Volume 39, Issue 2 , Pages 186-196, February 2010
Neuroleptic Dose in the Management of Delirium in Patients with Advanced Cancer
Article Outline
- Abstract
- Introduction
- Methods
- Results
- Baseline Characteristics
- Medication Administration by Delirium Subtype
- Haloperidol Daily Dose and HEDD by Delirium Subtype
- Haloperidol Daily Dose and HEDD According to Patients' Delirium Recall and Distress Based on the DEQ
- Median Average Haloperidol Daily Dose and HEDD According to Patients', Caregivers', Nurses', and Physicians' Delirium Symptom Recall and Related Distress
- Discussion
- References
- Copyright
Abstract
Neuroleptics are commonly used in the management of delirium. Limited information is available regarding the dosage requirements and efficacy of neuroleptics in the palliative care setting. We determined the type and dose of neuroleptic use by delirium subtype. The medical records of 99 inpatients with advanced cancer were reviewed retrospectively. The doses of different neuroleptics, expressed as haloperidol equivalent daily doses (HEDDs), were correlated with delirium recall, recalled delirium symptom frequency, and associated distress from the patients', family caregivers', nurses' and palliative care specialists' perspectives. Subtypes of delirium included hypoactive in 20 (20%), mixed in 66 (67%), and hyperactive in 13 (13%). The median HEDD was 2.5
mg, interquartile range (Q1–Q3) 1–4.7mg (mean 4.0±5.9mg), and it was significantly higher in agitated and mixed delirium as compared with hypoactive delirium (P=0.008). The neuroleptic dose was low and appeared to be ineffective in preventing patient delirium recall, with 73 (74%) patients remembering their episode of delirium as distressing. HEDD did not correlate with delirium recall, recalled symptom frequency, or distress for patients and family caregivers. However, HEDD increased with nurses' distress related to patients' symptoms (disorientation to place P=0.002, disorientation to time P=0.008, delusions P=0.041, and agitation P<0.001), and palliative care specialists' distress related to patients' hallucinatory symptoms (P=0.006) and agitation (P=0.006). In this study, the administered neuroleptic dose was influenced more by health care professional distress than by delirium symptom frequency. Future studies should examine the efficacy of neuroleptic dose according to individual delirium symptoms.
Key Words: Delirium, neoplasms, haloperidol, neuroleptic agents, palliative care
Introduction
Delirium is the most frequent neuropsychiatric complication in patients with advanced cancer, occurring in up to 85% of patients before death.1, 2, 3 It is characterized by a fluctuating level of consciousness, decreased attention and cognition, and restlessness and perceptual abnormalities that fluctuate over time.4, 5 Delirium interferes with symptom assessment and treatment in patients6 and is associated with significant morbidity7, 8 and mortality.4 In patients with advanced cancer, delirium poses an additional burden, as the cognitive and attention deficits hinder patients' ability to communicate with their families and prevent them from participating in important health care decisions regarding treatments and goals of care.6
Various neuroleptic medications have been used to control symptoms of delirium, including haloperidol, olanzapine, risperidone, and quetiapine.9 Among these medications, haloperidol is the most commonly used in everyday practice.10 Many of the studies on haloperidol have been carried out in the postoperative setting and the elderly population,11, 12, 13 with few studies on patients with advanced cancer.14, 15 In many instances, delirium is undertreated using suboptimal neuroleptic doses.16
The current management of delirium is often ineffective in reducing the symptom burden in patients with advanced cancer and associated family distress. A recent study from our group showed that 73 of 99 patients with advanced cancer (74%) remembered the episode of being delirious. Among those, 59 (81%) reported the experience as distressing. The family caregivers of these patients also reported levels of distress similar to or worse than those reported by the patients.17 This high percentage of recall and associated distress occurred with neuroleptics, primarily haloperidol, administered as per standard of care.
To date, no studies have examined the relationship between neuroleptic dose and delirium symptom frequency and associated distress. A clear understanding of current practices with neuroleptics, and an assessment of their effectiveness in treating delirium symptoms, and thereby reducing related distress, would provide important insights for optimizing the management of this devastating syndrome. In this study, we aimed to determine the pattern of neuroleptic use by delirium subtype in patients with advanced cancer, and the relationship between neuroleptic dose with recalled delirium symptom frequency and associated distress from the patients', family caregivers', nurses' and palliative care specialists' perspectives.
