Study of Stroke Related Edema Treatments
关键词
抽象
描述
Previous work has demonstrated the pathophysiological role of arginine-vasopressin (AVP) in ischemic stroke. The mechanism of action of AVP is by 3 receptor subtypes: V1a, V1b and V2 expressed in brain, pituitary gland, myocardium, vasculature and kidneys. The role of the vasopressin receptors V1a and or V2 subtype in cerebral edema formation after ischemic stroke remains controversial. The V1a receptor antagonism causes platelet inhibition, aquaporin-4 up regulation; reduce infarct size and vasodilation. V1 antagonists has also been shown to prevent ischemia-induced cerebral edema development, suggesting that the V1 vasopressin receptor is important in water regulation in brain cells. Another study indicated that the vasopressin receptor V1 is involved in the pathogenesis of secondary brain damage after focal cerebral ischemia. Recently, few studies have demonstrated that a V2 receptor antagonist (OPC-31260), may be one of the effective drugs for the early treatment of cytotoxic edema and brain injury. Treatment of OPC-31260 ameliorated cerebral neurological deficit in transgenic (GET-1) mice after water intoxication. Treatment of OPC-31260 also significantly abolished water accumulation and down regulated Aquaporin-4 (AQP-4) expression level in GET-1 mice after water intoxication. The intensity of AQP-4 staining was almost comparable with that of the controls without water intoxication. It was also shown that OPC-31260 at doses of 10 to 30 mg/kg produced a dose-dependent inhibition of subarachnoid hemorrhage-induced cerebral edema formation, accompanied by an increase in urinary volume and decrease in urine osmolality without a significant alteration of urine electrolytes. OPC-31260 is also effective in treating water retention diseases, such as hyponatremia caused by inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. V2 receptor antagonism will also help in abolishing water accumulation, decreased Glial Fibrillary Acidic Protein (GFAP) in astrocytes and most importantly causes renal tubule-selective diuretic effect called aquaresis (electrolyte sparing diuresis), which may have additional benefit in the reduction of cerebral edema.
This combined approach of V1a and V2 AVP receptor antagonism will lead to attenuation of ischemia related cerebral edema and infarct volume by modulating ischemia-evoked AQP-4 expression. This effect should help behavior and mortality which in turn will improve outcome in stroke patients. The purpose of this project is to test the effect of the mixed V1a and V2 receptor blockade on ischemic or hemorrhagic stroke outcome.
In summary, the investigators are using the approach of mixed vasopressin antagonism on post stroke edema, infarct volume and outcome. This research will lead to a greater understanding of the roles and interactions of the different AVP receptors and pathophysiology of post stroke cytotoxic edema. New information on the effects of mixed blockade of V1a and V2 receptors on the prevention of cytotoxic edema post stroke will be revealed.
日期
| 最后验证: | 11/30/2016 |
| 首次提交: | 09/25/2013 |
| 提交的预估入学人数: | 09/25/2013 |
| 首次发布: | 09/30/2013 |
| 上次提交的更新: | 12/12/2016 |
| 最近更新发布: | 12/13/2016 |
| 实际学习开始日期: | 08/31/2015 |
| 预计主要完成日期: | 08/31/2015 |
| 预计完成日期: | 08/31/2015 |
状况或疾病
干预/治疗
Drug: Conivaptan arm
Drug: Hypertonic Saline (3%) and/or Mannitol arm
Drug: Hypertonic Saline (3%) and/or Mannitol arm
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Active Comparator: Hypertonic Saline (3%) and/or Mannitol arm The subjects in this arm will be given hypertonic saline and/or Mannitol.
For hypertonic saline,various concentrations are used clinically,up to 30-mL boluses of 23.4% saline.Rapid increases in sodium in this context do not appear to cause other neurologic complications observed with rapid correction of hyponatremia.Sodium levels up to 160 mmol/L may be acceptable,beyond which it may lead to worsening delirium,seizures,and overall poor outcome.
For Mannitol,every 4 hours serum osmolarity,serum glucose,urea,sodium and potassium will be measured till the therapy is given.Major complications include hypovolemia and hypotension.Strict fluid goals and volume replacement are essential.Impaired mannitol clearance may manifest as nephrotoxicity.Common practice includes repeating measurements of serum osmolarity and withholding repeat doses of mannitol when osmolarity exceeds 320 milliosmol(mOsm).Monitoring the osmole gap may be a more sensitive method for discerning mannitol clearance. | Drug: Hypertonic Saline (3%) and/or Mannitol arm Hypertonic saline in the dose of 30ml/hr, with every 4 hourly measurements of serum osmolarity, serum sodium and potassium. Hypertonic saline will be increased by 30 ml to achieve target serum sodium of 150-160 and serum osmolarity 300-320 |
| Experimental: Conivaptan arm The subjects in this arm will be given infusion of Conivaptan. | Drug: Conivaptan arm Intravenous conivaptan 20 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 20 mg over 24 hours (0.83 mg/hour) for 2-4 days; may increase to a maximum dose of 40 mg over 24 hours (1.7 mg/hour) if serum sodium is not rising sufficiently; total duration of therapy not to exceed 4 days. |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion Criteria: - Subjects with age ≥18 years and ≤80 years at the time of screening. - Hemorrhagic stroke or large vessel ischemic stroke patients diagnosed by MRI or CT scan of Head. - Subjects who have presented to hospital within 24 hours of symptom onset. - The subject or his/ her legal representative is willing to undergo informed consent process prior to enrollment into this study. Exclusion Criteria: - Subject with age < 18 years and >80 years at the time of screening. - Subjects with absence of stroke by imaging of brain by CT scan or MRI. - Lacunar stroke or small vessel stroke. - Time of symptom onset cannot be determined. - Subjects with renal or hepatic failure. - Subjects with hypovolemia or hypotension as determined by the study team. - Subjects with hypernatremia. - Subject who is pregnant or lactating. - Subject is already participating in other investigational clinical trial. - The subject or legal representative is unable to provide informed consent. - The subject is medically unstable to participate in the trial as determined by the principal investigator. - The subject has any end stage medical condition as determined by the principal investigator. |
结果
主要结果指标
1. Modified Rankin Score [At the time of discharge from hospital, and 3 months after initial event]
2. National Institutes of Health Stroke Severity (NIHSS) scale [At the time of discharge from hospital, and 3 months after initial event]
3. Neurological status of the subject [At the time of discharge from hospital, and 3 months after discharge]
次要成果指标
1. All cause mortality data [3 months after initial event]
其他成果措施
1. MRI brain- findings [3 Months after Initial Event]
