chlorpromazine 50 mg (SD = 23.1) lorazepam 3 mg (SD = 3.6) Average maintenance doses: haloperidol 1.4 mg (SD = 1.2) chlorpromazine 36 mg (SD = 18.4) lorazepam 4.6 mg (SD = 4.7). Lorazepam arm stopped early due to adverse effects. DRS Scores ALL (n 30) baseline: 20.1 (SD 3.5, range 14 to 28) Day 2: 13.3 (SD 6.1, range 3 to 26) End of therapy: 12.8 (SD 6.4, range 3 to 26) Chlorpromazine (n 13) Baseline: 20.62 (SD 3.88) Day 2: 12.08 (SD 6.5) End of Therapy: 11.85 (SD 6.74) Haloperidol (n 11) Baseline: 20.45 (SD 3.45) Day 2: 12.45 (SD 5.87) End of Therapy: 11.64 (SD 6.1) Lorazepam (n 6) Baseline: 18.33 (SD 2.58) Day 2: 17.33 (SD 4.18) End of Therapy: 17.0 (SD 4.98) MMSE Scores Chlorpromazine (n 13) Baseline: 10.92 (SD 8.87) Day 2: 18.31 (SD 10.61)
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Participants

Interventions

Outcomes

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Breitbart 1996a

(Continued) End of Therapy: 15.08 (SD 10.43) Haloperidol (n 11) Baseline: 13.45 (SD 6.95) Day 2: 17.27 (SD 8.87) End of Therapy: 17.18 (SD 12.12) Lorazepam (n 6) Baseline: 15.17 (SD 5.31) Day 2: 12.67 (SD 10.23) End of Therapy: 11.5 (SD 8.69) Extrapyramidal Symptom Rating Scale Scores Chlorpromazine (n 13) Baseline: 7.42 (SD 8.08) End of Therapy: 5.08 (SD 4.48) Haloperidol (n 11) Baseline: 7.0 (SD 6.8) End of Therapy: 5.54 (SD 6.76) Lorazepam (n 6) Baseline: 7.6 (SD 10.11) End of Therapy: 12.2 (SD 8.93)

Notes

Length of therapy not provided, but was noted to be up to 6 days. Five patients died within 8 days of protocol initiation (2 Chlopromazine, 2 Haloperidol 1 Lorazepam), and 4 more expired within 7 days of completing the protocol (3 chlorpromazine and 1 lorazepam). Seventeen patients lived longer than 2 weeks following protocol initiation (mean 183 days, range 19-1,305). An additional 4 patients were known to have lived a minimum of 2 to 7 months, but were lost to follow up.

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

Characteristics of excluded studies [ordered by study ID]

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Adams 1984 Adams 1986 Akechi 1996

Not a prospective controlled clinical trial. Retrospective analysis. Not a prospective controlled clinical trial. Retrospective analysis. Not a prospective controlled clinical trial. Descriptive report only, no comparative drug or therapy. Additionally, not palliative care specic. Not a prospective controlled clinical trial. Open label prospective trial without a comparative drug or therapy. Additionally, not palliative care specic. Not a prospective controlled clinical trial. Retrospective analysis. Not a prospective controlled clinical trial. Retrospective analysis. Not a prospective controlled clinical trial. Retrospective analysis. Not a prospective controlled clinical trial. Descriptive study without comparative drug or treatment arms. Not a prospective controlled clinical trial. Descriptive study without comparative drug or treatment arms. Not a prospective controlled clinical trial. Retrospective survey. Not a prospective controlled clinical trial. Retrospective survey. Not a prospective controlled clinical trial. Retrospective survey. Not a prospective controlled clinical trial. Retrospective analysis.

Breitbart 2002

Burke 1991 Cobb 2000 Fainsinger 2000 Lawlor 2000 McIver 1994 Oliver 1985 Olofsson 1996 Pereira 1997 Stiefel 1992

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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DATA AND ANALYSES

This review has no analyses.

APPENDICES Appendix 1. MEDLINE search strategy

The subject search used a combination of controlled vocabulary and free text terms in addition to the Cochrane Collaborations Sensitive search strategy. These terms included the following: Disease: delirium, agitation, acute confusional states, encephalopathy, organic mental disorders, and terminal restlessness Individual treatments: alprazolam, bromazepam, chlordiazepoxide, clobazepam, clonazepam, chlorazepate, diazepam, estazolam, unitrazepam, urazepam, halazepam, ketazolam, lorazepam, midazolam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, chlorpromazine, haloperidol, droperidol, methotrimeprazine, olanzapine, propofol, risperidone, mesoridazine and thioridazine. Drug class names: antipsychotics, benzisoxazole, benzodiazepines, butyrophenones, phenothiazines, and thienobenzodiazepine

WHATS NEW
Last assessed as up-to-date: 17 February 2004.

12 August 2009

Amended

Contact details updated.

HISTORY
Protocol rst published: Issue 2, 2004 Review rst published: Issue 2, 2004

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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27 October 2008

Amended

Converted to new review format.

CONTRIBUTIONS OF AUTHORS
K. Jackson - Primary Review author. A. Lipman - Secondary Review author.

DECLARATIONS OF INTEREST
None known

SOURCES OF SUPPORT Internal sources

Texas Tech HSC School of Pharmacy Department of Pharmacy Practice, USA. University of Utah College of Pharmacy Department of Pharmacy Practice, USA.

External sources
No sources of support supplied

INDEX TERMS Medical Subject Headings (MeSH)

Antipsychotic Agents [therapeutic use]; Chlorpromazine [therapeutic use]; Delirium [ drug therapy; etiology]; Haloperidol [therapeutic use]; Lorazepam [therapeutic use]; Terminally Ill [ psychology]

MeSH check words

Humans

Drug therapy for delirium in terminally ill adult patients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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