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Randomized Controlled Trial
. 2024 Jan;50(1):103-113.
doi: 10.1007/s00134-023-07282-7. Epub 2024 Jan 3.

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

Camilla Bekker Mortensen  1   2   3 , Nina Christine Andersen-Ranberg  4   5 , Lone Musaeus Poulsen  4   5 , Anders Granholm  5   6 , Bodil Steen Rasmussen  5   7   8 , Maj-Brit Nørregaard Kjær  5   6 , Theis Lange  9   10 , Bjørn H Ebdrup  11   12 , Marie Oxenbøll Collet  5   6 , Anne Sofie Andreasen  13 , Morten Heiberg Bestle  5   12   14 , Bülent Uslu  15 , Helle Scharling Pedersen  4   16 , Louise Gramstrup Nielsen  17 , Johanna Hästbacka  18   19 , Troels Bek Jensen  20 , Kjeld Damgaard  21 , Trine Sommer  22 , Matthew Morgen  23 , Nilanjan Dey  24 , Guiseppe Citerio  25 , Stine Estrup  5   6 , Ingrid Egerod  5   6 , Karin Samuelson  26 , Anders Perner  5   6   12 , Ole Mathiesen  4   5   12
Affiliations
Randomized Controlled Trial

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

Camilla Bekker Mortensen et al. Intensive Care Med. 2024 Jan.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03392376.

Keywords: Delirium; Health-related quality of life; ICU; Long-term outcomes; Mortality; Treatment.

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Conflict of interest statement

AG, MBNK, MOC and AP are affiliated with the Department of Intensive Care at Rigshospitalet, which has received funding for other projects from The Novo Nordisk Foundation, Pfizer, and Fresenius Kabi, Sygeforsikringen “danmark”. AP has received an honorarium from Novartis for the participation in an advisory board. AP is on DSMB for The Mega-Rox trial, UK-Rox trial, Bone Zone trial. BSR are affiliated with the Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark, which has received funding for other project from Novo Nordisk Foundation, Danish Ministry of Education and Science and Beckett Foundation. MHB are affiliated with the Department of Anaesthesia and Intensive Care at Copenhagen University Hospital – North Zealand, which has received funding for other research projects from The Novo Nordisk Foundation, Sygeforsikringen “danmark”, Toyota Foundation, A.P. Moeller Foundation, Frimodt-Heineke Foundation, Svend Andersen Foundation, Ehrenreich Foundation, and Olga Bryde Nielsen Foundation, and has conducted contract research for AM-Pharma (the REVIVAL trial) and Inotrem (ASTONISH trial). MHB has received an honorarium from AM-Pharma for participation in an advisory board. TL is a member of DSMB for Novo Nordisk and Leo Pharma study. BE is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. JH has received funding from Paulo foundation, Finska Läkaresällskapet, NordForsk and Tor och Kirsti Johanssons Hjärt och Cancerstiftelse. GC has received istituational research grants from Neuroptics and Integra and is a board member at Neuroptics, Integra, Biogen, Invex Therapeutics and Idorsia. All other authors have no conflicts to disclose.

Figures

Fig. 1
Fig. 1
Consort diagram. Patient flow in the AID-ICU trial. Details up to 90 days were presented in the primary report [16].  1000 patients were randomised in the AID-ICU trial. Thirteen patients never received any trial medication and were excluded from the analysis. Twenty-five patients withdrew consent before 1-year follow-up. The primary HRQoL analyses were done in the ITT population (n = 987) with deceased patients assigned zero and missing data (n = 165 for EQ-5D-5L index values and n = 163 for EQ VAS scores) multiply imputed
Fig. 2
Fig. 2
1-year survival curve and heatmap. a Survival curves in the two groups at one year (day 365). Patients who withdrew consent for further data or were lost to follow-up were censored at the time of withdrawal or loss to follow-up. Cox regression adjusted for stratification variables found a hazard ratio (HR) 0.81 (95% CI 0.67–0.97). b The distribution of HRQoL (EQ-5D-5L and EQ-VAS) data are shown as a heatmap in all patients after multiple imputations; non-survivors were assigned zero. The colour scheme: red represents worse outcomes, and blue represents better outcomes. The horizontal axes represent the cumulated proportion of the patients scoring at or below the value on the secondary axes and represent the two tools used for HRQoL; EQ-5D-5L index value from below 0 (corresponding to health states valued worse than death) to 1 and EQ VAS from 0 to 100. Similar heatmaps for survivors only are presented in the ESM 1
Fig. 3
Fig. 3
The distribution of the single domains of EQ-5D-5L in survivors. Shows the distributions of the single domains of EQ-5D-5L in the two groups among survivors only (n = 512). The proportions of relatives answering the HRQoL questionnaire on behalf of patients was 5 of 277 (1.7%) in the haloperidol group and 6 of 235 (2.6%) in the placebo group. The numeric data corresponding to the figure are presented in Table S2 in the ESM 1
See this image and copyright information in PMC

References

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