Delirium Treatment With Transcranial Electrical Stimulation

Official title

DELirium Treatment With Transcranial Electrical Stimulation

Overview

The goal of this clinical trial is to investigate the effectiveness of standardized and personalized transcranial alternating current stimulation (tACS) in patients with delirium. To investigate this, will perform a double-blind, randomized, sham-controlled, multicenter trial. To test the safety and feasibility of tACS in delirious patients, the first 30 patients will be randomized to receive either active or sham tACS treatment in a 1:1 ratio through a pilot study. For the main phase of the study, patients will be randomized, resulting in an overall 1:1:1 allocation to standardized tACS, personalized tACS or sham treatment. Electroencephalogram (EEG) will be measured directly before and directly after the first stimulation session to assess whether tACS can reduce relative delta power. tACS or sham treatment will be given once daily for a maximum of 14 days, or until resolution of delirium or discharge (whichever comes first). During the treatment phase, presence and severity of delirium will be assessed daily. After the treatment phase, an additional EEG will be measured. Cognitive status will be assessed three months after the initial tACS session.

Detailed description

Delirium, a prevalent neuropsychiatric syndrome caused by an underlying medical condition, characterized by cognitive deficits such as inattention, extends hospital stay, increases healthcare costs and increases the risk of long-term cognitive decline. Prolonged and severe delirium is associated with worse long-term outcomes. There is currently no treatment that reduces the duration or severity of delirium.

Delirium is consistently characterized by diffuse oscillatory slowing of the EEG, including pronounced loss of alpha activity and increased relative delta power. Additionally, functional connectivity between brain regions is decreased during delirium. In light of this, tACS is a potential treatment option that directly addresses the brain dysfunction observed in delirium. Because tACS has shown the ability to improve multiple domains of cognition, including attention, and modify functional connectivity, we aim to investigate the effectiveness of tACS as treatment for delirium. We will utilize the EEG to measure the effects of tACS, using relative delta power as a primary outcome measure.

Additionally, EEG measurements can capture individual spectral and connectivity changes targeted with tACS, making EEG a promising input for personalized tACS treatment. Neural mass modelling is a way to model the behavior of groups of neurons resulting in oscillatory output similar to EEG. This type of model is able to represent delirium pathology and, when combined with individual EEG input, can be employed to optimize treatment effectiveness, leading to personalized tACS treatment.

The overarching aim of the study is to investigate whether treatment with tACS, either standardized or personalized, induces EEG alterations indicative of reversal of delirium. The primary outcome is relative delta power in the EEG measured after the first tACS session. Secondary outcomes include severity and/or duration of delirium measured with validated delirium assessment instruments.

Patients aged 50 years and older with delirium that persists for at least 2 days, despite adequate treatment of underlying causes will be included in the study (n = 159). Inclusion will take place in the intensive care unit (ICU) and non-ICU wards of the University Medical Centre (UMC) Utrecht, Radboud UMC and HagaZiekenhuis.The proposed tACS protocol is considered safe according to the latest published international safety guidelines. All participants will be screened for their relevant medical history and other tACS safety aspects.

Interventions

• Device transcranial alternating current stimulation (tACS)
  tACS is a non-invasive brain stimulation technique which involves the application of a low intensity electric current between two or more surface electrodes. tACS uses stimulation with a current alternating at a specific frequency that can entrain endogenous neuronal oscillations by inducing neural synchronization. The administration of tACS is proposed to phase-lock large populations of neurons in the superficial layers of the cerebral cortex causing neural synchronization in the corresponding
• Device Sham transcranial alternating current stimulation (tACS)
  Sham-tACS is a form of non-effective stimulation which can mimic the subjective sensation of active tACS treatment. During sham-tACS, the device will ramp up to 2.0 mA peak-to-peak intensity for 30 seconds, stimulate for 60 seconds and ramp down for 30 seconds, which mimics the sensation of actual tACS stimulation and improves blinding.The sham-tACS will be delivered via a transcranial electrical stimulation (tES) device (Nurostym tES, Brainbox Ltd, United Kingdom). This device has been CE-marke

Primary outcome measures

• Relative delta power [Time frame: 1 day]

Secondary outcome measures (9)

• Duration of delirium [Time frame: Two weeks]
• Severity of delirium [Time frame: Two weeks]
• Length of hospital stay [Time frame: 3 months]
• Cognitive status three months post delirium [Time frame: 3 months]
• Subjective sensations during treatment [Time frame: Two weeks]
• Average peak frequency [Time frame: Two weeks]
• Phase Lag Index [Time frame: Two weeks]
• Corrected Amplitude Envelope Correlation (AECc) [Time frame: Two weeks]
• Relative power [Time frame: Two weeks]

Eligibility criteria

Inclusion criteria

• Age over 50 years.
• Diagnosis of delirium
• Richmond Agitation and Sedation Scale (RASS) score of -2 to +2.
• Delirium duration of at least two days prior to study inclusion, based delirium assessments and/or descriptions in the medical and/or nursing files.
• Known causes underlying delirium are being treated adequately, as assessed by the treating physician.

Exclusion criteria

• Inability to conduct delirium assessment (e.g. coma, deaf, blind) or inability to speak Dutch or English.
• A moribund state.
• Alcohol/substance abuse withdrawal or stroke as precipitating factor for delirium.
• Diagnosis of dementia, based on medical record review and/or a score of ≥4.5 on the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
• One or more contra-indications for tACS:

• History of serious head trauma or brain surgery;
• Large or ferromagnetic metal parts in the head (except for a dental wire);
• Implanted cardiac pacemaker or neurostimulator;
• Skin diseases or inflammations;
• Epilepsy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Netherlands · 2 centers

• Radboudumc — Nijmegen
• HagaZiekenhuis — The Hague

Publications

• van der A J, Lodema Y, Ottens TH, Schutter DJLG, Emmelot-Vonk MH, de Haan W, van Dellen E, Tendolkar I, Slooter AJC. DELirium treatment with Transcranial Electrical Stimulation (DELTES): study protocol for a multicentre, randomised, double-blind, sham-controlled trial. BMJ Open. 2024 Nov 2;14(11):e092165. doi: 10.1136/bmjopen-2024-092165. PMID 39488424

Identifiers

NCT: NCT06285721 · DELTES

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