Table 2.
Study Outcomes Among Patients With Advanced Cancer and Agitated Delirium Receiving Lorazepam + Haloperidol vs Placebo + Haloperidol
| Lorazepam + Haloperidol Group(n = 29) | Placebo + Haloperidol Group (n = 29) | Difference Between Groups (95% CI) [Range] | P Valuea | |||
|---|---|---|---|---|---|---|
| No. of Patientsb | Mean (95% CI) | No. of Patientsb | Mean (95% CI) | |||
| Primary Outcomes | ||||||
| Change in RASS score (baseline to 8 h), pointsc | 26 | −4.1 (−4.8 to −3.4) | 26 | −2.3 (−2.9 to −1.6) | −1.9 (−2.8 to −0.9) | <.001 |
| Absolute RASS score at 8 h, pointsc | 26 | −2.5 (−3.2 to −1.9) | 26 | −0.7 (−1.3 to −0.1) | 1.8 (−2.7 to −0.9) | <.001 |
| Secondary Outcomes | ||||||
| Change in RASS score from baseline to 30 minc | 29 | −3.6 (−4.3 to −2.9) | 29 | −1.6 (−2.2 to −1.0) | −2.0 (−2.9 to −1.1) | <.001 |
| RASS score ≥1 within 8 h, No. of observations (%)c | 29 | 8 (28) | 29 | 22 (76) | % (95% CI), −48 (−71 to −26) | <.001 |
| Neuroleptic use within 8 hd | ||||||
| HEDD, median (IQR) [range], mg | ||||||
| Scheduled | 29 | 2.0 (2.0 to 4.0) [0.0 to 6.0] | 29 | 2.0 (2.0 to 4.0) [0.0 to 5.0] | 0 (0 to 0) [−5 to 6] | .68 |
| Rescue | 29 | 2.0 (2.0 to 2.0) [0.0 to 8.0] | 29 | 4.0 (2.0 to 5.0) [0.0 to 19.0] | −1.0 (−2.0 to 0) [−19.0 to 8.0] | .009 |
| No. of rescue doses | 29 | 1.0 (1.0 to 1.0) [0.0 to 4.0] | 29 | 2.0 (1.0 to 2.0) [0.0 to 7.0] | −0.5 (−1 to 0) [−7.0 to 4.0] | .008 |
| Total | 29 | 6.0 (4.0 to 6.0) [2.0 to 14.0] | 29 | 6.0 (4.0 to 8.0) [2.0 to 21.0] | −1.0 (−2 to 0) [−19.0 to 12.0] | .03 |
| Chlorpromazine, No. of doses (%) | 29 | 2 (6.9) | 29 | 4 (13.8) | −0.1 (−0.3 to 0.2) | .67 |
| Change in MDAS score (baseline to 8 h)e | 25 | 2.5 (0.7 to 4.4) | 25 | 0.4 (−2.2 to 3.0) | 2.1 (−1.0 to 5.2) | .18 |
| Change in respiratory rate/min (baseline to 8 h)e | 21 | −1.5 (−2.7 to −0.3) | 25 | −0.5 (−2.6 to 1.6) | −1.0 (−3.4 to 1.4) | .80 |
| Change in ESAS score (baseline to day 1), mean (SD)f | ||||||
| Pain | 18 | −2.4 (−3.7 to −1.0) | 7 | −1.7 (−5.6 to 2.1) | −0.7 (−3.6 to 2.2) | .67 |
| Fatigue | 11 | 0.1 (−1.2 to 1.3) | 6 | −1.8 (−5.2 to 1.5) | 1.9 (−0.7 to 4.5) | .23 |
| Nausea | 13 | −0.7 (−2.8 to 1.4) | 6 | −2.7 (−6.7 to 1.4) | 2.0 (−1.7 to 5.7) | .49 |
| Depression | 15 | −1.4 (−3.6 to 0.8) | 6 | 0.2 (−2.8 to 3.2) | −1.6 (−5.3 to 2.2) | .56 |
| Anxiety | 18 | −3.4 (−5.3 to −1.6) | 7 | −2.1 (−6.5 to 2.2) | −1.3 (−5.0 to 2.4) | .55 |
| Drowsiness | 17 | 1.9 (0.2 to 3.7) | 7 | −2.0 (−4.9 to 0.9) | 3.9 (0.8 to 7.1) | .03 |
| Shortness of breath | 18 | −1.0 (−2.1 to 0.1) | 7 | −0.4 (−4.6 to 3.7) | −0.6 (−3.3 to 2.2) | .41 |
| Appetite | 15 | 0.6 (−0.3 to 1.5) | 7 | 2.1 (−0.9 to 5.1) | −1.5 (−3.6 to 0.6) | .26 |
| Sleep | 18 | −2.9 (−4.8 to −1.0) | 7 | −2.4 (−6.0 to 1.1) | −0.5 (−4.0 to 3.1) | .74 |
| Feeling of well-being | 14 | −2.3 (−4.2 to −0.4) | 6 | −1.5 (−4.9 to 1.9) | −0.8 (−4.2 to 2.6) | .51 |
| Improvement in comfort on day 1, No. of patients (%)g | % (95% CI) | |||||
| Assessed by caregiver | 19 | 16 (84) | 19 | 7 (37) | 47 (14 to 73) | .007 |
| Assessed by nurse | 22 | 17 (77) | 20 | 6 (30) | 47 (17 to 71) | .005 |
| UKU adverse effects, No. of patients with increased level on day 3 vs baseline (%)h | ||||||
| Dystonia | 16 | 0 | 15 | 0 | ||
| Rigidity | 16 | 0 | 15 | 0 | ||
| Hypokinesia or akinesia | 16 | 3 (18.8) | 15 | 4 (26.7) | −8 (−40 to 28) | .68 |
| Hyperkinesia | 16 | 1 (6.3) | 15 | 2 (13.3) | −7 (−40 to 28) | .60 |
| Tremor | 16 | 0 | 15 | 0 | ||
| Akathisia | 16 | 3 (18.8) | 15 | 1 (6.7) | 12 (−22 to 45) | .60 |
| Epilepticseizure | 16 | 0 | 15 | 0 | ||
| Paresthesia | 16 | 0 | 15 | 0 | ||
| Discharged alive from the acute palliative care unit, No. of patients (%) | 29 | 9 (31) | 29 | 7 (24.1) | 6.9 (−20 to 33) | .77 |
