Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium.

PURPOSE: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. METHODS: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. RESULTS: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS. CONCLUSIONS: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Patient and public involvement in contemporary large intensive care trials: A meta-epidemiological study.

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials. METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary. RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved. CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Distribution of delirium motor subtypes in the intensive care unit: a systematic scoping review.

BACKGROUND: Delirium is the most common cerebral dysfunction in the intensive care unit (ICU) and can be subdivided into a hypoactive, hyperactive, or mixed motor subtype based on the clinical manifestation. The aim of this review was to describe the distribution, pharmacological interventions, and outcomes of delirium motor subtypes in ICU patients. METHODS: This systematic scoping review was performed according to the PRISMA-ScR and Cochrane guidelines. We performed a systematic search in six major databases to identify relevant studies. A meta-regression analysis was performed where pooled estimates with 95% confidence intervals were computed by a random effect model. RESULTS: We included 131 studies comprising 13,902 delirious patients. There was a large between-study heterogeneity among studies, including differences in study design, setting, population, and outcome reporting. Hypoactive delirium was the most prevalent delirium motor subtype (50.3% [95% CI 46.0-54.7]), followed by mixed delirium (27.7% [95% CI 24.1-31.3]) and hyperactive delirium (22.7% [95% CI 19.0-26.5]). When comparing the delirium motor subtypes, patients with mixed delirium experienced the longest delirium duration, ICU and hospital length of stay, the highest ICU and hospital mortality, and more frequently received administration of specific agents (antipsychotics, α2-agonists, benzodiazepines, and propofol) during ICU stay. In studies with high average age for delirious patients (> 65 years), patients were more likely to experience hypoactive delirium. CONCLUSIONS: Hypoactive delirium was the most prevalent motor subtype in critically ill patients. Mixed delirium had the worst outcomes in terms of delirium duration, length of stay, and mortality, and received more pharmacological interventions compared to other delirium motor subtypes. Few studies contributed to secondary outcomes; hence, these results should be interpreted with care. The large between-study heterogeneity suggests that a more standardized methodology in delirium research is warranted.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Health-related quality of life, anxiety and depression and physical recovery after critical illness - A prospective cohort study.

BACKGROUND: Critical illness is often followed by mental and physical impairments. We aimed to assess the health-related quality of life (HRQoL), symptoms of anxiety and depression, and physical function in critically ill patients after discharge from the intensive care unit. METHODS: For this prospective cohort study we included all available adult patients admitted to the ICU for >24 h during a 12-month period. Home visits took place at 3 and 12 months after discharge from the hospital and included Short-Form Health Survey (SF-36), Hospital Anxiety and Depression Scale, and Chelsea Critical Care Assessment Too (CPAx). RESULTS: We visited 79 patients at 3 and 53 at 12 months. In patients with data from both visits the mental components SF-36 scores (median (IQR)) were 55 (43-63) at 3, and 58.5 (49.5-64) at 12 months; physical component SF-36 scores were 35 (28-45) at 3, and 36 (28-42) at 12 months. SF-36 subdomains of mental health, social functioning, and role emotional were close to normal. Vitality, bodily pain, general health, physical functioning, and role physical were severely affected. Incidences of anxiety and depression symptoms were 16%/8% at 3 and 13%/8% at 12 months) and physical function (CPAx) was 47 at both time points). CONCLUSION: We found no change in HRQoL, anxiety, and depression, or physical function from 3 months to 1 year. Physical health-related quality of life was impaired at both time points. Subdomain scores for physical health-related quality of life were affected more than mental domains at both time points.

Guided self-determination in treatment of chronic pain - a randomized, controlled trial.

OBJECTIVES: To test whether Guided Self-Determination (GSD) used in chronic pain management could improve the health-related quality of life, patient activation and sense of coherence (SoC) as a measurement of life skills in patients with chronic pain. The method has been shown to be effective in other chronic conditions, but has not been tested in chronic pain. METHODS: A three-site randomised, controlled trial at three major multidisciplinary pain centres in Denmark. 200 patients were included and randomised. In the intervention period, both groups had regular visits to the pain centre with both doctors and nurses. The intervention group additionally received the GSD intervention with weekly sessions for eight weeks. Data were collected from February 2013 to July 2016 and consisted of three questionnaires answered before and after the 8-week intervention period, and after six months. The primary outcome was self-reported health related quality of life. Secondary outcomes included self-reported activation and SoC. RESULTS: We found no clinically relevant difference between the groups for health-related quality of life, patient activation or SoC at either baseline, at three months or at six months. We also analysed data for trends over time using mixed model analysis, and this did not show any significant differences between groups. CONCLUSIONS: GSD did not improve health-related quality of life, patient activation or SoC when administered to patients with chronic pain treated in a multidisciplinary pain centre. New research is recommended using a combination of self-reported and objective measures and longer follow-up.

