Journal of Pain & Palliative Care Pharmacotherapy

ISSN: 1536-0288 (Print) 1536-0539 (Online) Journal homepage: https://www.tandfonline.com/loi/ippc20

Effect of Antipsychotics and Non-

Pharmacotherapy for the Management of Delirium
in People Receiving Palliative Care

Kar Yee Lee, Edwin Chin Kang Tan, Jane R. Hanrahan, Christopher Chircop,
Felicia Michael & Jennifer A. Ong

To cite this article: Kar Yee Lee, Edwin Chin Kang Tan, Jane R. Hanrahan, Christopher Chircop,
Felicia Michael & Jennifer A. Ong (2020): Effect of Antipsychotics and Non-Pharmacotherapy for
the Management of Delirium in People Receiving Palliative Care, Journal of Pain & Palliative Care
Pharmacotherapy, DOI: 10.1080/15360288.2020.1784353

To link to this article: https://doi.org/10.1080/15360288.2020.1784353

View supplementary material

Published online: 30 Jul 2020.

Submit your article to this journal

Article views: 23

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ippc20
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY
https://doi.org/10.1080/15360288.2020.1784353

REPORT

Effect of Antipsychotics and Non-Pharmacotherapy for the Management of

Delirium in People Receiving Palliative Care
Kar Yee Lee, Edwin Chin Kang Tan, Jane R. Hanrahan, Christopher Chircop, Felicia Michael and
Jennifer A. Ong

ABSTRACT ARTICLE HISTORY

Evidence to support the use of antipsychotic medications for the management of delirium Received 11 December 2019
symptoms remains limited. The primary objective of this study was to compare the effect of Revised 21 May 2020
antipsychotic and non-antipsychotic treatments for delirium symptoms among palliative care Accepted 11 June 2020
inpatients. Secondary outcomes were use of midazolam and overall survival. This involved
KEYWORDS
retrospective analysis of medical records (November 2018 to April 2019) for adult palliative Delirium; palliative care;
care patients diagnosed with delirium at an Australian tertiary hospital. NuDESC was used to anti-psychotics
assess symptoms daily from baseline to Day 3. All 65 patients (mean age 73.5 ± 13.7 years,
48% female, 59% with cancer) included received standard care which included management
of underlying causes of delirium symptoms, of which 17 received additional treatment using
antipsychotic medications. Forty-eight did not receive any antipsychotic medication. An abso-
lute reduction in NuDESC score was observed in the group that did not receive additional
treatment using antipsychotics (by 1.37 units, 95% CI 0.79–1.95, p < 0.0001). A significantly
higher proportion of midazolam use (n ¼ 9, 53% versus n ¼ 2, 4%, p < 0.001) and shorter
median survival (13 days versus 26 days, p ¼ 0.03) was observed in the group of patients that
received antipsychotics. The use of antipsychotic medications in addition to standard treat-
ments targeting underlying precipitants did not lead to a significant improvement in delirium
symptoms and was associated with a greater midazolam use and lower median duration of
survival. Individualized treatment of underlying causes still appears to be essential in the man-
agement of delirium in patients receiving palliative care.

Introduction medications commonly used in this population

Delirium is one of the most common, yet poorly
recognized clinical syndromes across all palliative
care settings, with an increasing prevalence seen
toward the end of life (1). It is characterized by
an acute disturbance in attention and awareness
with a fluctuating nature, and can be categorized
into different subtypes: hyperactive (characterized
by agitation or restlessness), hypoactive (charac-
terized by drowsiness or slowness) or mixed
delirium (2). Hypoactive delirium, despite being
the most common subtype, is often unnoticed or
misperceived as depression or fatigue, and can be
further masked by the sedative effect of
such as opioids and benzodiazepines, which are
also known to precipitate delirium (3). Timely
identification and management of delirium in
routine practice is further impeded by the incon-
sistent terminology used by healthcare professio-
nals in documenting delirium symptoms and a
lack of systematic delirium assessment (3, 4). The
negative consequences of delirium episodes are
well-established, leading not only to poorer sur-
vival outcomes, but also profound distress to
patients and family members, as well as posing a
significant economic burden (3, 5, 6). Thus,
effective treatment is paramount to achieving the

