Cognitive Decline, Cognitive Impairment, Critical Illness, Delirium, Intensive Care Psychosis
Conditions
Keywords
delirium, intensive care unit, critical illness, cognitive impairment
Brief summary
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
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.
Interventions
DRUGHaloperidol
haloperidol for ICU delirium, titrated on validated screening tool-based diagnosis
DRUGPlacebo
placebo for ICU delirium, titrated on validated screening tool-based diagnosis
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Erasmus Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
placebo and haloperidol (verum) will have the same appearance
Intervention model description
Randomised controlled double-blind placebo controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for randomisation: 1. 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. 2. Written Informed Consent is obtained from patient or legal representative 3. Complies with inclusion criteria but NOT
Exclusion criteria
for eligibility: Eligibility Inclusion criteria for eligibility 1. Age ≥ 18 years 2. Admitted to ICU.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| delirium- and coma-free days | within the first 14 days after randomisation | days without brain dysfunction (=delirium OR coma) while at the ICU |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive deterioration: Verbal learning and memory | 3 and 12 months | 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). |
| Cognitive deterioration: Semantic fluency | 3 and 12 months | 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. |
| Cognitive deterioration: Working memory | 3 and 12 months | 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. |
| Cognitive deterioration: Cognitive flexibility | 3 and 12 months | 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. |
| Cognitive deterioration: Word retrieval | 3 and 12 months | 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. |
| Anxiety and depression | 3 and 12 months | 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. |
| Functional outcome | 3 and 12 months | 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. |
| mortality | 28 days and 1 year | mortality |
| Cognitive deterioration: Global cognitive functioning | 3 and 12 months | 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). |
| Adverse drug associated events: prolonged QTc by EKG | while on study drug treatment during study period at ICU (up to 14 days after randomisation) | prolonged QTc by EKG (ms) |
| Adverse drug associated events: muscle rigidity and other associated movements disorders | while on study drug treatment during study period at ICU (up to 14 days after randomisation) | muscle rigidity and other associated movements disorders \[measured with the Simpson Angus Scale\] |
| Adverse drug associated events: ventricular arrhythmia's | during study period at ICU (up to 14 days after randomisation) | ventricular arrhythmia's including torsade de pointes |
| Patients' memories related to their ICU stay | at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation | 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). |
| Patients' and family-members' experiences related to delirium | at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation | 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. |
| Caregiver Strain | at 3 months after randomisation | 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. |
| Posttraumatic stress syndrome | at 3 months after randomisation | 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). |
| length of stay at ICU | 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). | length of stay at ICU (days) |
Countries
Netherlands
Outcome results
None listed