Methods
Subjects
This study was approved by the Institutional Review Board at M. D. Anderson Cancer Center with waiver of informed consent. A retrospective chart review of 99 inpatients with advanced cancer, who had previously enrolled on an earlier study17 on delirium recall and related distress between August 2005 and August 2007, was performed. The inclusion and exclusion criteria have been described in detail previously.17 Specifically, patients had been included in the previous study if they had advanced cancer, older than 18 years, met the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV-TR) criteria for delirium during the inpatient admission, were able to communicate in English, and experienced complete resolution of all delirium symptoms (according to DSM-IV-TR criteria) within three days of study entry with a Memorial Delirium Assessment Scale (MDAS) less than 13.18 Inpatient sources included the acute palliative care unit, intensive care units, and oncology units. In all cases, patients received at least one consultation from a palliative medicine specialist.
Caregivers, defined as patient's spouse, adult child, sibling, parent, other relative, or significant other (any other person defined by the patient as a partner), 18 years or older, at the patient's bedside at least four hours each day during patient delirium episode, and able to communicate in English were also included in the prospective study. Clinical nurses, defined as the inpatient nurses who provided care while the patient was experiencing delirium during day shift, and the palliative care specialists, defined as mid-level advanced nurse practitioners and palliative care physicians delivering care for the patient during the episode of delirium, were also interviewed. Baseline patient characteristics, cancer diagnosis, and delirium characteristics (including subtype, duration, and etiology) were collected previously.17
Neuroleptic Doses
To determine the clinical use of haloperidol for the 99 patients, we retrospectively collected information regarding haloperidol orders (regularly scheduled and as-needed prescribed dose, route, frequency) and administered haloperidol doses (regularly scheduled and as needed) from the time of diagnosis of delirium to the day of resolution. In addition to haloperidol, we documented the administered doses of sedative neuroleptics (chlorpromazine and olanzapine) and benzodiazepines (lorazepam and midazolam) given to the patients over the same period of time.
To facilitate comparison among patients who received multiple neuroleptics, we calculated the haloperidol equivalent daily dose (HEDD) using the concept of defined daily dose (DDD).19 DDD is a theoretical unit of measurement defined as the assumed standard daily dose for a drug used for its main indication in adults.20 The DDDs for haloperidol (oral or parenteral), chlorpromazine (parenteral), and olanzapine (oral) are 8mg, 100mg, and 10mg, respectively. Based on the assumption that these dosages have equivalent treatment effect, we used the following formula for determination of HEDD:
Delirium Recall, Recalled Symptoms, and Associated Distress
The key measured clinical outcomes included the Mini-Mental State Examination (MMSE),21 the MDAS,18 the Delirium Experience Questionnaire (DEQ),22 and a questionnaire to measure delirium recall. The study assessments were conducted less than or equal to three days after delirium resolution to ensure the highest possible level of recall by the patient, family caregiver, nurse and palliative care specialist.
Details of each instrument have been discussed in detail previously.17 Briefly, the DEQ was administered to patients who had recovered from a delirium episode and assessed recall of the delirium experience and the level of distress related to the delirium episode in patients.22 The questions included the following: 1) Do you remember being confused? (Yes or No), 2) If no, are you distressed that you cannot remember? (Yes or No), 3) How distressed? (0–4 numerical rating scale with 0=not at all and 4=extremely), 4) If you do remember being confused, was the experience distressing? (Yes or No), 5) How distressing? (0–4), and 6) Can you describe the experience? (answer was tape recorded and transcribed verbatim).
The research nurse interviewed patients, family caregivers, nurses and palliative care specialists separately and recorded the recalled frequency of delirium symptoms and associated distress for themselves.17 Various symptoms of delirium were examined: disorientation to time, disorientation to place, visual hallucinations, tactile hallucinations, auditory hallucinations, delusional thoughts, and psychomotor agitation. All respondents were asked to recall the frequency of these symptoms, scoring 0=not present, 1=a little of the time, 2=some of the time, 3=good part of the time, and 4=most or all of the time. In addition, they were asked to score the emotional distress for themselves associated with each delirium symptom on a scale from 0 to 4 (0=no distress, 1=a little, 2=a fair amount, 3=very much, and 4=extremely distressed). Results for the three hallucinatory symptoms were combined during analysis in this study.
