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Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial

BACKGROUND: Delirium during intensive care unit (ICU) stay is frequent and associated with significant morbidity, mortality and healthcare-related costs. International guidelines suggest its prevention. However, curative treatment remains unclearly established. Despite contradictory and ambiguous ac...

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Autores principales: Louis, Clémence, Godet, Thomas, Chanques, Gérald, Bourguignon, Nathalie, Morand, Dominique, Pereira, Bruno, Constantin, Jean-Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987410/
https://www.ncbi.nlm.nih.gov/pubmed/29866205
http://dx.doi.org/10.1186/s13063-018-2656-x
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author Louis, Clémence
Godet, Thomas
Chanques, Gérald
Bourguignon, Nathalie
Morand, Dominique
Pereira, Bruno
Constantin, Jean-Michel
author_facet Louis, Clémence
Godet, Thomas
Chanques, Gérald
Bourguignon, Nathalie
Morand, Dominique
Pereira, Bruno
Constantin, Jean-Michel
author_sort Louis, Clémence
collection PubMed
description BACKGROUND: Delirium during intensive care unit (ICU) stay is frequent and associated with significant morbidity, mortality and healthcare-related costs. International guidelines suggest its prevention. However, curative treatment remains unclearly established. Despite contradictory and ambiguous academic literature, international guidelines suggest the use of second-generation (atypical) antipsychotics over haloperidol. However, haloperidol remains the most widely used neuroleptic worldwide as a first-line treatment of agitation and/or delirium. Dexmedetomidine, an alpha2-adrenergic receptors agonist, has shown its efficiency in the treatment of delirium in intubated patients but also in its prevention. Dexmedetomidine represents a widely used alternative to haloperidol. Only few studies have compared the efficacy of dexmedetomidine in non-intubated ICU patients as a first-line curative treatment of delirium. The main objective of the 4D trial is to demonstrate that dexmedetomidine decreases delirium duration compared to placebo. METHODS/DESIGN: The 4D trial is an investigator-initiated, prospective, multicenter, randomized, double-blinded, two-arm trial, randomizing 300 non-intubated ICU patients with a diagnosis of agitated delirium to receive dexmedetomidine or placebo as a cure. In case of agitation (RASS≥ + 2), immediate haloperidol administration will be allowed, to protect patient and staff in charge, while waiting for study treatment action. The primary outcome measure is a composite of duration of agitation or delirium or the use of intubation with deep sedation and mechanical ventilation. Secondary outcomes include mortalities at 7 and 30 days, ICU length of stay and occurrence of adverse effects related to dexmedetomidine use (bradycardia or hypotension requesting any treatment; or haloperidol use (neuroleptic malignant syndrome, extrapyramidal syndrome, prolonged QTc). The sample size will allow the detection of a 50% decrease of agitation duration (120 min), of an absolute reduction of delirium duration (1 day) and of a 50% relative decrease of intubation and mechanical ventilation, with a type 1 error rate of 1.8% (error risk inflation due to components of composite) and power of 90%, assuming a 15% incidence of intubation and mechanical ventilation requirements, an agitation duration of 240 min and a delirium duration of 3 days. One hundred and ten patients by group will be needed. An intermediate analysis is scheduled and requires the inclusion of 150 patients. DISCUSSION: The 4D trial may provide important data on the safety of commonly used sedative dexmedetomidine and could have a significant impact on future treatment of non-intubated ICU patients presenting with agitated delirium. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT 03317067. Registered on 23 October 2017. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13063-018-2656-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-59874102018-07-10 Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial Louis, Clémence Godet, Thomas Chanques, Gérald Bourguignon, Nathalie Morand, Dominique Pereira, Bruno Constantin, Jean-Michel Trials Study Protocol BACKGROUND: Delirium during intensive care unit (ICU) stay is frequent and associated with significant morbidity, mortality and healthcare-related costs. International guidelines suggest its prevention. However, curative treatment remains unclearly established. Despite contradictory and ambiguous academic literature, international guidelines suggest the use of second-generation (atypical) antipsychotics over haloperidol. However, haloperidol remains the most widely used neuroleptic worldwide as a first-line treatment of agitation and/or delirium. Dexmedetomidine, an alpha2-adrenergic receptors agonist, has shown its efficiency in the treatment of delirium in intubated patients but also in its prevention. Dexmedetomidine represents a widely used alternative to haloperidol. Only few studies have compared the efficacy of dexmedetomidine in non-intubated ICU patients as a first-line curative treatment of delirium. The main objective of the 4D trial is to demonstrate that dexmedetomidine decreases delirium duration compared to placebo. METHODS/DESIGN: The 4D trial is an investigator-initiated, prospective, multicenter, randomized, double-blinded, two-arm trial, randomizing 300 non-intubated ICU patients with a diagnosis of agitated delirium to receive dexmedetomidine or placebo as a cure. In case of agitation (RASS≥ + 2), immediate haloperidol administration will be allowed, to protect patient and staff in charge, while waiting for study treatment action. The primary outcome measure is a composite of duration of agitation or delirium or the use of intubation with deep sedation and mechanical ventilation. Secondary outcomes include mortalities at 7 and 30 days, ICU length of stay and occurrence of adverse effects related to dexmedetomidine use (bradycardia or hypotension requesting any treatment; or haloperidol use (neuroleptic malignant syndrome, extrapyramidal syndrome, prolonged QTc). The sample size will allow the detection of a 50% decrease of agitation duration (120 min), of an absolute reduction of delirium duration (1 day) and of a 50% relative decrease of intubation and mechanical ventilation, with a type 1 error rate of 1.8% (error risk inflation due to components of composite) and power of 90%, assuming a 15% incidence of intubation and mechanical ventilation requirements, an agitation duration of 240 min and a delirium duration of 3 days. One hundred and ten patients by group will be needed. An intermediate analysis is scheduled and requires the inclusion of 150 patients. DISCUSSION: The 4D trial may provide important data on the safety of commonly used sedative dexmedetomidine and could have a significant impact on future treatment of non-intubated ICU patients presenting with agitated delirium. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT 03317067. Registered on 23 October 2017. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13063-018-2656-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-04 /pmc/articles/PMC5987410/ /pubmed/29866205 http://dx.doi.org/10.1186/s13063-018-2656-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Study Protocol
Louis, Clémence
Godet, Thomas
Chanques, Gérald
Bourguignon, Nathalie
Morand, Dominique
Pereira, Bruno
Constantin, Jean-Michel
Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title_full Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title_fullStr Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title_full_unstemmed Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title_short Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial
title_sort effects of dexmedetomidine on delirium duration of non-intubated icu patients (4d trial): study protocol for a randomized trial
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987410/
https://www.ncbi.nlm.nih.gov/pubmed/29866205
http://dx.doi.org/10.1186/s13063-018-2656-x
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