| Duration of acute palliative care unit stay, median (IQR),d | 29 | 6 (4 to 9) | 29 | 6 (3 to 8) | Difference, 1(−1 to 3)i | .35 |
| Overall survival from treatment administration, median (95% CI), hj | 29 | 68 (49 to 130) | 29 | 73 (38 to 106) | HR, 1.2 (0.7 to 2.2) | .56 |
Abbreviations: ESAS, Edmonton Symptom Assessment System; HEDD, haloperidol equivalent daily dose; HR, hazard ratio; IQR, interquartile range; MDAS, Memorial Delirium Assessment Scale; RASS, Richmond Agitation-Sedation Scale; UKU, Udvalg for Kliniske Undersøgelser.
The change in study outcomes was compared before and after medication administration between groups using 2-tailed Wilcoxon Rank Sum test for continuous variables and 2-tailed Fisher exact test for categorical variables. All secondary outcomes should be considered hypothesis-generating.
Patients with data available for each analysis are shown. The number of patients with missing data varied because of attrition (eg, death), the specific timing of study assessments (eg, day 1 vs day 3), and the availability of caregivers and bedside nurses.
RASS is a validated 10-point numeric rating scale that was assessed by the bedside nurse immediately prior to study medication administration and then at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, and 8 h. (score range, −5 [unarousable] to 4 [very agitated and combative]; 0 indicates that a patient is alert and calm).
The total dose of neuroleptics during the first 8 h was calculated based on the concept of HEDD, in which 8 mg of parenteral haloperidol is equivalent to 100 mg of parenteral chlorpromazine.20 This concept has been used in multiple studies to examine neuroleptic use.21,22 The 95% CIs for the median between-group difference were estimated by the Hodges-Lehmann method of location shift for 2-sample data.
Avalidated 10-item, clinician-rated assessment scale for delirium in patients with cancer18,19 that examines the level of consciousness, disorientation, memory, recall, attention, disorganized thinking, perceptual disturbance, delusions, psychomotor activity, and sleep (each item score range, 0–3; total score range, 0–30; a score of13 or higher indicates delirium). This assessment was conducted by the bedside nurse or research coordinator at the time of enrollment; time of study medication administration; at 2 h, 4 h, 8 h, and 24 h after study medication administration; and then daily until discharge.
The ESAS is a symptom battery that has been validated and widely used in different clinical settings, including the acute palliative care unit.14,15,23 Because patients were delirious, caregivers were asked to provide their proxy rating of ESAS daily. It assessed the symptom intensity of 10 symptoms (pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and feeling of well-being) over the past 24 h. Each symptom was assessed using an 11-point numeric rating scale (range, 0–10; a higher score indicates worse symptoms).
Assessed by asking the following question independently: “In my opinion, the patient was more comfortable after the study medication.” The responses ranged from “strongly agree,” “agree,” “neutral,” “disagree,” and “strongly disagree.”
In this study, “strongly agree” and “agree” were combined for analysis.
Eight neurologic symptoms were documented using the UKU adverse effects rating scale at baseline and day 3 (dystonia, rigidity, hypokinesia or akinesia, hyperkinesia, tremor, akathisia, epileptic seizures, paresthesias). Each item was assigned a score from 0 (absent) to 3 (most severe) based on symptom severity of the last 3 d.16
Estimated by the Hodges-Lehmann method of location shift for 2-sample data.
Overall survival was calculated from time of study medication administration to death or last follow-up.