Kar Yee Lee, is with Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia. Edwin Chin Kang
Tan, is with Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia; Aging Research Center,
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden. Centre for Medicine Use and
Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; Jane R. Hanrahan, is with Faculty of Medicine and
Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia. Christopher Chircop, is with Department of Pharmacy,
Westmead Hospital, Sydney, Australia. Felicia Michael, is with Department of Palliative Care, Westmead Hospital, Sydney, Australia.
CONTACT Jennifer Ong jennifer.ong@sydney.edu.au The University of Sydney, School of Pharmacy, Pharmacy and Bank Building A15, Sydney,
NSW 2006, Australia.
Supplemental data for this article can be accessed at https://doi.org/10.1080/15360288.2020.1784353.
ß 2020 Taylor & Francis Group, LLC
2 K. Y. LEE ET AL.
goal of palliative care: to optimize the quality of
life of patients living with life-limiting illness by
alleviating their distress (7).
A previous study has found that up to half of
delirium episodes in the palliative care population
may be reversed by addressing its underlying
causes (5), although investigations for potential
precipitants may be minimal at the end of life
(typically within one week of death) as reversibil-
ity may not be possible in certain patients groups,
such as those with advanced cancer or delirium
caused by hypoxic encephalopathy, or not aligned
with the patients’ goals of care (8, 9). Guidelines
advocate early identification and addressing
reversible precipitants (e.g. reorientation, optimiz-
ing hydration, reviewing pain management) as an
initial approach in delirium management, which
typically forms the ‘standard treatment’, whilst
antipsychotics with or without a concurrent
benzodiazepine should be reserved for patients
with severe distress or compromised safety (10,
11). Despite this, optimal management strategies
remain uncertain due to the paucity of evidence
(8, 12). Antipsychotics, particularly haloperidol,
have been the mainstay of delirium treatment,
albeit are not approved for this indication (13,
14). In recent years, the rationale for anti-
psychotic use has been widely debated in view of
evidence from the first randomized placebo-con-
trolled trial in the palliative care setting (15).
More specifically, Agar et al. (16) have shown
that haloperidol and risperidone resulted in
greater delirium severity, side effects and more
concerningly, increased risk of mortality compared
to placebo. Similar findings was observed in a pre-
post study conducted by Okuyama et al. (17),
which showed antipsychotic medications used to
manage hypoactive delirium worsened delirium
symptoms by Day 3 for a majority of the subjects
(56%, n ¼ 121) and cause further deterioration in
symptoms in patients whose death was expected
within a few days or whose symptoms were caused
by organ failure. Similarly, duration of delirium
and proportion of patients that experienced side
effects was lower in the non-pharmacotherapy
group compared to groups that received haloperi-
dol or other antipsychotics in a retrospective ana-
lysis by Felton et al. (18). Altogether, these studies
prompt questioning of the use of antipsychotics in
the management of delirium symptoms for
patients in a palliative care setting.
Despite emerging evidence and guidelines
advising the cautious use of antipsychotics,
adherence to guidelines has been suboptimal in
practice, with guidelines used inconsistently and
a marked variation seen in the management
approach among specialists, who highlight the
poor applicability of study recommendations to
real-life practice (14, 19). Tailoring of treatment
for underlying delirium precipitants for each
patient may be hindered by time constraints in
practice (20) and further compounded by the
lack of robust studies evaluating its effectiveness
against antipsychotic use for the treatment of
delirium symptoms. Thus, our study aimed to
compare the effect of using an additional anti-
psychotic and non-antipsychotic treatment (i.e.
standard treatment for the underlying causes) on
the delirium symptoms and overall survival of
inpatients receiving palliative care.
Methods
Study design and setting
A retrospective review of medical records for
patients who received a palliative care consult-
ation and were diagnosed with delirium at the
Westmead Hospital (Sydney, Australia) from
November 2018 to April 2019 was conducted.
Cases of delirium were identified using relevant
International Statistical Classification of Diseases
and Related Health Problems, Tenth Revision,
Australian Modification (ICD-10-AM) codes via
the hospital electronic database (Appendix 1,
Supplementary material). A total score of two or
more on the Nursing Delirium Screening Scale
(NuDESC) was necessary for a diagnosis of
delirium (21). Key descriptors suggestive of
delirium (Appendix 2, Supplementary material)
were obtained from medical records to identify
the day of the onset of delirium symptoms (i.e.
baseline, Day 0). Information from the medical
records of eligible patients were tracked for
three days from the onset of delirium symp-
toms (baseline).

Treatment groups
The type of treatment received by each patient
was at the discretion of their treating physician
and nurses. The antipsychotic treatment group
comprised those who were administered an anti-
psychotic, as defined and listed in the Australian
Medicines Handbook (2019), for symptomatic
treatment of delirium at any time during the
three-day study period. The non-antipsychotic
treatment group comprised those who received
standard treatment for the underlying causes of
delirium (e.g. antibiotics for infection, fluids for
dehydration) and supportive care only.
Study population
Adult patients (18 years old) who were diag-
nosed with delirium and received palliative care
consultation within a single admission (identi-
fied by unique hospital visit number) were
included. Exclusion criteria were patients who
were at the end of life (i.e. died within a week
from onset of delirium symptoms); discharged
within three days of delirium presentation;
received a regular antipsychotic medication
within 48 h prior to the delirium presentation;
received a single as-needed antipsychotic dose
for non-delirium indication within 24 h prior to
the delirium presentation; delirium due to sub-
stance withdrawal; and delirium managed in the
intensive care unit.
Outcomes and measurements
The primary outcome was the change in delir-
ium symptom scores from baseline to Day 3.
Delirium symptoms were evaluated using the
NuDESC, a five-item delirium assessment tool
that has been validated for monitoring delirium
severity in the palliative care setting (21, 22).
Our pilot study revealed that no delirium assess-
ment tool was routinely used at the study site.
Therefore, a score between 0 and 2 was assigned
for each NuDESC item in the tool based on all
delirium symptoms described in the patient
medical records and using a pre-specified crite-
ria to ensure consistency in scoring (Appendix
3, Supplementary material). Patients who were
recorded as not being interviewed during the
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 3
shift due to reduced level of arousal were rated
2 on both item 2 (disorientation) and item 5
(psychomotor retardation) of the NuDESC (2,
23). However, where records showed that the
patient had developed a coma (defined as
recorded Glasgow Coma Scale score of 8 or
below) during the study period, delirium symp-
tom scores, which cannot be accurately deter-
mined in this instance were treated as missing
data. In line with a previous study (16), a
change in the NuDESC score of at least 1 unit
was considered clinically significant where the
overall symptoms of delirium was categorized as
‘improved’ or ‘worsened’ if the NuDESC score
on day 3 was at least 1 unit lower or higher
than the baseline score, respectively. Otherwise,
overall delirium symptoms were considered to
remain ‘unchanged’. Secondary outcomes were
the use of subcutaneous midazolam and overall
survival from the day of delirium presentation.
Covariates
Baseline variables that were considered as poten-
tial confounders included gender, age, cancer
diagnosis, comorbidity burden, pre-existing cog-
nitive impairment, and the use of opioids and
midazolam (expressed as oral morphine and
diazepam equivalents, respectively). Cumulative
Illness Rating Scale (CIRS) (24) score was calcu-
lated for each patient as an indicator of comor-
bidity burden based on their medical history
(Appendix 4, Supplementary material).
Data collection
Data was collected using a standardized data
abstraction form comprising clinicodemographic
characteristics (e.g. age, gender, medical and
medication history); daily delirium symptoms
from baseline to Day 3; treatment received; date
of discharge and/or death. The subtypes of delir-
ium were classified based on the described psy-
chomotor symptoms as either hyperactive
(characterized by agitation or restlessness), hypo-
active (characterized by slowness or drowsiness)
or mixed subtype (characterized by normal or
fluctuating psychomotor activity) according to
4 K. Y. LEE ET AL.

