Reduction of Edema With a Specialized Cocktail for Ultra-early Management in Intracerebral Hemorrhage

Phase 3Not Yet RecruitingNCT06863558

Second Affiliated Hospital, School of Medicine, Zhejiang University58 enrolled

Overview

Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability rates, often worsened by perihematomal edema (PHE), which increases intracranial pressure and leads to poor outcomes. Preclinical studies suggest that a pharmacological cocktail (PPA) may help reduce cerebral edema by modulating potassium balance, preserving aquaporin-4 expression, and enhancing lymphatic drainage. This multicenter, randomized controlled trial (RCT) aims to evaluate the safety and efficacy of PPA in ICH patients. A total of 58 patients with supratentorial ICH (≥3 mL hematoma volume) who are not undergoing surgical evacuation will be randomized to receive either PPA therapy or standard treatment. The primary outcome is the change in cerebral edema volume at 5-7 days, assessed by CT imaging. Secondary outcomes include 90-day functional outcomes (mRS), need for decompressive craniectomy, and safety assessments. This study seeks to explore PPA as a potential treatment strategy for cerebral edema in ICH patients.

Intracerebral hemorrhage (ICH) is a severe subtype of stroke, accounting for 15-20% of all strokes. Compared to ischemic stroke, ICH has a higher mortality and disability rate, with its incidence steadily rising worldwide, imposing a substantial burden on families and healthcare systems. A key factor contributing to poor prognosis in ICH is perihematomal edema (PHE), which rapidly progresses during the acute phase, leading to increased intracranial pressure (ICP), brain tissue displacement, and potential brain herniation. Even in patients who survive the acute phase, persistent cerebral edema can cause long-term neurological deficits and impair quality of life. Therefore, effective management of cerebral edema is critical for improving outcomes in ICH patients. Preclinical studies suggest that a pharmacological cocktail (PPA), consisting of adrenergic antagonists, may help reduce cerebral edema by modulating extracellular potassium homeostasis, maintaining aquaporin-4 (AQP-4) expression, and enhancing lymphatic drainage. In both traumatic brain injury and ischemic stroke models, PPA has shown potential in alleviating cerebral edema and improving neurological recovery. Based on these findings, this multicenter, randomized controlled trial (RCT) aims to evaluate the safety and efficacy of PPA in reducing cerebral edema in ICH patients. The study will enroll 58 patients diagnosed with supratentorial ICH (≥3 mL hematoma volume) who are not undergoing surgical evacuation. Participants will be randomly assigned to receive PPA therapy or standard treatment. The primary outcome is change in cerebral edema volume at 5-7 days, assessed by CT imaging. Secondary outcomes include functional outcomes at 90 days (mRS), need for decompressive craniectomy, incidence of hypotension, and adverse events. This study aims to explore PPA as a novel pharmacological approach for managing cerebral edema in ICH, potentially improving patient prognosis and clinical outcomes.

Interventions

PPA InterventionDRUG

Participants in this group will receive a pharmacological cocktail (PPA) for five days in addition to standard medical treatment for acute ischemic stroke. The regimen includes terazosin or urapidil, and propranolol or esmolol, with individualized blood pressure management. The specific protocol is as follows: * Terazosin (no less than 1 mg orally or via nasogastric tube, nightly) or Urapidil (100 mg in 30 mL saline, IV infusion at no less than 2 mL/h) * Propranolol (10 mg orally or via nasogastric tube, three times daily) or Esmolol (1 g in 40 mL saline, IV infusion at no less than 2 mL/h; use for no more than 48 hours. Beyond 48 hours, switch to Propranolol)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥18 years * Clinical diagnosis of supratentorial intracerebral hemorrhage (ICH) * Symptom onset within 3 days (≤72 hours) before randomization * Baseline CT-confirmed hematoma volume ≥3 mL * Not scheduled for hematoma evacuation surgery (either not indicated or declined by the patient/family) * Written informed consent obtained from the patient or legally authorized representative Exclusion Criteria: * Baseline brain herniation or severe hypotension (SBP \<90 mmHg) * Contraindications to PPA medications (terazosin, urapidil, esmolol, propranolol), such as asthma or severe bradycardia * Severe comorbidities that may interfere with efficacy assessment or pose a high safety risk (e.g., end-stage organ failure, advanced malignancy) * Presence of secondary causes of ICH (e.g., arteriovenous malformation, aneurysm rupture, hemorrhagic transformation of ischemic stroke) * Pregnancy or lactation * Participation in another interventional trial that may influence study outcomes

Outcomes

Primary Outcomes

Change in Cerebral Edema Volume at 5-7 Days

The primary outcome of this study is the change in cerebral edema volume, as assessed by non-contrast CT imaging at baseline (pre-treatment) and 5-7 days after treatment initiation. Edema volume will be quantified using standardized imaging analysis techniques. The difference in cerebral edema volume between the PPA intervention group and the standard treatment group will be compared to evaluate the efficacy of the pharmacological cocktail in reducing brain swelling.

Time frame: Baseline and 5-7 days post-treatment

Secondary Outcomes

90-Day Functional Outcome (Modified Rankin Scale, mRS)

Functional outcomes will be assessed using the modified Rankin Scale (mRS) at 90 days post-treatment, mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome

Time frame: 90 days post-treatment

Incidence of Hypotension During the Treatment Period

The occurrence of clinically significant hypotension (defined as systolic blood pressure \<90 mmHg) will be monitored throughout the intervention period. The frequency, severity, and need for medical intervention will be compared between the two study groups.

Time frame: Time Frame: During the 5-day treatment period

Change in Hematoma Volume

Assessment of hematoma volume on CT imaging at baseline and 5-7 days post-treatment to evaluate any changes in bleeding size.

Time frame: 5-7 days post-treatment

Need for Decompressive Craniectomy

The proportion of patients who require decompressive craniectomy due to increased intracranial pressure or neurological deterioration.

Time frame: Up to 7 days

Mortality at 90 Days

All-cause mortality will be recorded and compared between the PPA intervention and standard treatment groups to evaluate the impact of the intervention on survival.

Time frame: 90 days post-treatment

Incidence of Serious Adverse Events (SAEs)

All serious adverse events (SAEs), including cardiovascular complications, major bleeding, and severe drug reactions, will be recorded and compared between groups.

Time frame: Up to 90 days post-treatment