Haloperidol for Delirium in Adult Critically Ill Patients

Study Overview
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Brief Summary
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The EuRIDICE trial will study whether haloperidol as a first line treatment for ICU delirium reduces delirium duration (and severity). Adverse outcomes typically associated with delirium will also be studied and include long term cognition, functional outcome and quality of life. Further, patient and family experiences and cost-effectiveness will be assessed. Finally, safety concerns associated with the use of haloperidol in this vulnerable population will be studied.

Detailed Description
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BACKGROUND. Although widely used, the efficacy and safety of haloperidol for delirium in critically ill adults remain unclear. A randomised controlled trial is warranted to study the effect of haloperidol on delirium or coma, long-term outcomes, safety concerns, and cost-effectiveness. SUMMARY. The investigators will perform a multi-center, randomised, double-blind, placebo-controlled clinical trial to evaluate the use of haloperidol for delirium treatment in 742 critically ill adults with delirium. Days spent without delirium- or coma in the first 14 days after randomisation is the primary outcome. Study drug will be initiated at 2.5mg IV q8h and increased after 24 hours to 5mg IV q8h if delirium persists. Study drug dose will be tapered when delirium has resolved during 24 hours. All patients will be managed with a standardized pain, agitation and delirium protocol. Standard operating procedures for agitation (analgesia titration, alpha2 agonists) and hallucination management (atypical antipsychotics) will be implemented to accommodate possible imbalances of these symptoms in both treatment arms. Open-label haloperidol administration is discouraged during the trial. The sample size provides a power of 90% to detect statistically significant results (p<.05) and a true treatment difference of one day for the primary outcome between trial arms. This trial is expected to answer the clinically relevant question whether haloperidol still deserves a place in ICU delirium management. The primary outcome (delirium- and coma-free days) will be related to the secondary outcomes cognitive dysfunction, functional and psychological outcomes and patient- and family experiences. An extensive cost-effectiveness analysis will be done. Mortality at one year and safety concerns of haloperidol (QTc prolongation on EKG and rigidity) will be assessed as secondary endpoints. In conclusion, this large multicentre trial will assess efficacy and safety of haloperidol for ICU delirium.

Official Title
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Efficacy of Haloperidol to Decrease the Burden of Delirium in Adult Critically Ill Patients (EuRIDICE): a Prospective Randomised Multi-center Double-blind Placebo-controlled Clinical Trial

Conditions
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Delirium, Critical Illness, Intensive Care Psychosis, Cognitive Impairment, Cognitive Decline

Intervention / Treatment
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* Drug: Haloperidol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for randomisation: Delirium, as assessed with the Intensive Care Delirium Screening Checklist - ICDSC: ≥4 or Confusion Assessment Method for the ICU - CAM-ICU: positive). NB Delirium can occur in the course of ICU admission or be present at admission. Written Informed Consent is obtained from patient or legal representative Complies with inclusion criteria but NOT exclusion criteria for eligibility: Eligibility Inclusion criteria for eligibility Age ≥ 18 years Admitted to ICU. Exclusion criteria for eligibility Admitted to ICU with a neurological diagnosis (such as acute stroke, traumatic brain injury, intracranial malignancy, anoxic coma). Previous non-acute stroke or other previous neurological condition without cognitive deterioration is not an exclusion criterion. Pregnancy (to be excluded by pregnancy test in women of child baring age) History of ventricular arrhythmia including torsade de pointes (TdP) Known allergy to haloperidol History of dementia or an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score ≥ 4 History of malignant neuroleptic syndrome or parkinsonism (either Parkinson's disease or another hypokinetic rigid syndrome) Schizophrenia or other psychotic disorder Inability to conduct valid delirium screening assessment (e.g. coma, deaf, blind) or inability to speak Dutch The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours after evaluation (may be reassessed daily) Exclusion Criteria for randomisation: Prolonged QT-interval (QTc > 500ms) (recent) torsade de pointes (TdP) (recent) malignant neuroleptic syndrome or parkinsonism Evidence of acute alcohol (or substance) withdrawal requiring pharmacological intervention (e.g. benzodiazepines or alfa-2 agonist) to treat IQCODE not assessed The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours. No (previously) signed informed consent by patient or representative Current participation in another intervention trial that is evaluating a medication, device or behavioural intervention