142 paents reviewed from
November 2018 to April 2019
131 paents with delirium diagnosis and
received palliave care consultaon
within a single admission
66 paents excluded
38 End of life (died within 7 days of
delirium presentaon)
13 Regular use of anpsychoc within 48
hours of delirium presentaon
8 Managed in intensive care unit
4 Discharged within 3 days and delirium
status unknown
1 Single as-needed anpsychoc dose for
non-delirium indicaon within 24 hours
of delirium presentaon
65 eligible paents, all received standard
treatment for underlying causes and supporve
specified as random effects. Fixed effects included
covariates, treatment group, time and the inter-
action terms between time and treatment group.
Survival distributions was predicted using the
Kaplan-Meier curves and the difference in esti-
mated survival time between the two groups was
analyzed using log rank test. Statistical significance
was defined as p < 0.05 with 95% confidence inter-
vals (CI) reported. Analyses were undertaken using
the Statistical Package for the Social Sciences soft-
ware (SPSS, version 25). Only descriptive statistics
were provided for tests which were not adequately
power (i.e. <80%) due to small sample sizes,
including absolute reduction in Day 3 delirium
scores in group that was administered anti-
psychotic medications, as well as mean difference
in delirium scores between treatments groups daily
and on Day 3.

Ethics
Ethics approval and waiver of consent were
48 paents without 17 paents with
anpsychoc treatment anpsychoc treatment at obtained from the Western Sydney Local Health
any me
District Human Research Ethics Committee and
Figure 1. Flow diagram of patient inclusion. Research Governance Office (reference: 2019/
ETH12153; approved on 28 August 2019).
the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) (2). Results
We retrieved a total of 142 records from the elec-
Statistical analysis tronic database, of which 11 were for patients
who did not receive palliative care consultation
Clinicodemographic data was summarized using
and delirium diagnosis within a single admission,
descriptive statistics. Categorical variables between
and a further 66 records were excluded with rea-
groups were compared statistically using Chi-
sons described earlier and in Figure 1. All 65
squared tests or Fisher’s exact tests, while continu-
records retained and included in our study
ous variables with skewed distribution were ana-
showed all these patients received at least one
lyzed using Mann-Whitney U tests to compare the
form of treatment that did not involve anti-
difference between the two treatment groups.
psychotic medication for delirium symptoms (e.g.
Mean difference in absolute delirium scores was treatment for underlying cause of delirium and
calculated for each study group using paired data, supportive care). Seventeen patients received add-
which comprised baseline and Day 3 NuDESC itional treatment using an antipsychotic medica-
scores. A linear mixed-effects model was used to tion (whilst 48 did not receive any
compare the change in delirium symptom scores antipsychotic treatment).
from baseline to Day 3 between both groups. This
model adjusted for the correlation between
repeated measurements on individual patients and Baseline characteristics
the effect of covariates, as well as account for miss- Table 1 summarizes the patients’ baseline charac-
ing values in the analysis (25). Patients were teristics. Overall, both groups of patients had
 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 5

Table 1. Baseline patient characteristics by treatment group (n ¼ 65).

Characteristics Without antipsychotic treatment (n ¼ 48) With antipsychotic treatment (n ¼ 17) p value
Female, n (%) 22 (46) 9 (53) 0.61a
Age, median (IQR), years 73.5 (67.3–85.0) 71.0 (58.5–83.5) 0.32b
Age < 65 years, n (%) 8 (17) 6 (35) 0.17c
Cancer diagnosis, n (%) 26 (54) 12 (71) 0.24a
Preexisting risk factors, n (%)
Cognitive impairment or dementia diagnosis 8 (17) 1 (6) 0.43c
Vision 17 (35) 9 (53) 0.21a
Hearing 8 (17) 3 (18) >0.99c
Mobility 40 (83) 14 (82) >0.99c
Patients receiving opioid, n (%) 22 (46) 15 (88) 0.002a
Opioid dose, median (IQR)d 0 (0–29.2) 30.0 (7.5–60.0) 0.006b
Patients receiving benzodiazepine, n (%) 0 (0) 2 (12) 0.07c
Benzodiazepine dose, median (IQR)e 0 (0–0) 0 (0-0) 0.003b
CIRS score, median (IQR) 17 (15–21) 15 (13–21) 0.22b
Length of hospital stay, median [95% CI], daysf 24 [17, 31] 39 [15, 63] 0.33f
Delirium symptom score (NuDESC), median (IQR) 3 (2–4) 3 (2–5) 0.69b
Delirium subtype, n (%)
Hyperactive 11 (23) 4 (24) >0.99c
Hypoactive 18 (38) 5 (29) 0.55a
Mixed 19 (40) 8 (47) 0.59a
SD: standard deviation; IQR: interquartile range; CIRS: Cumulative Illness Rating Scale; NuDESC: Nursing Delirium Screening Scale.
a
Chi-squared test performed.
b
Mann-Whitney U test performed.
c
Fisher’s exact test performed.
d
Oral morphine equivalents (in milligrams).
e
Oral diazepam equivalents (in milligrams).
f
Log rank test performed with 19 patients in the group without antipsychotic treatment and 10 patients in the group with antipsychotic treatment cen-
sored at their date of death.
Statistically significant difference between groups (p < 0.05) are highlighted in bold.