Statistical Analysis
To document the use of haloperidol in clinical practice, descriptive statistics, including medians, means, standard deviations, ranges, and frequencies, together with 95% confidence intervals, were used. To determine if the haloperidol dosing differed among the three delirium subtypes, we used the Kruskal-Wallis test for nonparametric variables. The Mann-Whitney test was used to compare the average daily haloperidol dose in patients with low (i.e., score of 0 or 1) or high (i.e., score of 2, 3, 4) frequency of recalled delirium symptoms as documented in the research nurse interview. The Kruskal-Wallis test determined if the haloperidol dose varied according to distress in patients, family caregivers, nurses and palliative care specialists. Spearman's correlation coefficient was used to determine the degree of correlation among recalled delirium symptom frequency, associated distress, and medication doses. The above analyses were also made using HEDD instead of the haloperidol daily dose. A two-sided P-value of less than 0.05 was considered to be of statistical significance.
To determine the relative degree of the variation in HEDD that was related to delirium-related distress, distress variables that demonstrated a significant association (P<0.10) with HEDD were included in a nonparametric multiple regression model and the R2 was determined for each of several combinations of factors using backward elimination.
The Statistical Package for the Social Sciences (SPSS version 16.0, SPSS, Inc., Chicago, IL) software was used for statistical analysis.
Results
Baseline Characteristics
The characteristics of the 99 patients and their corresponding caregivers in this cohort are shown in Table 1. The average patient age was 60; 54% were male. Lung, gastrointestinal, and genitourinary cancers constituted more than half of all the cases. Caregivers tended to be younger, with a median age of 55. In contrast to patients, 73% of all caregivers were female.
Table 1. Baseline Patient and Family Caregiver Characteristics
| Patient (n=99) | Family Caregiver (n=99) | |
|---|---|---|
| Average age (range) | 60 (25–83) | 55 (25–80) |
| Female, n (%) | 46 (46) | 72 (73) |
| Ethnicity, n (%) | ||
| Caucasian | 76 (77) | 76 (77) |
| African American | 15 (15) | 15 (15) |
| Hispanic | 7 (7) | 6 (7) |
| Asian | 1 (1) | 2 (2) |
| Primary cancer diagnosis, n (%) | ||
| Lung | 30 (30) | NA |
| Gastrointestinal | 20 (20) | |
| Genitourinary | 13 (13) | |
| Breast | 8 (8) | |
| Gynecologic | 8 (8) | |
| Leukemia | 5 (5) | |
| Melanoma | 5 (5) | |
| Other | 10 (10) | |
| Median duration of acute episode of delirium in days (25–75 quartile) | 3 (2–5) | NA |
| Median MDASa score (25–75 quartile) | 3 (2–5) | NA |
| Median MMSEa score (25–75 quartile) | 28 (26–29) | NA |
| Educational level, n (%) | ||
| High school or lower | 42 (42) | 29 (29) |
| College or above | 56 (57) | 68 (68) |
| Not available | 1 (1) | 3 (3) |
| Relationship to patient, n (%) | ||
| Spouse/significant others | NA | 61 (62) |
| Adult child | 21 (21) | |
| Sibling | 8 (8) | |
| Friend | 4 (4) | |
| Parent | 5 (5) | |
| Medications administered to patient, n (%) | ||
| Haloperidol | 71 (72) | NA |
| Olanzapine | 17 (17) | |
| Chlorpromazine | 12 (12) | |
| Lorazepam | 14 (14) | |
| Midazolam | 2 (2) | |
| No neuroleptic or benzodiazepine | 18 (18) | |
aMDAS and MMSE were performed at the time of enrollment into the study after patients had recovered from their delirium episode. |
Delirium subtypes included hypoactive (20%), mixed (67%), and hyperactive (13%), with a median duration of 2.5 days (interquartile range [Q1–Q3] 1.3–5 days), three days (2–4 days), and four days (2–7 days), respectively.
Medication Administration by Delirium Subtype
Table 1 lists the medications used for managing delirium in our cohort. Haloperidol was given to most of the patients (72%), whereas olanzapine and chlorpromazine were given only to 17% and 12%, respectively. When medication use was analyzed by delirium subtype, chlorpromazine (P=0.01, Fisher's exact test), lorazepam (P=0.016), and midazolam (P=0.016) were preferentially given to patients with hyperactive delirium but not haloperidol (P=0.47) or olanzapine (P=0.11). Among patients who received haloperidol, those with hyperactive delirium tended to be given other neuroleptics (P=0.03) and benzodiazepines (P=0.004) more often than patients with other delirium subtypes.