Development of a core outcome set for general intensive care unit patients-A protocol.

INTRODUCTION: Different outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general. METHODS: The COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi-structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi-structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the measurements of the outcomes selected in Step 1. A 'patient and public involvement panel' consisting of a smaller group of patients, family members, clinicians and researchers will be included in the development, analysis and interpretation of the COS. DISCUSSION: The outlined multiple method studies will establish a COS for ICU patients in general, which may be used to increase the standardisation and comparability of results of RCTs conducted in patients in the ICU setting.

[Generalised, symmetric muscle weakness in survivors after intensive therapy].

ICU-acquired weakness (ICUAW) is often found in critically ill patients and is characterised by a generalised, symmetric weakness, affecting limb (proximal more than distal) and respiratory muscles. It is a diagnosis of exclusion. ICUAW is associated with increased morbidity and mortality, and decreased quality of life. The aetiology is not completely understood, and there is no established treatment or prevention yet. The most important risk factors are high disease severity, multiorgan failure, systemic inflammation and prolonged immobilisation. Individual needs for rehabilitation must be defined, as argued in this review.

Delirium in Intensive Care.

Purpose of Review: Delirium in the intensive care unit (ICU) has become increasingly acknowledged as a significant problem for critically ill patients affecting both the actual course of illness as well as outcomes. In this review, we focus on the current evidence and the gaps in knowledge. Recent Findings: This review highlights several areas in which the evidence is weak and further research is needed in both pharmacological and non-pharmacological treatment. A better understanding of subtypes and their different response to therapy is needed and further studies in aetiology are warranted. Larger studies are needed to explore risk factors for developing delirium and for examining long-term consequences. Finally, a stronger focus on experienced delirium and considering the perspectives of both patients and their families is encouraged. Summary: With the growing number of studies and a better framework for research leading to stronger evidence, the outcomes for patients suffering from delirium will most definitely improve in the years to come.

Patient and public involvement in contemporary large intensive care trials: Protocol for a meta-epidemiological study.

BACKGROUND: Patient and public involvement (PPI) in randomized clinical trials (RCTs) has increased in recent years but remains the exception rather than the rule. We aim to assess the frequency and extent of PPI in large, contemporary RCTs conducted in an intensive care setting. METHODS AND DESIGN: We will conduct a meta-epidemiological study of RCTs conducted in intensive care settings published since 2019 and assess their use of PPI. We will extract trial characteristics and verify the use of PPI with trial authors unless specifically stated in the published paper. The primary outcome will be the proportion of trials that use PPI. Secondary outcomes will explore which groups are consulted, at which stage of the trial process this occurs, and by what means these opinions are collected and implemented. DISCUSSION: This meta-epidemiological study will provide an important insight into the use of PPI in large, contemporary intensive care trials. We wish to reveal ways in which patient involvement could be incorporated more broadly and purposefully here and help to empower clinicians, researchers and patients to collaborate further on future research processes and goals.

Sleep-wake rhythms determined by actigraphy during in-hospital stay following discharge from an intensive care unit.

BACKGROUND: Sleep and circadian disturbances play a major role in recovery after critical illness. Ample research has shown sleep to be disturbed during the stay at the intensive care unit (ICU); however, the trajectory of sleep after ICU discharge is sparsely described. The current study aimed to describe the development of the sleep-wake rhythm in subjects discharged from ICU to a hospital ward. METHODS: Following discharge from the ICU to a general hospital ward, the participants were monitored with an ActiGraph for sleep assessment for 7 days or until hospital discharge or death. Data were analysed for day-to-day change with t-tests and for the whole period with repeated measures analysis. RESULTS: For the 38 included patients, repeated measures analysis showed no significant improvement in total sleep time and wake time. However, for secondary outcomes, improvements for wake after sleep onset (P = .02) and reduction in the number of naps (P = .03) both in the day-to-day and overall trend analysis were observed. CONCLUSION: The duration of sleep and wake time did not improve during ward stay. However, sleep became less fragmented and naps during the day declined. Due to the small sample size further, larger trials are needed.

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Health care use before and after intensive care unit admission-A nationwide register-based study.