similar clinicodemographic characteristics, except
for the proportion of patients who received an
opioid. For patients in the group receiving anti-
psychotic treatment, a significantly greater pro-
portion were administered opioids (n ¼ 15, 88%)
and had a higher median oral morphine equiva-
lent (30.0 mg, IQR: 7.5-60.0 mg) compared to the
group without antipsychotic treatment (n ¼ 22,
46%, p ¼ 0.002; 0, IQR: 0–29.2 mg, p ¼ 0.006).
The sum of ranks for median benzodiazepine
dose was also significantly higher in the group
that received antipsychotic medications (not
shown). The most common delirium subtype
overall was mixed delirium (42%), followed by
hypoactive (35%) and the least common was
hyperactive delirium (23%).
regular oral care (n ¼ 19, 29%); managing consti-
pation (n ¼ 18, 28%); optimizing mobility
(n ¼ 11, 17%); supplementary oxygen (n ¼ 7,
11%); managing urinary retention (n ¼ 6, 9%);
physical restraint (n ¼ 4, 6%); treating malig-
nancy-related hypercalcemia (n ¼ 3, 5%); natural
sleep preservation (n ¼ 2, 3%); special one-on-one
nursing (n ¼ 2, 3%); and optimizing sensory per-
ception (n ¼ 1, 2%) (Table 2). Among the 17
patients who received an antipsychotic medica-
tion, the average daily dose for patients adminis-
tered with haloperidol only (n ¼ 14) was 1.2 mg;
chlorpromazine only (n ¼ 1) was 25 mg; haloperi-
dol and droperidol (n ¼ 1) was 1 mg and 1.7 mg;
haloperidol and olanzapine (n ¼ 1) was 1.7 mg
and 3.3 mg.

Treatment received Delirium symptoms

All 65 patients included in our study received at
least one form of care that did not involve anti-
psychotic medications to address possible causes
of delirium or manage symptoms, which
included: treatment of infection (n ¼ 44, 68%);
optimizing hydration status (n ¼ 40, 62%); pain
management (n ¼ 32, 49%); medication review
(n ¼ 26, 40%); reorientation (n ¼ 25, 38%);
The absolute reduction in delirium symptom
scores on Day 3 was 0.71 units (95% CI 0.24 to
1.65) and 1.37 units (95% CI 0.79 to 1.95,
p<.0001) for patients who did and did not
receive antipsychotics, respectively. From the uni-
variable analysis (Table 3), patients receiving
antipsychotics had a smaller mean reduction in
delirium scores compared to those without
6 K. Y. LEE ET AL.

Table 2. Treatments for underlying causes of delirium or non- antipsychotic treatment, with a difference of 0.66
antipsychotic management of symptoms (n ¼ 65). units (95% CI 0.41 to 1.74). Similar results
Intervention Frequency %
were obtained in the multivariable mixed-model
Treatment of infection 44 68
Optimize hydration 40 62 analysis (Table 3 and Figure 2). Patients receiving
Optimize pain management 32 49 antipsychotics had consistently higher delirium
Medication review 26 40
Reorientation 25 38 symptom scores per day, that was on average
Regular mouth care 19 29
Manage constipation 18 28
0.70 units (95% CI -0.16 to 1.56) higher than
Optimize mobility 11 17 those without antipsychotic treatment, but this
Supplemental oxygen 7 11
Manage urinary retention 6 9 was also not statistically significant. Patients with
Physical restraint 4 6 a cancer diagnosis had a significantly lower mean
Treatment of malignancy-related hypercalcaemia 3 5
Preserve natural sleep 2 3 delirium symptom score per day compared to
Special one-on-one nursing 2 3 those with non-cancer diagnosis (0.87 units, 95%
Optimize sensory perception 1 2

Table 3. Linear mixed-model analysis of delirium symptom scores and the associated variables.a
Univariable Multivariable
Delirium symptom score B (95% CI) p value B (95% CI) p value
Change in score between baseline and Day 3
Without antipsychotic treatment (reference)b,c 0 – 0 –
With antipsychotic treatment 0.66(0.41 to 1.74) 0.22 0.66 (0.41 to 1.74) 0.22
Female 0.00(0.76 to 0.75) >0.99 0.48 (1.15 to 0.19) 0.16
Age, y 0.02 (0.00 to 0.05) 0.10 0.01 (0.01 to 0.04) 0.37
Cancer diagnosis 1.12 (1.83 to 0.41) 0.002 0.87 (1.62 to 0.12) 0.02
CIRS score 0.04 (0.12 to 0.04) 0.34 0.05 (0.12 to 0.02) 0.14
Preexisting cognitive impairment or dementia diagnosis 0.74 (0.33 to 1.82) 0.17 0.73 (0.26 to 1.73) 0.14
Oral morphine equivalent 0.00 (0.01 to 0.00) 0.16 0.00 (0.01 to 0.00) 0.20
Oral diazepam equivalent 0.33 (0.10 to 0.76) 0.13 0.21 (0.17 to 0.58) 0.27
B: estimate; CI: confidence interval; CIRS: Cumulative Illness Rating Scale.
a
Dependent variable was the daily delirium symptom score across baseline to Day 3. The independent variables also included time and interaction terms
(time  treatment group).
b
The group without antipsychotic treatment had two patients missing score on Day 3.
c
Absolute reduction in delirium symptom score in the group without antipsychotic treatment was 1.37 units (95% CI 0.79 to 1.95).
Variables that contributed significantly to the dependent variable (p < 0.05) are highlighted in bold.