Haloperidol Daily Dose and HEDD by Delirium Subtype
In addition to the mean haloperidol daily dose and HEDD, the median has been reported in Table 2. The large difference between mean and median scores is because two Caucasian patients with hyperactive delirium needed much larger doses of neuroleptics. A 66-year-old female patient, with non-small cell lung cancer and leptomeningeal disease, received a total haloperidol daily dose of 45mg by intermittent regular parenteral doses and finally infusional haloperidol, with multiple as-needed haloperidol doses throughout. In addition, this patient received chlorpromazine (total HEDD dose=46mg) and midazolam. A 60-year-old male patient, with a diagnosis of non-small cell lung cancer, with metastases to pleura, lymph nodes and bone, received a total haloperidol daily dose of 27mg by intermittent regular and as-needed parenteral doses. The total HEDD dose was 28mg with both chlorpromazine and olanzapine being administered.
Table 2. Average Haloperidol Daily Dose and Equivalent Daily Dose by Delirium Subtype
| Hypoactive Delirium (n=20) | Mixed Delirium (n=66) | Hyperactive Delirium (n=13) | P-valuea | All Delirium Subtypes (n=99) | |
|---|---|---|---|---|---|
| Total haloperidol daily dose (mg) | |||||
| Median (Q1–Q3) | 1.4 (0.4–2.4) | 1.0 (0–3.2) | 2.8 (0.3–6) | 0.285 | 1.3 (0–3.2) |
| Mean (SD) | 1.5 (1.5) | 2.1 (2.6) | 7.7 (13.5) | 2.7 (5.6) | |
| Regular haloperidol daily dose (mg) | |||||
| Median (Q1–Q3) | 1.3 (0–1.9) | 0.9 (0–2.5) | 1.6 (0–4.5) | 0.569 | 1 (0–2.5) |
| Mean (SD) | 1.3 (1.3) | 1.7 (2.0) | 5.3 (9.3) | 2.1 (3.9) | |
| As-needed haloperidol daily dose (mg) | |||||
| Median (Q1–Q3) | 0.08 (0–0.6) | 0.0 (0–0.5) | 0.7 (0–2.8) | 0.081 | 0 (0–0.7) |
| Mean (SD) | 0.3 (0.3) | 0.5 (1.2) | 2.3 (5.0) | 0.7 (2.1) | |
| Total HEDD dose (mg) | |||||
| Median (Q1–Q3) | 1.5 (0.5–2.6) | 2.6 (0.9–4.7) | 5 (2.5–13.4) | 0.008 | 2.5 (1–4.7) |
| Mean (SD) | 1.8 (1.6) | 3.4 (3.1) | 10.4 (13.1) | 4.0 (5.9) | |
| Regular HEDD dose (mg) | |||||
| Median (Q1–Q3) | 1.3 (0.1–2) | 2 (0.58–4) | 4.3 (1.6–9.0) | 0.021 | 2 (0.7–4) |
| Mean (SD) | 1.5 (1.4) | 2.7 (2.6) | 7.3 (8.8) | 3.0 (4.2) | |
| As-needed HEDD dose (mg) | |||||
| Median (Q1–Q3) | 0.08 (0–0.6) | 0 (0–1) | 2.0 (0–3.3) | 0.041 | 0.14 (0–1) |
| Mean (SD) | 0.27 (0.3) | 0.73 (1.3) | 3.1 (5.1) | 0.95 (2.3) | |
aThe Kruskal-Wallis test was used to determine differences in haloperidol dosages among different subtypes of delirium. |
Table 2 highlights the average haloperidol daily dose. The median average total haloperidol daily dose was 1.3mg (Q1–Q3 0–3.2mg), with no significant difference in dose by delirium subtype (P=0.29).
Haloperidol was responsible for 76% of the overall HEDD, whereas olanzapine and chlorpromazine constituted the remainder. The median average total HEDD was 2.5mg (Q1–Q3 1–4.7) (Table 2). There was a significant increase in total neuroleptic requirement across the spectrum of delirium subtypes (P=0.008, Kruskal-Wallis test), with patients with hypoactive delirium receiving the least, and patients with hyperactive delirium receiving the highest HEDD. This difference remained significant when HEDD was analyzed by regular doses (P=0.021) and as-needed doses (P=0.041).
Haloperidol Daily Dose and HEDD According to Patients' Delirium Recall and Distress Based on the DEQ
The DEQ provided information regarding patients' recall and level of distress related to the delirium episode. Neither the haloperidol dose nor HEDD varied according to patients' delirium recall or associated distress level (data not shown).
