Comparing Between CO2 and Phenylephrine Treatment in Patients With Progressive Lacunar Infarction (CARBOGEN Study)

Study Overview
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Brief Summary
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Lacunar infarction is an ischemic stroke occurred by small perforating artery occlusion . Twenty percent of ischemic stroke is lacunar infarction. However, outcome of lacunar infarction is excellent, about 20-40% patients are suffered neurological worsening. Progressive lacunar infarction is associated poor functional outcome and neurological deficit. Currently, no treatment for progressive lacunar infarction is recommended on the guideline. Several small study reported that phenylephrine and magnesium may be helpful for progressive lacunar infarction. Carbogen is a mixture of 5% CO2 with 95% O2. Carbogen is safe and it is used for the treatment of sudden sensory neural hearing loss or ocular ischemia. CO2 dilate cerebral arteriole and concentration of CO2 is correlated with cerebral blood flow. Lacunar infarction is small and perfused with marginal flow by neighboring perforating arteriole. Increased cerebral blood flow following dilation of cerebral arteriole by CO2 might halt and revert progressive lacunar infarction. Induced hypertension is alternative treatment of progressive lacunar infarction. Increasing blood pressure also induce cerebral blood flow. Phenylephrine is an α1 agonist, phenylephrine act on peripheral artery and little effect on cerebral artery or heart. Several studies reported that the effectiveness of phenylephrine on progressing stroke. Therefore, this study will compare the effectiveness of carbogen versus phenylephrine in lacunar infarction patients who suffered neurological worsening.

Official Title
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Comparing Between CO2 and Phenylephrine Treatment in Patients With Progressive Lacunar Infarction (CARBOGEN Study)

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: carbogen
* Drug: phenylephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥20 years Anterior circulation progressive lacunar infarction. Neurological worsening either 1 point in NIHSS score or MRC grade Exclusion Criteria: Age <20 Cortical infarction Posterior circulation lacunar infarction Relevant artery stenosis more than 50% or occlusion Moyamoya disease Difficulty in inhalation of Carbogen (panic, severe anxiety disorder) Drug allergy for phenylephrine Persistent bradycardia (pulse rate < 50 /min) History of hemorrhagic stroke Pre-stroke mRS ≥2

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a single center, prospective, randomized, open-label trial with blinded end-point assessment (PROBE) design study. For the patients with neurological worsening after lacunar infarction, the carbogen group and the phenylephrine group will be randomized by 1: 1. Patients will be enrolled from April 2021 to December 2022 (based on the date of stroke). We will collect medical history, laboratory findings, neurological scores, and functional recovery. Functional recovery scores are performed by independent researchers in the blind state. All data is collected using e-CRF, and the image study will be anonymized and sent to the central adjudication. Central adjudication will review the image study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carbogen group<br> | Drug: carbogen<br>* Patients will inhale carbogen gas for 10 minutes and rest for 50 minutes.<br>|
| Active Comparator: Phenylephrine group<br> | Drug: phenylephrine<br>* Start phenylephrine with 0.5 mg/hr and titrate upto 3.5 mg/hr or systolic blod pressure 200 mmHg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percent improvement of NIHSS score in each group | (baseline NIHSS score-post-treatment NIHSS score)/baseline NIHSS score×100 | 48 hours | 
| difference of NIHSS score in each group | baseline NIHSS score-post-treatment NIHSS score | 48 hours | 
| percent improvement of MRC score in each group | (baseline MRC score-post-treatment MRC score)/baseline MRC score×100 | within 48 hours | 
| difference of MRC score in each group | baseline MRC score-post-treatment MRC score | within 48 hours | 
| Safety outcome: Side effect | Side effect (cerebral hemorrhage, myocardial infarction, Losing consciousness, difficulty breathing, dizziness, fatigue, headache, anxiety, etc) | within 7 days | 
| Safety outcome: discontinuing patients | Number of discontinuing patients due to side effects | within 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison between groups by percent improvement of NIHSS score | (baseline NIHSS score-post-treatment NIHSS score)/baseline NIHSS score×100 | 48 hours | 
| Comparison between groups by difference of NIHSS score | baseline NIHSS score-post-treatment NIHSS score | 48 hours | 
| Comparison between groups by percent improvement in MRC score | (baseline MRC score-post-treatment MRC score)/baseline MRC score×100 | within 48 hours | 
| Comparison between groups by difference of MRC score | baseline MRC score-post-treatment MRC score | within 48 hours | 
| Functional independence | modified Rankin score 0 to 2 | upon discharge, 3 months after onset | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CO2, carbogen, phenylephrine, lacunar infarction, progressive stroke