Figure 2. Linear mixed-model analysis of the delirium symptom score per day, with the 95% confidence intervals represented by
error bars. The independent variables included treatment group, time, interaction terms (time x treatment group) and covariates in
Table 3. The group without antipsychotic treatment had two patients missing score on day 3. There was no statistically significant
difference in the reduction in delirium symptom scores on day 3 between the two groups (p ¼ 0.22).

Table 4. Other outcomes by treatment group (n ¼ 65).
Without antipsychotic
Outcomes
Change in delirium symptoms, n (%)a,b
Improved
Unchanged
Worsened
No. patients receiving midazolam, n (%)
Patients who died, n (%)
Median time survived from day 0 until death, days
a
Defined as ‘improved’ or ‘worsened’ if the NuDESC score on day 3 was at least 1 unit lower or higher than the baseline score, respectively. Defined as
‘unchanged’ if there was no change in score on day 3 compared to baseline.
b
Two missing values in the group without antipsychotic treatment.
c
Chi-squared test performed.
d
Fisher’s exact test performed.
e
Mann-Whitney U test performed.
Statistically significant difference between groups (p < 0.05) are highlighted in bold.
CI 0.12 to 1.62, p ¼ 0.02), while the other covari-
ates included in the model did not contribute sig-
nificantly to the delirium symptom scores
(Table 3).
The proportion of patients with ‘improved’
delirium symptoms on Day 3 in the group with-
out antipsychotic treatment (n ¼ 33, 72%) was
greater than that of the group receiving antipsy-
chotics (n ¼ 8, 47%). Furthermore, the proportion
of patients in the group without antipsychotic
treatment whose delirium symptoms were classi-
fied as ‘unchanged’ (n ¼ 7, 15%) or ‘worsened’
(n ¼ 6, 13%) was lower compared to that of the
group receiving antipsychotics (n ¼ 5, 29% and
n ¼ 4, 24%, resp.). However, there was no statis-
tically significant difference in the change in
symptoms between both groups (Table 4).
Use of midazolam
There were significantly fewer patients who were
administered midazolam during the study period
in the group without antipsychotic treatment
(n ¼ 2, 4%) compared to the group receiving anti-
psychotics (n ¼ 9, 53%) (p < 0.001). Among
patients who received midazolam, the median
dose was 4.2 mg (IQR: 3.3–8.2 mg) in the group
without antipsychotic treatment and 5.0 mg (IQR:
2.0–12.6 mg) for those receiving antipsychotics,
but the difference in dose per day or overall was
not statistically significant (Table 4).
Overall survival
During the follow-up period of 127–321 days (i.e.
about 4–10 months), a total of 51 (out of 65)
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 7
With antipsychotic treatment at
treatment (n ¼ 48) any time (n ¼ 17) p value
33 (72) 8 (47) 0.19c
7 (15) 5 (29)
6 (13) 4 (24)
2 (4) 9 (53) <.001d
37 (77) 14 (82) 0.75d
26 13 0.03e
patients had died, which included 37 patients
(77%) from the group that received standard care
only and 14 patients (82%) who received an anti-
psychotic (Table 4). The median survival from
the day of delirium presentation for patients
receiving antipsychotics was significantly shorter
than those without antipsychotic treatment
(13 days versus 26 days, p ¼ 0.03) which is similar
to the estimated median survival calculated by
the Kaplan-Meier method (13 days versus 29 days,
p ¼ 0.047; Figure 3).
Discussion
Main findings
Our study aimed to evaluate the effectiveness of
the use of antipsychotic medication for the man-
agement of delirium among palliative care inpa-
tients, in addition to non-antipsychotic
treatments and management of underlying pre-
cipitants. There was a statistical improvement in
delirium symptom scores in the group of patients
that did not receive an antipsychotic medication,
whilst patients who received additional anti-
psychotic treatment showed no significant
improvement in the delirium symptoms com-
pared to those who received only standard
treatment for underlying precipitants and other
non-antipsychotic interventions. However, those
who received antipsychotics were observed to
have a higher prevalence of midazolam use and
shorter median survival. It could be speculated
that the group that required administration of
antipsychotic agents (and midazolam) had worse
symptoms of delirium (higher NuDESC score)
than the group that did not receive any
8 K. Y. LEE ET AL.
Figure 3. Kaplan-Meier survival curves comparing the overall survival from the day of delirium presentation between treatment
groups. Eleven patients in the group without antipsychotic treatment and three patients in the group receiving antipsychotics
were censored at their date of discharge. The estimated median survival time was significantly shorter in the group receiving anti-
psychotics (29 days versus 13 days, p ¼ 0.047).
antipsychotic agent. However, median NuDESC
scores at baseline (Day 0) were comparable.
Although higher delirium symptom scores
were observed in patients receiving antipsy-
chotics, our study did not find a statistically sig-
nificant difference in scores between the two
study groups, contrary to the previous study by
Agar et al. (16). Variability may stem from the
heterogeneity of our participants, which included
a greater proportion of non-cancer patients com-
pared to the previous study. Furthermore, the
previous study evaluated symptoms related to the
hyperactive subtype only, corresponding to three
of the five criteria of the NuDESC tool (i.e.
inappropriate behavior, inappropriate communica-
tion and illusions/hallucinations) whereas all crite-
ria of the NuDESC tool to assess delirium
symptoms including two related to the hypoactive
delirium subtype (i.e. disorientation and psycho-
motor retardation) were utilized in this study,
which has been reported to be more common
among palliative care patients (21). This may
have potentially resulted in higher NuDESC
scores in both groups of our study. Lastly, due to
the nature of retrospective study designs, patients
in our study were allocated to the exposure group
as long as they were administered an anti-
psychotic medication at any given time during
the study period. This difference to the previous
study, which commenced antipsychotic medica-
tion at baseline and continued it regularly
throughout the study period. This is different
may underestimate the true effects of
antipsychotics.
The greater prevalence of midazolam use seen
among patients receiving antipsychotics was in
accordance with the previous study (16). One
possible reason is that midazolam was used in
addition to antipsychotics for refractory symp-
toms with severe distress or compromised patient
safety as per guideline recommendations (10, 11),
but such symptom trends could not be captured
by the NuDESC in our study and should be
interpreted cautiously. Midazolam may have been
commenced before antipsychotic treatment for
rapid symptom control due to its faster onset of
action (26), as our study observed that some
patients in the group without antipsychotic treat-
ment also received midazolam. Furthermore, the
higher midazolam use associated with anti-
psychotic treatment could also be due to a pos-
sible preference by physicians’ to use both drugs
concurrently (19).
Similar to findings from Felton et al. (18), no
difference in post-delirium length of stay between
groups was observed. The poorer overall survival

