The Effect of Adding Lorazepam to Haloperidol on Agitated Delirium in Patients with Advanced Cancer

Kayla Peltier, Mercer University College of Pharmacy

Delirium has been identified as the most common serious neuropsychiatric complication in cancer patients. First-line treatment for delirium is often non-pharmacological and includes re-orienting the patient frequently, encouraging cognitively stimulating activities, avoiding immobility if possible, and promoting good sleep patterns and sleep hygiene. If non-pharmacological therapies are not effective or the patient is displaying severe agitation and poses a risk to self-harm or harm others, then treatment with pharmacological agents (including antipsychotic and sedating medications) may be considered. [1]

The authors of the study state that while antipsychotics and benzodiazepines are often used to treat delirium, the use of benzodiazepines is controversial due to a lack of adequate, well-controlled randomized trials. Therefore, this study aims to compare the effect of lorazepam to placebo as an adjuvant to haloperidol therapy in patients with agitated delirium in the setting of advanced cancer. [2]

Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial
Design Single-center, double-blind, parallel-group, randomized clinical trial; N= 90
Objective To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer
Study Groups Lorazepam + haloperidol (L+H; n= 47; 29 included in primary analysis)

Placebo + haloperidol (P+H; n= 43; 29 included in primary analysis)

Methods Inclusion Criteria

–       18 years and older

–       Diagnosis of delirium by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, in the opinion of the attending physician and bedside nurse

–       History of agitation with a Richmond Agitation-Sedation Scale (RASS) score of 2 or more over the past 24 hours despite receiving scheduled haloperidol of 1 mg to 8 mg per day

Exclusion Criteria

–       Dementia

–       Use of benzodiazepines or chlorpromazine within the past 48 hours

–       Contraindications to neuroleptics (e.g. Parkinson disease, myasthenia gravis, acute narrow-angle glaucoma, seizure disorders, documented corrected QT interval prolongation, or hypersensitivity)

–       Contraindications to benzodiazepines (e.g. hypersensitivity)

Patients with hyperactive or mixed delirium were allocated in a 1:1 ratio to receive lorazepam 3 mg intravenously (IV) or placebo in addition to haloperidol. Patients were routinely treated for any potentially reversible causes and provided with non-pharmacologic measures and intensive symptom management. After randomization, patients were initiated on a standard dose of haloperidol 2mg IV every 4 hours and another 2 mg every hour as needed for agitation. The RASS score for every patient was monitored every two hours until the score was 2 or more and required rescue medication according to the bedside nurse’s judgment before administering the treatment options. Once treatment threshold was obtained, a single dose of 3 mg of lorazepam or an identical placebo was infused over 1.5 minutes, then all patients received 2 mg of haloperidol immediately afterwards. The use of other medications and withholding of scheduled haloperidol was permissible as per standard of practice according to the clinical judgement of the attending physician and bedside nurse.

Duration February 2014 – June 2016
Primary Outcome Measure Change in RASS (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration
Baseline Characteristics
  No. of Patients (%)
  L+H (n= 29) P+H (n= 29)
Age, mean (range), y 66 (43-90) 64 (30-88)
Women 11 (37.9) 16 (55.2)
Race/ethnicity
  White 21 (72.4) 23 (79.3)
  Black 4 (13.8) 4 (13.8)
  Hispanic 2 (6.9) 0
  Other 2 (6.9) 2 (6.9)
Education
  High school or less 7 (24.1) 8 (27.6)
  Some college 11 (37.9) 6 (20.7)
  Completed college 10 (34.5) 14 (48.3)
  Not available 1 (3.5) 1 (3.5)
Cancer Type
  Breast 0 5 (17.2)
  Gastrointestinal 9 (31.0) 4 (13.8)
  Genitourinary 2 (6.9) 1 (3.4)
  Gynecological 2 (6.9) 2 (6.9)
  Head and neck 0 1 (3.4)
  Hematological 8 (27.6) 2 (6.9)
  Respiratory 4 (13.8) 10 (34.5)
  Other 4 (13.8) 4 (13.8)
Cancer stage
  Metastatic 20 (69.0) 26 (89.7)
  Locally advanced 1 (3.4) 0
  Recurrent or persistent 8 (27.5) 3 (10.3)
Karnofsky performance status, %a
  10 7 (24.1) 5 (17.2)
  20 15 (51.7) 12 (41.4)
  30 4 (13.8) 10 (34.5)
  40 3 (10.3) 2 (6.9)
Reason for acute palliative care unit admission b
  Delirium 14 (48.3) 17 (58.6)
  Pain 22 (75.9) 26 (89.7)
  Dyspnea 13 (44.8) 8 (27.6)
  Other 13 (44.8) 10 (34.5)
MDAS score, median (IQR)c 30.0 (23.0-30.0) 28.0 (19.0-30.0)
Medication in prior 48 h
  Haloperidol scheduled 29 (100) 29 (100)
  Haloperidol as needed 26 (89.7) 20 (69.0)
  Chlorpromazine scheduled 0 0
  Chlorpromazine as needed 5 (17.2) 1 (3.4)
  Benzodiazepine scheduled 0 0
  Benzodiazepine as needed 1 (3.5) 1 (3.5)
Haloperidol use in prior 24 h
  Scheduled, median (IQR), mg 3.0 (2.0-5.0) 3.0 (2.0-5.0)
  Rescue, median (IQR), mg 4.0 (2.0-6.0) 2.0 (0.0-4.0)
  No. of breakthrough doses,

