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.

Trial registration: ClinicalTrials.gov NCT03317067.

Keywords: Delirium; Dexmedetomidine; Haloperidol; ICU patients; Intubation; Mechanical ventilation; Sedation.

Conflict of interest statement

Ethics approval and consent to participate

Due to the specific medical condition of recruited patients (agitated delirium), an emergency inclusion procedure will be possible. Written pursuit consent will be obtained from all participants (once the medical condition has resolved) or their next-of-kin. The Institutional Review Board of the University Hospital of Clermont-Ferrand (France) approved the trial. By 7 June 2017, the study had been approved for all centers by a central ethics committee (Comité de Protection des Personnes Sud-Est V, Grenoble, France, 17-CHCF-02) with the registration number EudraCT 2017–000731-14. Any further additional important protocol modification will require the approval of a central ethics committee (Comité de Protection des Personnes Sud-Est V, Grenoble, France, 17-CHCF-02). The 4D trial was registered on 23 October 2017 at http://www.clinicaltrials.gov with trial identification number NCT 03317067.

Competing interests

JMC received consulting fees from Baxter.

TG reports receiving lecture fees and support for meeting (travel reimbursement) from Baxter Gambro.

The remaining authors declare that they have no competing interests.

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Figures

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) flowchart illustrating the randomization and flow of patients in the study

Fig. 2

Patients’ schedule of activities according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure. CAM-ICU Confusion Assessment Method-Intensive Care Unit, RASS Richmond Assessment Sedation Scale, SUE serious unexpected events, SUSAR severe unexpected serious adverse event, UE unexpected events

Fig. 3

Study protocol diagram. Trial medication administration according to patient’s RASS. ICU intensive care unit, RASS Richmond Agitation Sedation Scale