Median Average Haloperidol Daily Dose and HEDD According to Patients', Caregivers', Nurses', and Physicians' Delirium Symptom Recall and Related Distress
The median average haloperidol daily dose was analyzed according to patients', caregivers', nurses', and physicians' recall of delirium symptoms based on the research nurse interview (disorientation to time, place, hallucinations, delusions, and agitation), and the associated distress related to each symptom (Table 3). No significant difference was detected in the haloperidol dose between high and low levels of recalled delirium symptom frequency and associated distress for both patients and caregivers. However, the dose of haloperidol significantly increased with nurses' recalled symptoms (delusions P=0.002, agitation P=0.024) and nurse distress related to patients' symptoms (delusions P=0.003, agitation P=0.004), as well as palliative care specialists' distress related to patient's hallucinatory symptoms (P=0.03).
Table 3. Median Average Haloperidol Daily Dose and Equivalent Daily Dose According to Patients', Caregivers', Nurses', and Physicians' Delirium Symptom Recall and Related Distress
| Delirium Symptoms | Patients | Caregivers | Nurses | Palliative Care Specialists | ||||
|---|---|---|---|---|---|---|---|---|
| Frequency | Distress | Frequency | Distress | Frequency | Distress | Frequency | Distress | |
| Haloperidol Daily Dose | ||||||||
| Disorientation to place | ||||||||
| High | 1.3 (35) | 1.2 (36) | 1.0 (58) | 1.0 (55) | 1.7 (36) | 4.3 (8) | 1.1 (51) | 1.9 (13) |
| Low | 1.4 (56) | 1.4 (48) | 1.7 (41) | 1.5 (35) | 1.2 (44) | 1.5 (65) | 1.5 (43) | 1.0 (76) |
| P-value | 0.39 | 0.89 | 0.068 | 0.14 | 0.82 | 0.13 | 0.78 | 0.56 |
| Disorientation to time | ||||||||
| High | 1.0 (47) | 1.0 (40) | 1.2 (64) | 1.0 (52) | 2.3 (43) | 5.6 (6) | 1.5 (59) | 2.0 (16) |
| Low | 1.8 (44) | 1.5 (45) | 1.5 (35) | 1.5 (41) | 1.0 (36) | 1.5 (69) | 1.0 (35) | 1.1 (75) |
| P-value | 0.15 | 0.48 | 0.66 | 0.20 | 0.067 | 0.087 | 0.66 | 0.37 |
| Hallucinations | ||||||||
| High | 1.0 (39) | 1.0 (33) | 1.3 (46) | 1.7 (47) | 1.6 (9) | 1.8 (6) | 1.8 (38) | 3.6 (10) |
| Low | 1.4 (56) | 1.5 (47) | 1.2 (52) | 1.0 (43) | 1.5 (71) | 1.3 (63) | 1.2 (56) | 1.0 (79) |
| P-value | 0.65 | 0.93 | 0.84 | 0.22 | 0.91 | 0.45 | 0.41 | 0.030 |
| Delusions | ||||||||
| High | 1.3 (18) | 1.0 (23) | 1.0 (33) | 1.3 (36) | 4.3 (10) | 4.3 (7) | 1.1 (20) | 0.75 (9) |
| Low | 1.3 (78) | 1.3 (57) | 1.3 (65) | 1.3 (49) | 1.1 (70) | 1.3 (64) | 1.5 (75) | 1.3 (80) |
| P-value | 0.68 | 0.94 | 0.39 | 0.77 | 0.002 | 0.003 | 0.80 | 0.95 |
| Agitation | ||||||||
| High | 1.5 (46) | 1.3 (45) | 1.4 (66) | 1.3 (69) | 2.5 (25) | 4.6 (11) | 1.7 (48) | 2.3 (23) |
| Low | 1.0 (48) | 1.4 (40) | 1.0 (33) | 1.3 (22) | 1.0 (55) | 1.1 (62) | 1.0 (47) | 1.0 (69) |
| P-value | 0.74 | 0.77 | 0.30 | 0.95 | 0.024 | 0.004 | 0.076 | 0.23 |
| Haloperidol Equivalent Daily Dose | ||||||||
| Disorientation to place | ||||||||
| High | 3.2 (35) | 2.6 (36) | 2.5 (58) | 2.0 (55) | 3.5 (36) | 7.0 (8) | 2.7 (51) | 3.3 (13) |
| Low | 2.3 (56) | 1.8 (48) | 2.5 (41) | 2.8 (35) | 2.3 (44) | 2.5 (65) | 2.0 (43) | 2.0 (76) |
| P-value | 0.40 | 0.48 | 0.70 | 0.24 | 0.21 | 0.002 | 0.94 | 0.32 |
| Disorientation to time | ||||||||
| High | 2.7 (47) | 2.5 (40) | 2.5 (64) | 1.8 (52) | 4.0 (43) | 7.0 (6) | 2.7 (59) | 3.7 (16) |
| Low | 2.2 (44) | 2.7 (45) | 2.5 (35) | 3.0 (41) | 1.7 (36) | 2.5 (69) | 2.0 (35) | 2.0 (75) |
| P-value | 0.82 | 0.94 | 0.42 | 0.54 | 0.013 | 0.008 | 0.43 | 0.18 |
| Hallucinations | ||||||||