median (IQR)

2.0 (1.0-3.0) 2.0 (0.0-3.0)
RASS score immediately prior to treatment, mean (SD)d 1.6 (0.6) 1.6 (0.6)
Abbreviation: IQR, interquartile range; MDAS, Memorial Delirium Assessment Scale; RASS, Richmond Agitation-Sedation Scale.

a A validated assessment of performance status that ranges from 0% (deceased) to 100% (normal, no complaints).

b Patients could have multiple reasons for admission.

c A validated 10-item, clinician-rated assessment scale for delirium in patients with cancer that examines the level of consciousness, disorientation, memory, recall, attention, disorganized thinking, perceptual disturbance, delusions, psychomotor activity, and sleep; assigning a score range for each category of 0 to 3, for a total score range of 0 to 30; a total score of 13 or higher indicates delirium.

d A validated 10-point numeric rating scale that ranges from −5 (unarousable) to 4 (very agitated and combative); a score of 0 indicates that a patient is alert and calm.

Results
  L+H Group (n= 29) P+H Group (n= 29)    
  No. of Patientsa Mean (95% CI) No. of Patientsa Mean (95% CI) Difference Between Groups (95% CI) [Range] p value
Change (baseline to 8 h), pointsb 26 −4.1 (−4.8 to −3.4) 26 −2.3 (−2.9 to −1.6) −1.9 (−2.8 to −0.9) <0.001
Absolute RASS score at 8 h, pointsb 26 −2.5 (−3.2 to −1.9) 26 −0.7 (−1.3 to −0.1) 1.8 (−2.7 to −0.9) <0.001
a 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.

b 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).

Adverse Events Common Adverse Events

  L+H Group (n= 29) P+H Group (n= 29)    
  No. of Patientsa Mean (95% CI) No. of Patientsa Mean (95% CI) Difference Between Groups (95% CI) [Range] p value
Udvalg for Kliniske Undersøgelser (UKU) adverse effects, No. of patients with increased level on day 3 vs baseline (%)b
  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) 0.68
  Hyperkinesia 16 1 (6.3) 15 2 (13.3) -7 (-40 to 28) 0.60
  Tremor 16 0 15 0    
  Akathisia 16 3 (18.8) 15 1 (6.7) 12 (-22 to 45) 0.60
  Epileptic

seizure

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) 0.77
a 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.

b 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.

Serious Adverse Events: One patient (3%) in L+H group and three patients (10%) in P+H group died within 8 hours of study medication administration.
Study Author Conclusions The addition of lorazepam to haloperidol significantly reduces agitation at 8 hours in patients with advanced cancer when compared to treatment with haloperidol alone.

This preliminary study demonstrates that the addition of lorazepam to haloperidol compared to haloperidol alone produced a significant reduction in agitation at eight hours in advanced cancer patients with agitated delirium.

References:

[1] Alexander K, Goldberg J, Korc-grodzicki B. Palliative Care and Symptom Management in Older Patients with Cancer. Clin Geriatr Med. 2016;32(1):45-62.

[2] Hui D, Frisbee-hume S, Wilson A, et al. Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. JAMA. 2017;318(11):1047-1056.

 

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