observed in those receiving antipsychotics was
also comparable to findings from the previous
study by Agar et al. (16). One possible reason for
poorer survival could be the risk associated with
antipsychotics exposure, as demonstrated by pre-
vious studies (16, 27). However, it could also be
that antipsychotics were administered to these
patients in anticipation of imminent death and
the physicians’ perceived irreversibility of delir-
ium (13, 16). Although records for patients who
were at the end-of-life (died within 7 days) of
delirium presentation were excluded from our
study, other relevant characteristics such as the
trajectory of patients’ life-limiting disease or per-
formance status, which may have been perceived
by physicians as predictive of death and lead to
the administration of antipsychotics, were not
captured in our study.
The small proportion of patients receiving add-
itional antipsychotics compared to those who
received standard treatment for underlying pre-
cipitants alone was unexpected as a combination
approach is known to be common practice (14,
19). One possible reason is that treatment of
reversible precipitants is performed before com-
mencing antipsychotic treatment at the study site
(14), especially for hypoactive delirium which
was common in our study population. Our study
may have also identified delirium some time
before it was formally documented, which may
have led to a delay in the initiation of anti-
psychotic therapy (28).
Strengths and limitations
Our study was designed to include all inpatients
who were considered as having palliative care
needs including those receiving palliative care
consultation services, a population underrepre-
sented in the current literature compared to those
managed in palliative care units or hospices (8).
Compared to previous studies predominantly in
patients with cancer (16, 17), our study popula-
tion comprised comparable proportions of
patients with cancer and other life-limiting ill-
ness. This may be more representative of the
heterogenous palliative care population, which
includes those with any progressive, advanced
disease with no prospect of cure (7, 8).
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 9
However, several limitations should be consid-
ered when interpreting the results of this study.
First, some tests were not adequately powered to
compare the difference in outcomes between
both treatment groups, thus limiting the conclu-
sions that could be drawn on mean difference in
delirium scores daily and on Day 3. Second,
delirium symptoms were rated retrospectively
based on available medical records. Whilst this is
not ideal, we believe that this is the best way to
evaluate the effect of treatments at a study site
without a systematic and standardized delirium
assessment. Furthermore, despite its effectiveness
for screening purposes, the simple NuDESC is
less accurate compared to other tools (such as
the Revised Delirium Rating Scale, and the
Memorial Delirium Assessment Scale) for dis-
cerning the severity of delirium symptoms (29),
but these other tools require detailed documenta-
tion of all observations and interviews performed,
which may be less appropriate for retrospective
rating. Also, despite using a range of delirium-
related ICD-10-AM codes, some relevant cases
may still have been missed as delirium is known
to be under-detected and under-reported in this
population (1, 4). Moreover, it was impractical to
determine whether patients included in our study
were presenting with delirium symptoms for the
first time. As a result, this could have impacted
outcomes as the likelihood of delirium resolution
is known to decrease with recurrent episodes (5).
Finally, our study excluded patients who died
within a week of delirium presentation, thus lim-
iting the generalizability of our findings to those
who are at the end-of-life phase. Considering that
delirium becomes more prevalent as death
approaches, future studies evaluating the effect of
interventions in this group of patients and how
they differ from those in earlier stages of pallia-
tive care is warranted (8).
Implications for practice and research
Extending the previous work within and outside
the field of palliative care (16, 17, 30), our study
further supports the proposal that individualized
treatment of underlying precipitants should
remain the key approach in the management of
delirium among palliative care patients, and
10 K. Y. LEE ET AL.
antipsychotics should not be first-line treatment.
The pre-requisite to tailoring effective manage-
ment is perhaps timely identification of this com-
plex syndrome to allow for early investigation of
underlying causes. Nurses play an important role
in promptly recognizing any acute changes in the
patients’ cognition, communicating their observa-
tions to the multidisciplinary team, and monitor-
ing the effect of interventions performed.
However, this may require a structural change in
current practice such as the implementation of
routine assessments and systematic documenta-
tion of delirium symptoms (28, 31). Furthermore,
implementation of individualized delirium
management (particularly with the use of non-
pharmacological interventions such as one-on-
one nursing) can be challenging due to time
constraints in the busy hospital setting, and prac-
titioners and nurses may still resort to antipsy-
chotics as a more convenient alternative (16, 19).
Thus, besides evaluating the effectiveness of
standard treatments for underlying causes (specif-
ically non-pharmacological interventions) against
antipsychotics or combination treatment, further
studies should also explore the practicality of
adopting delirium treatment routines without the
use of antipsychotics in clinical practice.
Delirium is highly distressing for both the
patient and family members as it impairs mean-
ingful communication and compromises quality
of life (3). Whilst our study and other previous
studies have defined outcomes based on the
change in delirium scores (16, 17), there is cur-
rently no evidence that this directly reflects an
improvement in patients’ distress or quality of
life (16). Given that this is the primary focus of
palliative care (7), further research establishing
key outcomes which are clinically significant to
patients and their family are pivotal to inform
evidence-based practice that is patient-centred
(32). Finally, whilst randomized controlled trials
are ideal for evaluating the efficacy of interven-
tions, observational studies which rely on routine
medical records may remain vital to provide
insight into treatment exposures and delirium
outcomes, given the ethical and practical chal-
lenges in conducting research in the palliative
care population (33). However, our study
identified that this may be challenging at a study
site without routine systematic delirium
assessments.
Conclusion
An improvement in delirium symptoms by treat-
ing underlying causes can be seen within three
days. Addition of antipsychotics do not appear to
lead to any significant improvement and are asso-
ciated with a higher prevalence of midazolam use
as well as poorer overall survival among inpa-
tients receiving palliative care consultation.
Individualized management targeting underlying
causes should remain the cornerstone in delirium
management in people receiving palliative care.
Acknowledgements
All individuals who have devoted significant work to this
manuscript have been included as authors. Author contri-
bution: Study concept and design: J.O.; Data collection:
K.Y., C.C., F.M.; Data analysis and interpretation: K.Y.,
E.C.K.T., C.C., F.M., and J.O.; Critical revision for import-
ant intellectual content and supervision of study: J.O.,
E.C.K.T., C.C., and J.H.
Disclosure statement
The authors declared no conflicts of interest with respect to
the research, authorship and/or publication of this article.
Funding
This research received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.
E.C.K.T. was supported by an Australian National Health
and Medical Research Council-Australian Research Council
(NHMRC-ARC) Dementia Research Development
Fellowship (APP1107381).
ORCID
Jennifer A. Ong http://orcid.org/0000-0002-0958-460X
References
1. Watt CL, Momoli F, Ansari MT, Sikora L, Bush SH,
Hosie A, Kabir M, Rosenberg E, Kanji S, Lawlor PG,
et al. The incidence and prevalence of delirium across
palliative care settings: a systematic review. Palliat

