The goal of this randomized controlled trial is to evaluate whether the adjuvant application of non-thermal plasma (NTP) during standard surgical drainage of chronic subdural hematoma (cSDH) can reduce the recurrence rate at 6 months. The main questions it aims to answer are:

• Does NTP application significantly lower the radiological and clinical recurrence rate of cSDH compared to surgery alone?
• Is NTP safe when applied to the subdural space and surgical wound bed?
• Does NTP improve functional outcomes and time to hematoma resolution?

Participants will be randomly assigned to one of two groups:

• Experimental group (n = 20): Standard burr hole drainage or craniotomy plus intraoperative NTP application over the exposed dura mater, the residual membrane, soft tissue layers, and the skin incision.
• Control group (n = 20): Standard surgical drainage alone (no NTP).

Follow-up includes clinical assessments and computed tomography (CT) scans at 1 week, 3 months, and 6 months post-surgery. The primary outcome is recurrence (symptomatic reaccumulation requiring re-intervention or ≥50% volume increase on CT).

This is a prospective, randomised, controlled, parallel-group trial conducted at the ISSEMYM Medical Centre Toluca, "Lic. Arturo Montiel Rojas" (Metepec, State of Mexico, Mexico), in collaboration with the National Institute of Nuclear Research (ININ, Ocoyoacac, State of Mexico, Mexico). The study aims to evaluate the efficacy and safety of intraoperative non-thermal plasma (NTP) application as an adjunct to standard surgical drainage for chronic subdural hematoma (cSDH).

The pathophysiology of cSDH recurrence is driven by the residual vascular parietal membrane (neomembrane), which maintains chronic inflammation, fragile neoangiogenesis, and recurrent microhemorrhages. Standard burr hole drainage or craniotomy evacuates the liquid collection but does not neutralise this biological substrate. Preclinical and clinical evidence suggest that NTP, through controlled delivery of reactive oxygen and nitrogen species (RONS), exerts local anti-inflammatory and pro-regenerative effects. Therefore, NTP applied directly to the subdural space and surgical wound bed may modulate the pathological membrane and reduce recurrence rates.

Eligible patients (≥18 years) with symptomatic cSDH requiring surgery will be randomised 1:1 to either the control group (standard surgery alone) or the experimental group (standard surgery + NTP). Randomisation will be performed using a computer-generated sequence with sealed opaque envelopes. The treating neurosurgeon cannot be blinded due to the nature of the intervention, but the neuroradiologist assessing follow-up CT scans will be blinded to group allocation.

The NTP device (13.56 MHz RF generator, 20 Watts, helium gas at 0.5 LPM) will be operated by trained biomedical personnel from ININ under direct neurosurgical supervision. Application protocol:

• Subdural space: NTP applied to the exposed dura mater and any visible residual membrane for 60 seconds per 5 cm² at 5 mm distance.
• Soft tissue layers: sequential application during closure of the periosteum and subcutaneous tissue (same parameters).
• Skin incision: final application after skin closure.

The control group receives identical surgical treatment without NTP. Both groups receive standard perioperative care, including antibiotics and pain management as per institutional protocol.

Follow-up visits are scheduled at 1 week (± 2 days), 3 months (± 2 weeks), and 6 months (± 2 weeks) post-surgery. At each visit, the clinical assessment includes the Glasgow Coma Scale (GCS), the Modified Rankin Scale (mRS), and documentation of any adverse events. Non-contrast head CT scans are performed at all three time points. The primary endpoint - recurrence - is defined as symptomatic reaccumulation requiring surgical re-intervention OR an asymptomatic volume increase ≥50% on CT scan. Secondary endpoints include time to ≥50% radiological resolution, change in mRS, and safety (adverse events).

The protocol has been approved by the Health Research and Research Ethics Committee (approval number UEeIM.282/25). Written informed consent will be obtained from all participants or their legal representatives. The study is conducted in accordance with the Declaration of Helsinki and Mexican health regulations. Data confidentiality is maintained through coding and secure storage. Participants may withdraw at any time without affecting their medical care. ININ provides the NTP equipment, gas, and technical personnel. ISSEMYM provides surgical resources, hospital facilities, and clinical follow-up. No commercial funding is involved. Results will be disseminated via peer-reviewed publications and scientific conferences, regardless of the outcome.

Inclusion Criteria:

• Adults ≥ 18 years of age
• Diagnosis of symptomatic chronic subdural hematoma (cSDH) requiring surgical drainage (burr hole drainage or craniotomy)
• Ability to provide written informed consent (or consent from legal representative if patient is incapacitated)

Exclusion Criteria:

• Pure acute or subacute subdural hematoma
• Uncontrolled coagulopathy or bleeding disorder
• History of intracranial aneurysm or prior cerebrovascular event with residual deficit
• Presence of active intracranial metallic implants or electronic devices (e.g., programmable shunt, cardiac pacemaker, deep brain stimulator) in the head region
• Pregnancy or lactation
• Participation in another interventional clinical trial within 30 days prior to screening

The neuroradiologist evaluating CT scans will be blinded to treatment allocation.