| High | 2.7 (39) | 3.5 (33) | 2.8 (46) | 3.2 (47) | 2.5 (9) | 4.6 (6) | 2.7 (38) | 7.5 (10) |
| Low | 1.9 (56) | 2.0 (47) | 1.9 (52) | 1.7 (43) | 2.8 (71) | 2.5 (63) | 2.0 (56) | 2.0 (79) |
| P-value | 0.59 | 0.30 | 0.39 | 0.14 | 0.91 | 0.20 | 0.51 | 0.006 |
| Delusions | ||||||||
| High | 3.1 (18) | 2.5 (23) | 1.5 (33) | 1.8 (36) | 4.6 (10) | 4.3 (7) | 3.6 (20) | 4.0 (9) |
| Low | 2.3 (78) | 2.5 (57) | 3.0 (65) | 2.8 (49) | 2.0 (70) | 2.3 (64) | 2.0 (75) | 2.0 (80) |
| P-value | 0.53 | 0.90 | 0.18 | 0.52 | 0.006 | 0.041 | 0.43 | 0.75 |
| Agitation | ||||||||
| High | 2.6 (46) | 2.5 (45) | 3.0 (66) | 2.5 (69) | 3.5 (25) | 6 (11) | 3.3 (48) | 4.3 (23) |
| Low | 1.8 (48) | 1.8 (40) | 1.7 (33) | 1.6 (22) | 2.0 (55) | 1.9 (62) | 1.7 (47) | 1.9 (69) |
| P-value | 0.16 | 0.27 | 0.05 | 0.36 | 0.028 | 0.001 | 0.028 | 0.006 |
When the same analysis was performed using HEDD instead of haloperidol daily dose, a similar pattern was observed (Table 3). The HEDD did not significantly vary by patients' and family caregivers' symptom recall frequency and distress, but it significantly increased with nurses' recalled symptoms (disorientation to time P=0.013, delusions P=0.006, agitation P=0.028) and distress related to patients' symptoms (disorientation to place P=0.002, disorientation to time P=0.008, delusions P=0.041, and agitation P<0.001). For palliative care specialists, a high level of recalled patient agitation (P=0.028), and distress related to patients' hallucinations (P=0.006) and agitation (P=0.006) were associated with an elevation in HEDD.
In addition, we distinguished among regular doses and as-needed doses for both haloperidol and HEDD (data not shown). We found that the nurses' recall and own distress related to particular patient symptoms were an important determinant of both haloperidol- and HEDD-administered regular doses and as-needed doses. Regular haloperidol doses increased with nurse recall of delusions and related distress. As-needed haloperidol doses increased with nurse recall and distress of both delusions and agitation, and distress to patient disorientation of time. Regular HEDD doses were influenced by nurse recall of delusions and disorientation to time, and nurse distress to agitation and disorientation to location, and palliative care specialist distress related to patient agitation and hallucinations. Nurse recall and distress to delusions, agitation, and disorientation to location and also distress to disorientation to time were associated with higher as-needed HEDD doses.
To confirm the above findings, we further analyzed the data using Spearman's correlation test (data not shown), with similar results supporting the finding that a higher level of recalled symptom and self-reported distress in health care professionals, but not patients and families, was associated with increased average haloperidol daily dose and HEDD.
To determine the extent in which distress in health care professionals contributed to HEDD, we fitted all six variables pertaining to distress that demonstrated a significant association with HEDD (Table 3) into a nonparametric multiple regression model (i.e., distress in nurses related to recalled patient disorientation to place, time, delusion and agitation, and distress in palliative care specialists related to recalled patient hallucination and agitation). The R2 statistic was 0.32 with all six distress variables and 0.31 with only three of the distress variables (nurses' distress related to patients' disorientation to location and agitation, and palliative care specialists' distress related to agitation).
