EEG-TMS for Postoperative Delirium After Cardiac Surgery (RECOVER-C)

Transcranial Magnetic Stimulation for Postoperative Delirium After Cardiac Surgery: A Prospective, Single-Center, Randomized Double-Blind Controlled Study

This is a prospective, single-center, randomized, double-blind, sham-controlled trial evaluating the safety and efficacy of transcranial magnetic stimulation (TMS) for the treatment of postoperative delirium in patients undergoing cardiac surgery with extracorporeal circulation. Eligible patients aged 50 years or older who develop delirium after surgery, as assessed by the CAM-ICU, will be randomized to receive either active TMS or sham stimulation. The intervention consists of three daily cycles of intermittent and continuous theta burst stimulation over five days. The primary outcome is the duration of delirium within the five-day intervention period. Secondary outcomes include delirium severity, time to successful discharge, and survival at 30 and 90 days. A total of 144 participants will be enrolled.

Study Overview

• Status: Not yet recruiting
• Conditions: Delirium
• Intervention / Treatment: Device: Theta Burst Stimulation (TBS); Device: Sham Stimulation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dan Huang, MD; Phone Number: +86 159 2110 8822; Email: huangdan@renji.com
• Study Contact Backup: Name: Shujing Lin; Phone Number: +86 155 5836 6370; Email: linshujing@renji.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Theta Burst Stimulation (TBS); Participants receive active theta burst stimulation (TBS) delivered via a 12 cm coil. Each daily session consists of three cycles. One 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. The intervention is administered once daily for up to 5 days, with pauses if delirium resolves and resumption if delirium recurs.	Device: Theta Burst Stimulation (TBS); A patterned form of transcranial magnetic stimulation delivered via a 12 cm coil. The active intervention consists of intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex and continuous TBS (cTBS) applied to the right dorsolateral prefrontal cortex at 80% of resting motor threshold.; Other Names: TBS; Puzhuo Magnetic Stimulator
Sham Comparator: Sham Stimulation; Participants receive sham stimulation using a coil identical in appearance to the active coil, which produces similar auditory and scalp sensations but delivers no electromagnetic penetration to the brain. The procedure, duration, frequency, and schedule are identical to the active TBS arm. The intervention is administered once daily for up to 5 days, with pauses and resumption following the same rules as the active arm.	Device: Sham Stimulation; Sham stimulation delivered using a coil identical in appearance to the active coil, which produces similar auditory and scalp sensations but delivers no electromagnetic penetration to the brain.; Other Names: Sham TBS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of delirium	The total duration of delirium (in days) within the 5-day intervention period. Delirium is assessed twice daily (at least 6 hours apart) using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Duration is calculated as the number of days from the first positive CAM-ICU assessment to the last positive CAM-ICU assessment before delirium resolution, with partial days counted proportionally.	Within the 5-day period following randomization, measured daily until delirium resolution or end of day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Delirium	Delirium severity measured daily using the Delirium Rating Scale-Revised-98 (DRS-R-98) during the 5-day intervention period. Scores range from 0 to 39, with higher scores indicating more severe delirium.	Daily during the 5-day intervention period
Length of hospital stay	Time from randomization to successful discharge, defined as discharge from the hospital followed by survival in the community for at least 48 hours.	From randomization to date of successful discharge
Survival at 30 Days	Survival status at 30 days post-randomization.	30 days after randomization
Survival at 90 Days	Survival status at 90 days post-randomization.	90 days after randomization
Rescue Medication Use	Number of participants receiving rescue medication for uncontrollable delirium, and the number of days each participant receives rescue medication during the 5-day intervention period.	Within the 5-day intervention period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Specific Adverse Events	Number of participants experiencing device-related adverse events, including seizure, vasovagal reflex, drowsiness, headache, facial discomfort, dental discomfort, and ocular or eyelid discomfort.	From first stimulation session through 90 days after randomization

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Investigators: Principal Investigator: Dan Huang, MD, Renji Hospital; Study Director: Shujing Lin, Renji Hospital; Study Director: Tong Wu, Renji Hospital; Study Director: Xi Chen, MD, Renji Hospital; Study Director: Nan Wang, Renji Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 27, 2026
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: March 31, 2026
• First Submitted That Met QC Criteria: April 13, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Delirium
• Other Study ID Numbers: IIT-20250513

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared with other researchers due to ethical and confidentiality considerations. Only summary statistics and study results will be made publicly available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No