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

Abstract

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.

• Authors: Clémence Louis, Thomas Godet, Gérald Chanques, Nathalie Bourguignon, Dominique Morand, Bruno Pereira, Jean-Michel Constantin, AZUREA network
• Journal: Trials (Trials) Vol. 19 Issue 1 Pg. 307 (Jun 04 2018) ISSN: 1745-6215 [Electronic] England
• PMID: 29866205 (Publication Type: Clinical Trial Protocol, Journal Article)

Chemical References

• Hypnotics and Sedatives
• Dexmedetomidine

Topics

• Delirium (diagnosis, drug therapy, psychology)
• Dexmedetomidine (adverse effects, therapeutic use)
• Double-Blind Method
• France
• Humans
• Hypnotics and Sedatives (adverse effects, therapeutic use)
• Intensive Care Units
• Multicenter Studies as Topic
• Prospective Studies
• Randomized Controlled Trials as Topic
• Time Factors
• Treatment Outcome