Discussion
Our results indicate that the HEDD of neuroleptics varied according to delirium subtype. However, the delirium subtype variation in median HEDD dose (1.5–5mg) and overall median HEDD dose for all delirium subtypes (2.5mg) was low. Both haloperidol dose and HEDD increased with nurse and palliative care specialist distress related to certain recalled delirium symptoms. For both these groups, recalled patient agitation was associated with HEDD.
This is the first study to specifically examine the relationship between neuroleptic dose and delirium symptom frequency and associated distress. Although a number of randomized controlled trials using outcome measures, such as the Delirium Rating Scale,23 MMSE,23 MDAS,24 and Delirium Index25 concluded that haloperidol and other neuroleptics were efficacious in the management of delirium,11, 12 none have studied distress as an outcome. For patients who have recovered from delirium, both the inability to recall what happened during the episode, and frequently also the ability to recall delirium symptoms (e.g., hallucinations) can be a great source of distress for patients, while perceiving a loved one to be suffering may also result in considerable distress in family caregivers. These findings suggest that optimization of current management of delirium in palliative care patients is urgently needed.
The average daily doses of haloperidol and other neuroleptics in our study were low, which is consistent with the literature (Table 4). Patients with hyperactive delirium received higher doses of neuroleptics than patients with mixed delirium, who in turn were given higher doses than those with hypoactive delirium. These findings are consistent with the fact that hyperactive and, to a certain extent, mixed delirium are associated with increased agitation, which is more easily detected by health care professionals than hypoactive symptoms, and thus treated more frequently.10 A previous retrospective study by the psychiatry department in our institution showed that patients with mixed rather than hyperactive delirium required the highest doses of haloperidol.15 However, in that study, 71% of patients had hyperactive delirium, compared with only 13% in our cohort. Differences in defining delirium subtypes may account for this variation.
Table 4. Summary of Haloperidol Dosages for Management of Delirium
| Study | Patient Population | Study Design | Average Daily Haloperidol Dose (milligrams) |
|---|---|---|---|
| Riker et al. 199427 | Critical care patients with agitation (n=8) | Prospective study of infusional haloperidol | 68–269 |
| Akechi et al. 199614 | Hospitalized cancer patients with delirium seen by psychiatry (n=10) | Prospective dose finding | 5.4±3.4 |
| Olofsson et al. 199615 | Hospitalized cancer patients with delirium seen by psychiatry (n=90) | Retrospective | 10.4 |
| Breitbart et al. 199623 | Hospitalized human immunodeficiency virus patients with delirium (n=11) | Prospective randomized study of haloperidol vs. chlorpromazine vs. lorazepam | 2.8±2.4 |
| Nakamura et al. 199728 | Hospitalized patients with delirium (n=66) | Prospective study of haloperidol or mianserin with serum dose levels | 2–6 |
| Sipahimalani and Masand 199829 | Hospitalized patients with delirium (n=11) | Retrospective | 5.1±3.5 |
| Schwartz and Masand 200030 | Hospitalized patients with delirium (n=11) | Retrospective | 3.4mg |
| Breitbart et al. 200222 | Hospitalized cancer patients with delirium (n=154) | Prospective series | 4.8±0.49 |
| Skrobik et al. 200425 | Critical care patients (n=45) | Prospective randomized study of haloperidol vs. olanzapine | 6.5 |
| Han and Kim 200424 | Hospitalized patients with delirium (n=12) | Prospective randomized study of haloperidol vs. risperidone | 1.71±0.84 |
| Hu et al. 200431 | Hospitalized elderly patients with delirium (n=72) | Prospective randomized study of haloperidol vs. olanzapine vs. placebo | 7.08±2.26 |
| Kim et al. 200532 | Hospitalized patients with delirium (n=24) | Prospective study of haloperidol or risperidone with biologic correlate | 1.67±1.32 |
| Clinical Reviews | Patient Population | Average Daily Haloperidol Dose | |
| Cohen 200233 | Critical care patients with delirium | 2–10mg IV, repeated every 2–4 hours as needed | |
| Centeno et al. 20042 | Advanced cancer patients with delirium | Initial dosage of 2mg PO or 1mg SC every 6 hours, with an additional dose every 1 hour as needed | |
| Vella-Brincat and Macleod 200434 | Palliative care patients with delirium | 0.5–1.5mg PO (mild), 1.5–5mg (severe), 10mg SC/IV (very severe). Repeat every 30–40minutes as needed. Typically 1.5–20mg PO/day | |
| Inouye 200613 | Older persons with delirium | 0.5–1.0mg PO twice a day, with additional doses every 4 hour as needed | |
A key finding of our study is that patients' and caregivers' recalled delirium symptom frequency and associated distress did not alter with haloperidol dose or HEDD, suggesting that current medication use may have limited efficacy in reducing delirium-associated distress. Indeed, Breitbart et al.22 examined 154 cancer patients with delirium and found that 54% recalled their delirium despite pharmacotherapy, predominantly with olanzapine, with a high level of distress in both patients and caregivers. We previously reported an even higher rate of delirium recall by patients.17 In this study, further analysis from the same cohort appears to confirm the lack of efficacy of neuroleptics in reducing delirium-associated distress in patients and caregivers. One potential explanation is that the current medication doses routinely used are inadequate. An American College of Physicians-American Society of Internal Medicine (ACP-ASIM) End-of-Life Care Consensus Panel recommended haloperidol 0.5–1mg orally/subcutaneously/intravenously every 30 minutes as needed, titrated to effect, with a usual maximal dose of only 3mg per day.26 Further research on the efficacy and safety of using higher doses of haloperidol and other neuroleptics in the palliative care setting is needed.