BACKGROUND: The aim of this study was to describe healthcare utilization of patients admitted to ICU before and after ICU admission. METHODS: Register-based study including adult patients discharged from ICU between January 1st, 2011 and December 31st, 2014. Reference group was a sex- and age-matched population not admitted to an ICU in the study period. Outcomes were hospital admissions, contacts to general practitioner or emergency services and municipality services from 1 year before ICU admission and up to 3 years after. RESULTS: The study included 82 384 patients and an equal number of reference persons. Of patients with ICU admission, 48% were married (reference group 57%), 48% had elementary school education (reference group 38%) and 18% had a Charlson co-morbidity score of 5+ (4% in reference group). We found that 51% of patients with an ICU admission had been admitted to hospital in the year before ICU admission (reference group 15%) and 97% had a contact to a general practitioner (reference group 89%) in the same period. CONCLUSIONS: Patients admitted to an ICU had increased use of both primary and secondary health care both before and for years after ICU treatment, even after adjustment for comorbidities and socio-economic factors.

Cognitive Function During Opioid Tapering in Patients with Chronic Pain: A Prospective Cohort Study.

PURPOSE: Evidence for efficacy and safety lacks for long-term opioid therapy in patients with chronic non-cancer pain and adverse effects, including affection of cognitive function and quality of life, is of concern. We aimed to investigate cognitive function and health-related quality of life in patients with chronic non-cancer pain during opioid reduction. PATIENTS AND METHODS: At two multidisciplinary pain centers, all patients with planned opioid reduction were screened for eligibility. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail Making Test A and B. Health-related quality of life was assessed using Short Form-36 (SF36) and Hospital Anxiety and Depression Scale (HADS). RESULTS: We included 51 participants and 40 participants attended follow-up of median 254 (IQR 106-357) days. Baseline RBANS score was 82 (IQR 65-93) with reference population norm value of 100 (SD±15). Daily opioid consumption was reduced from median 80 (IQR 45-161) oral morphine milligram equivalents to 19 (IQR 0-60) mg. RBANS score estimate increased by 6.2 (95% CI 3.1-9.3, p=0.0004) points after tapering. No differences were observed for Trail Making Test times, HADS or SF36 scores. CONCLUSION: Generally, cognitive function showed minor improvement after opioid tapering with stationary health-related quality of life, depression and anxiety scores. The clinical significance is unclear, as no minimal clinically important difference in RBANS score is available.

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.

BACKGROUND: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial. METHODS: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables. CONCLUSION: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.

Healthcare providers' knowledge and handling of impairments after intensive unit treatment: A questionnaire survey.

BACKGROUND: Numerous patients experience long-term impairments after discharge from the intensive care unit (ICU), including physical, psychological and cognitive deficiencies. This study aims to investigate the knowledge and handling of post-intensive care impairments among Danish doctors and nurses in the medical and surgical wards. METHODS: An electronic questionnaire survey was distributed to consultants and development nurses, head nurses and assistant head nurses at departments of abdominal surgery and internal medicine of hospitals with an ICU in the Region Zealand of Denmark. RESULTS: We invited 350 employees to participate, 48% responded. Most participants, 82.8% nurses and 86.6% doctors, reported their knowledge of in-hospital needs of the ICU patients to be average or higher. Sixty per cent of doctors reported having average or higher knowledge of the patients' post-discharge needs. More than half the doctors (60.2%) reported that they "Rarely" or "Never" addressed possible ICU-related impairments in the discharge summary. During hospital admission, 22.9% replied "No screening performed" for physical impairment, while the rates for psychological and cognitive impairments were 70.7% and 57.3%, respectively. Most respondents believed that doctors (92.8%) and nurses (92.1%) in the ward and ICU doctors (89.4%) play an important role in detecting ICU-related impairments; 63.8% felt that general practitioners play a key role. CONCLUSION: Doctors and nurses generally reported having average or higher knowledge of ICU patients' in-hospital needs, but few screened systematically for ICU-related impairments. Most respondents believed that detecting these problems is a shared responsibility between professionals in the primary and, especially, the secondary healthcare sector.

Agents intervening against delirium in the intensive care unit (AID-ICU) - Protocol for a randomised placebo-controlled trial of haloperidol in patients with delirium in the ICU.

BACKGROUND: Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU-acquired delirium. METHODS: AID-ICU is an investigator-initiated, pragmatic, international, randomised, blinded, parallel-group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post-randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, health-related quality-of-life and cognitive function at 1-year follow-up. A sample size of 1000 patients is required to detect a 7-day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%. PERSPECTIVE: The AID-ICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal high-quality data on the benefits and harms of haloperidol for the treatment ICU-acquired delirium.