Med. 2019;33(8):865–77. doi:10.1177/0269216319
854944.
2. American Psychiatric Association. Diagnostic and
statistical manual of mental disorders. 5th ed.
Washington, USA: American Psychiatric Publishing;
2013.
3. Leonard M, Agar M, Mason C, Lawlor P. Delirium
issues in palliative care settings. J Psychosom Res.
2008;65(3):289–98. doi:10.1016/j.jpsychores.2008.05.
018.
4. Hey J, Hosker C, Ward J, Kite S, Speechley H.
Delirium in palliative care: detection, documentation
and management in three settings. Palliat Support
Care. 2015;13(6):1541–5. doi:10.1017/S1478951513
000813.
5. Lawlor PG, Gagnon B, Mancini IL, Pereira JL,
Hanson J, Suarez-Almazor ME, Bruera ED.
Occurrence, causes, and outcome of delirium in
patients with advanced cancer: a prospective study.
Arch Intern Med. 2000;160(6):786–94. doi:10.1001/
archinte.160.6.786.
6. Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers
L, Inouye SK. One-year health care costs associated
with delirium in the elderly population. Arch Intern
Med. 2008;168(1):27–32. doi:10.1001/archinternmed.
2007.4.
7. World Health Organization. WHO Definition of
Palliative Care [Internet]. 2019 [cited 2019 March 14].
https://www.who.int/cancer/palliative/definition/en/.
8. Lawlor PG, Rutkowski NA, MacDonald AR, Ansari
MT, Sikora L, Momoli F, Kanji S, Wright DK,
Rosenberg E, Hosie A, et al. A scoping review to map
empirical evidence regarding key domains and ques-
tions in the clinical pathway of delirium in palliative
care. J Pain Symptom Manage. 2019;57(3):661–81.
doi:10.1016/j.jpainsymman.2018.12.002.
9. Leonard M, Raju B, Conroy M, Donnelly S, Trzepacz
PT, Saunders J, Meagher D. Reversibility of delirium
in terminally ill patients and predictors of mortality.
Palliat Med. 2008;22(7):848–54. doi:10.1177/
0269216308094520.
10. eTG complete. Delirium in palliative care [Internet].
Victoria, Australia: Therapeutic Guidelines Ltd; 2019.
[cited 2019 11 July]. June 2019. https://tgldcdp-tg-org-
au.ezproxy1.library.usyd.edu.au/viewTopic?topicfile=
palliative-care-psychological-symptoms&
guidelineName=Palliative%20Care#toc_d1e518.
11. National Institute for Health and Care Excellence.
Delirium: Prevention, diagnosis and management
[Internet]. 2019. [updated March 2019; cited 2019 10
July]. https://www.nice.org.uk/guidance/cg103/chapter/
1-Guidance#treating-delirium.
12. Candy B, Jackson KC, Jones L, Leurent B, Tookman
A, King M. Drug therapy for delirium in terminally
ill adult patients. Cochrane Database Syst Rev. 2012;
(11).
JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY 11
13. Bush SH, Tierney S, Lawlor PG. Clinical assessment
and management of delirium in the palliative care set-
ting. Drugs. 2017;77(15):1623–43. doi:10.1007/s40265-
017-0804-3.
14. Morandi A, Davis D, Taylor JK, Bellelli G, Olofsson
B, Kreisel S, Teodorczuk A, Kamholz B, Hasemann
W, Young J, et al. Consensus and variations in opin-
ions on delirium care: a survey of European delirium
specialists. Int Psychogeriatr. 2013;25(12):2067–75.
doi:10.1017/S1041610213001415.
15. Meagher D, Agar MR, Teodorczuk A. Debate article:
antipsychotic medications are clinically useful for the
treatment of delirium. Int J Geriatr Psychiatry. 2018;
33(11):1420–7. doi:10.1002/gps.4759.
16. Agar MR, Lawlor PG, Quinn S, Draper B, Caplan
GA, Rowett D, Sanderson C, Hardy J, Le B,
Eckermann S, et al. Efficacy of oral risperidone, halo-
peridol, or placebo for symptoms of delirium among
patients in palliative care: a randomized clinical trial.
JAMA Intern Med. 2017;177(1):34–42. doi:10.1001/
jamainternmed.2016.7491.
17. Okuyama T, Yoshiuchi K, Ogawa A, Iwase S,
Yokomichi N, Sakashita A, et al. Current pharmaco-
therapy does not improve severity of hypoactive delir-
ium in patients with advanced cancer:
pharmacological audit study of safety and efficacy in
real world (Phase-R). Oncologist. 2019;24(7):
e574–e582. doi:10.1634/theoncologist.2018-0242.
18. Felton MA, Jarrett JB, Hoffmaster R, D’Amico FJ,
Sakely H, Pruskowski J. Comparison of haloperidol,