An interesting, but perhaps not completely unexpected, finding is that health care professionals' recall of symptoms and resulting distress, in contrast to those of patients and caregivers, was significantly associated with increased haloperidol doses and HEDD. This was particularly true for nurses, who spend long hours providing care for delirious patients and their families, and understandably could experience significant physical and emotional distress during the process.17, 22 The finding that medication doses increased with health care professional distress implies that they were given in a reactive, rather than a proactive manner. In fact, 31% of the variation in neuroleptic dose could be accounted for by merely three types of distress (nurses' distress related to patients' disorientation to location, nurses' distress related to patients' agitation, and palliative care specialists' distress related to patient's agitation). Further research is needed on the effectiveness of increasing neuroleptic dosing in delirium management and potential associated reduction in distress.
We found that distress in nurses, more than distress in palliative care specialists, was associated with increased administration of as-needed doses of neuroleptics. This is understandable as nurses traditionally decide when as-needed doses should be given. However, we were surprised by the fact that nurses' recall of symptoms and self-reported distress also had a stronger impact on the regular doses than that of palliative care specialists, because palliative care specialists have more control over prescriptions and define regular orders. We postulate that when nurses, who have a lot more contact with patients, detect delirium and experience distress, they persuade palliative care specialists to prescribe higher doses. Alternatively, frequent use of as-needed doses may also indirectly influence palliative care specialists to increase the regular neuroleptic orders.
One of the strengths of this study is the application of DDD19 for converting neuroleptic doses to HEDD, which allowed us to compare the dosages of multiple medications using a common unit similar to the concept of morphine equivalent daily dose. Although olanzapine and chlorpromazine contributed to only 24% of total HEDD, their addition provided a more comprehensive examination of medication use for management of delirium compared with haloperidol alone. This methodology has potential implications for the evaluation and comparison of multiple studies using a universal unit. We also provided a comprehensive examination of the key participants involved in patient care (i.e., caregivers, nurses, palliative care specialists), and in the process, we were able to demonstrate some important differences among them.
This study has a number of limitations, including the small number of patients and retrospective nature of data collection for medication doses. Determination of HEDD using the concept of DDD also warrants further validation. Furthermore, the delirium symptoms were based on recalled information by various parties, rather than a prospective evaluation of patients during the delirium episode. The patients we studied had already recovered from their delirium. This represents a selected group with better outcomes and thus may limit our study's generalizability. Further studies are needed to confirm our findings.
In conclusion, findings from this study have important implications for the management of delirium in patients with advanced cancer. In clinical practice, low doses of neuroleptics are used, which appear to be ineffective in preventing delirium recall. It is not known whether higher neuroleptic dosing and their earlier anticipatory administration before symptoms are severe will reduce the frequency of delirium recall or delirium-related distress in patients and caregivers. Further research is needed to determine effective and safe neuroleptic dosing schedules for the different delirium subtypes and also on the role of nonpharmacologic and environmental strategies to improve the comprehensive management of this distressing syndrome.
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Drs. Hui and Bush contributed equally to this study. Dr. Bruera is supported in part by National Institutes of Health grant numbers RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01. Dr. Hui is funded by a fellowship from the Clinician Investigator Program, Royal College of Physicians and Surgeons of Canada.
PII: S0885-3924(09)01139-7
doi:10.1016/j.jpainsymman.2009.07.009
© 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Volume 39, Issue 2 , Pages 186-196, February 2010