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised controlled double-blind placebo controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: haloperidol<br>study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h. Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations). | Drug: Haloperidol<br>* haloperidol for ICU delirium, titrated on validated screening tool-based diagnosis<br>* Other names: not any;|
| Placebo Comparator: placebo<br>study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h. Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations). | Drug: Placebo<br>* placebo for ICU delirium, titrated on validated screening tool-based diagnosis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| delirium- and coma-free days | days without brain dysfunction (=delirium OR coma) while at the ICU | within the first 14 days after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive deterioration: Global cognitive functioning | Global cognitive functioning as assessed with the Montreal Cognitive Assessment (MOCA). Total score will be reported, with a range of 0-30 (higher values representing better cognitive functioning). | 3 and 12 months | 
| Cognitive deterioration: Verbal learning and memory | Auditory-verbal learning and memory will be assessed with the Rey Auditory Verbal Learning Test. Three subscores will be reported: total correct words in 5 trials (range: 0 -75), total correct words after delay (range: 0-15) and total correct words at recognition (range: 0-30). | 3 and 12 months | 
| Cognitive deterioration: Semantic fluency | Semantic fluency will be tested with the Semantic Category Fluency Test. The amount of animals given within a time of 60 seconds will represent the score. | 3 and 12 months | 
| Cognitive deterioration: Working memory | Working memory will be assessed using the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III). Subscales will be reported for both digit span under forward and backward recall conditions. In addition, a total score will be reported, which equals the sum of both separate digit spans. | 3 and 12 months | 
| Cognitive deterioration: Cognitive flexibility | Cognitive flexibility, one of the executive funcions, will be assessed with the Trialmaking tests A and B. The total amount of seconds needed to finish each test will be reported, with less seconds needed representing better cognitive flexibility. | 3 and 12 months | 
| Cognitive deterioration: Word retrieval | Word retrieval is tested with the Boston Naming Test (30-item version). The total score (range: 0-30) represents the amount of correct answered drawings. | 3 and 12 months | 
| Anxiety and depression | Anxiety and depression will be assessed with the Hospital Anxiety and Depression Scale (HADS). Two subscales will be reported, one for anxiety symptoms (range: 0-21) and one for depression symptoms (range: 0-21). Higher values represent a worse outcome. A subscore >8 indicates anxiety or depression, respectively. | 3 and 12 months | 
| Functional outcome | Health-related quality of life will be assessed with the Short Form-35 (SF-36). Nine subscales will be reported on a 0 - 100 scale: physical functioning, role functioning - physical, bodily pain, general health, vitality, social functioning, role functioning - emotional, mental health and reported health transition. Higher values represent a better health-related quality of life. | 3 and 12 months | 
| mortality | mortality | 28 days and 1 year | 
| length of stay at ICU | length of stay at ICU (days) | days of ICU stay (time in days from ICU admission until ICU discharge). Assessed up to a maximum of 12 months after randomisation (end of follow-up period). | 
| Adverse drug associated events: prolonged QTc by EKG | prolonged QTc by EKG (ms) | while on study drug treatment during study period at ICU (up to 14 days after randomisation) | 
| Adverse drug associated events: muscle rigidity and other associated movements disorders | muscle rigidity and other associated movements disorders [measured with the Simpson Angus Scale] | while on study drug treatment during study period at ICU (up to 14 days after randomisation) | 
| Adverse drug associated events: ventricular arrhythmia's | ventricular arrhythmia's including torsade de pointes | during study period at ICU (up to 14 days after randomisation) | 
| Patients' memories related to their ICU stay | Patients' memories for their ICU stay will be evaluated with the ICU Memory Tool (ICU-MT). Subscores will be reported for factual memories (range: 0-11), delusion memories (range: 0-6) and memories of feelings (range: 0-4). | at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation | 
| Patients' and family-members' experiences related to delirium | Delirium recall and distress related to the delirium episode will be assessed with the Delirium Experience Questionnaire (DEQ). Scores will represent whether patients remember their delirium episode. In addition, a score representing delirium-related distress levels (range: 0-4, with higher values representing more distress) will be reported for both patients and family-members. | at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation | 
| Caregiver Strain | The strain experienced by family-members or relatives will be assessed with the Caregiver Strain Index. A total score (range: 0-13) will be reported, with higher values representing higher experienced strain. | at 3 months after randomisation | 
| Posttraumatic stress syndrome | Posttraumatic stress symptoms in patients and families will be assessed with the Impact of Event Scale - Revised (IES-R). A mean total IES-R score will be reported (range: 0-4), with posttraumatic stress disorder defined as a mean IES-R score ≥ 1.6. In addition, subscores will be reported for intrusion, avoidance and hyperarousal (range: 0-4). | at 3 months after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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delirium, intensive care unit, critical illness, cognitive impairment