EEG-TMS for Postoperative Delirium After Cardiac Surgery

Postoperative delirium (POD) is a common and serious complication following cardiac surgery, associated with prolonged hospitalization, cognitive decline, and increased mortality. Currently, no specific pharmacological therapy has demonstrated consistent efficacy for POD. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can modulate cortical excitability and has shown preliminary promise in treating delirium, potentially through mechanisms involving neuroinflammation modulation and enhancement of neural connectivity.

This is a prospective, single-center, randomized, double-blind, sham-controlled trial designed to evaluate the safety and efficacy of theta burst stimulation (TBS), a patterned form of TMS, for the treatment of POD in patients undergoing cardiac surgery with extracorporeal circulation.

Patients are screened preoperatively. Those who meet eligibility criteria and provide informed consent undergo baseline assessments, including high-density electroencephalography (HD-EEG) and a battery of neuropsychological and patient-reported outcome measures (cognition, sleep quality, stress, anxiety, depression, and pain). Postoperatively, all patients are assessed twice daily (at least 6 hours apart) for delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Delirium severity is assessed using the Delirium Rating Scale-Revised-98 (DRS-R-98).

Upon the first positive CAM-ICU assessment, patients are randomly assigned in a 1:1 ratio to either the active TMS group or the sham stimulation group. An independent statistical unit generates the randomization sequence. To ensure allocation concealment and blinding, each participant receives a unique anonymous treatment code. A research nurse not involved in recruitment, treatment, or outcome assessment prepares the coil (active or sham side) based on a sealed allocation table, without the presence of the treating operator. The operator knows only the treatment code and cannot distinguish the coil's active side from the sham side by appearance, device interface, or procedural feedback. Outcome assessors, patients, and statisticians remain blinded throughout the study.

The intervention period lasts a maximum of 5 days. For participants in the active TMS group, each daily session consists of three cycles of TBS delivered using a 12 cm coil. Each cycle includes intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (600 pulses, 3 repetitions, approximately 10 minutes), followed 30 minutes later by continuous TBS (cTBS) applied to the right dorsolateral prefrontal cortex (600 pulses, 3 repetitions, approximately 2 minutes). Stimulation intensity is set at 80% of the resting motor threshold. Cycles are separated by 15-minute intervals. Participants in the sham group undergo an identical procedure using a sham coil that produces similar auditory and scalp sensations but delivers no electromagnetic penetration to the brain.

If a participant has two consecutive negative CAM-ICU assessments during the 5-day period, stimulation is paused. It is resumed if delirium recurs. The intervention is permanently discontinued if the participant develops new-onset coma due to structural brain disease or a life-threatening serious adverse event deemed related to the intervention.

Participants transferred out of the intensive care unit during the intervention period continue to receive the assigned stimulation and assessments. Those who are re-hospitalized within the 90-day follow-up and develop delirium again will continue to receive their assigned intervention.

A tiered rescue medication protocol is implemented for both groups to manage uncontrollable delirium while ensuring participant safety. First-line non-pharmacological interventions are prioritized for mild cases. If pharmacological intervention is required, dexmedetomidine is the first-line agent, followed by haloperidol or quetiapine. Benzodiazepines and propofol are reserved for severe agitation or emergency situations. All rescue medication use is documented in the case report form.

Data collection includes baseline demographic and clinical characteristics, intraoperative details, daily delirium assessments, vital signs during stimulation sessions, and adverse events. Post-discharge follow-up occurs at 30 and 90 days to assess survival and neuropsychological outcomes. The primary analysis will compare the duration of delirium within the 5-day intervention period between groups using linear regression models adjusted for predefined covariates. A sample size of 144 participants (72 per group) provides 80% power to detect a clinically meaningful difference in delirium duration, assuming a two-sided alpha of 0.05 and accounting for an anticipated 5% dropout rate.

Inclusion criteria

• Aged 50 years or older;
• undergoing cardiac surgery with cardiopulmonary bypass (coronary artery bypass grafting, aortic valve replacement, mitral valve surgery, or combined procedures);
• positive assessment by CAM-ICU postoperatively.

Exclusion criteria

• Chronic antipsychotic treatment;
• Receipt of antipsychotic medication before enrollment;
• Patients with permanent loss of autonomy;
• Not suitable for delirium assessment: including language disorder, deafness, blindness, aphasia, or coma;
• Withdrawal of treatment or brain death;
• Known pregnancy or breastfeeding;
• Unable to provide consent according to national regulations;
• Patients involuntarily hospitalized by regulatory authorities (compulsory measures);
• Alcohol-induced delirium / delirium tremens;
• Contraindications to transcranial magnetic stimulation, including intracranial or cervical metal implants, history of brain surgery, history of epilepsy, cardiac pacemaker or implantable cardioverter-defibrillator, cochlear implant, known intracranial space-occupying lesions, cardiac pacemaker implantation, recent stroke (<3 months);
• Acute infectious diseases;
• Preoperative severe hemodynamic instability (e.g., requiring intra-aortic balloon pump or extracorporeal membrane oxygenation support).