non-haloperidol antipsychotics, and no pharmacother-
apy for the management of delirium in an inpatient
geriatric palliative care population. J Pain Palliat Care
Pharmacother. 2018;32(2-3):141–8. doi:10.1080/
15360288.2018.1513434.
19. Boland JW, Kabir M, Bush SH, Spiller JA, Johnson
MJ, Agar M. Delirium management by palliative
medicine specialists: a survey from the association for
palliative medicine of Great Britain and Ireland. BMJ
Support. 2019;bmjspcare–2018–001586. doi:10.1136/
bmjspcare-2018-001586.
20. Agar M, Currow D, Draper B, Phillips P, Plummer J.
Anticholinergic levels and risk of delirium in
advanced cancer. Support Care Cancer. 2012;1:S202.
21. Gaudreau JD, Gagnon P, Harel F, Tremblay A, Roy
MA. Fast, systematic, and continuous delirium assess-
ment in hospitalized patients: the nursing delirium
screening scale. J Pain Symptom Manage. 2005;29(4):
368–75. doi:10.1016/j.jpainsymman.2004.07.009.
22. Barnes CJ, Webber C, Bush SH, McNamara-Kilian M,
Brodeur J, Marchington K, Sabri E, Lawlor PG.
Rating delirium severity using the nursing delirium
screening scale: a validation study in patients in pal-
liative care. J Pain Symptom Manage. 2019;58(4):
e4–e7. doi:10.1016/j.jpainsymman.2019.06.027.
23. European Delirium Association, American Delirium
Society. The DSM-5 criteria, level of arousal and
12 K. Y. LEE ET AL.
delirium diagnosis: inclusiveness is safer. BMC Med.
2014;12(1):141.
24. Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL,
Morichi V, Spazzafumo L, Mancinelli L, Espinosa E,
Rappelli A, et al. A manual of guidelines to score the
modified cumulative illness rating scale and its valid-
ation in acute hospitalized elderly patients. J Am
Geriatr Soc. 2008;56(10):1926–31. doi:10.1111/j.1532-
5415.2008.01935.x.
25. Adamis D. Statistical methods for analysing longitu-
dinal data in delirium studies. Int Rev Psychiatry.
2009;21(1):74–85. doi:10.1080/09540260802675346.
26. Nobay F, Simon BC, Levitt MA, Dresden GM. A pro-
spective, double-blind, randomized trial of midazolam
versus haloperidol versus lorazepam in the chemical
restraint of violent and severely agitated patients.
Acad Emergency Med. 2004;11(7):744–9. doi:10.1111/
j.1553-2712.2004.tb00738.x.
27. Maust DT, Kim HM, Seyfried LS, Chiang C,
Kavanagh J, Schneider LS, Kales HC. Antipsychotics,
other psychotropics, and the risk of death in patients
with dementia: Number needed to harm. JAMA
Psychiatry. 2015;72(5):438–45. doi:10.1001/jamapsy-
chiatry.2014.3018.
28. Hosie A, Agar M, Lobb E, Davidson PM, Phillips J.
Palliative care nurses’ recognition and assessment of
patients with delirium symptoms: a qualitative study
using critical incident technique. Int J Nurs Stud. 2014;
51(10):1353–65. doi:10.1016/j.ijnurstu.2014.02.005.
29. Lawlor PG, Bush SH. Delirium diagnosis, screening
and management. Curr Opin Support Palliat Care.
2014;8(3):286–95. doi:10.1097/SPC.0000000000000062.
30. Neufeld KJ, Yue J, Robinson TN, Inouye SK,
Needham DM. Antipsychotic medication for preven-
tion and treatment of delirium in hospitalized adults:
a systematic review and meta-analysis. J Am Geriatr
Soc. 2016;64(4):705–14. doi:10.1111/jgs.14076.
31. Hosie A, Lobb E, Agar M, Davidson PM, Phillips J.
Identifying the barriers and enablers to palliative care
nurses’ recognition and assessment of delirium symp-
toms: a qualitative study. J Pain Symptom Manage.
2014;48(5):815–30. doi:10.1016/j.jpainsymman.2014.01.
008.
32. Rose L, Agar M, Burry LD, Campbell N, Clarke M,
Lee J, Siddiqi N, Page VJ. Development of core out-
come sets for effectiveness trials of interventions to
prevent and/or treat delirium (Del-COrS): study
protocol. BMJ Open. 2017;7(9):e016371doi:10.1136/
bmjopen-2017-016371.
33. Sweet L, Adamis D, Meagher DJ, Davis D, Currow
DC, Bush SH, Barnes C, Hartwick M, Agar M, Simon
J, et al. Ethical challenges and solutions regarding
delirium studies in palliative care. J Pain Symptom
Manage. 2014;48(2):259–71. doi:10.1016/j.jpainsym-
man.2013.07.017.