Angiotensin Metabolite Profile After Subarachnoid Hemorrhage

Study Overview
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Brief Summary
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The outcome of subarchnoid hemorrhage depends on the severity of the bleeding and the development of secondary neurologic deficits caused by cerebral vasospasm. The primary endpoint is a comparison of renin angiotensin system (RAS) parameters (plasma concentrations of Angiotensin [Ang] I, Ang II, Ang 1-7, and Ang 1-5, angiotensin metabolite based markers of RAS enzyme activities as well as active ACE and ACE2 concentrations in plasma and CSF) between patients with and without vasospasm, mechanical ventilation, antihypertensive therapy with a RAS modifying drug and low versus high Hunt and Hess grade of subarachnoid hemorrhage.

Detailed Description
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Wider research context. The clinical course and neurological outcome of patients with subarachnoid hemorrhage following rupture of an intracranial aneurysm depend on surgical repair of the ruptured aneurysm to avoid rebleeding and the development of cerebral vasospasm that may cause delayed ischemic deficits. Up to 65% of patients require mechanical ventilation mostly due to neurologic deficits or hypoxia. The renin angiotensin system (RAS) is acutely activated after subarachnoid hemorrhage with increased renin and angiotensin (Ang) II plasma levels, but effects of the vasoconstrictor Ang II on development of vasospasm have not been investigated in patients. The RAS may also be activated by mechanical ventilation, but it is unknown if this has an impact on occurrence of vasospasm. Arterial hypertension is an important risk factor for subarachnoid hemorrhage and vasospasm, and around 50% of patients have a history of high blood pressure. During weaning from mechanical ventilation arterial hypertension is a wide spread clinical problem, but how RAS modifying drugs act on the angiotensin metabolite profile that may already be dysregulated after subarachnoid hemorrhage remains unclear. Objectives. To investigate associations between angiotensin metabolite profile (Ang I, Ang II, Ang 1-7 and Ang 1-5 concentrations) and angiotensin converting enzyme (ACE) and ACE2 activities in plasma as well as ACE and ACE2 activities in cerebrospinal fluid (CSF) and development of cerebral vasospasm in patients with and without mechanical ventilation following subarachnoid hemorrhage, and to find out how the angiotensin metabolite profile is changed by antihypertensive therapy with a RAS modifying drug in these patients. Methods. Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations will be measured by liquid chromatography tandem mass spectrometry in 60 patients after subarachnoid hemorrhage in plasma. Active ACE and ACE2 concentrations will be measured in plasma and in CSF in patients with CSF drainages. Samples will be taken within 72 hours of subarachnoid hemorrhage and 7, 14 and 21 days following initial bleeding. Another plasma sample will be obtained if an antihypertensive therapy with a RAS modifying drug has been started. Angiotensin metabolite based markers of RAS enzyme activities will be calculated for renin and ACE activities and alternative RAS activation.

Official Title
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Angiotensin Metabolite Profile After Subarachnoid Hemorrhage

Conditions
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Subarachnoid Hemorrhage, Aneurysmal

Intervention / Treatment
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* Other: Sampling of plasma and cerebrospinal fluid at specified time points


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of subarachnoid hemorrhage because of aneurysmal rupture admitted to the ICU Invasive monitoring of arterial blood pressure Exclusion Criteria: Patients who decline study participation Brain stem death Chronic renal impairment with creatinine > 2mg/dL or hemodialysis Chronic liver failure of Child Pugh class C or higher Chronic heart failure Hormone producing neuroendocrine tumor Sarcoidosis Pregnancy Planned transfer to another hospital shortly after aneurysm repair

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients after aneurysmal subarachnoid hemorrhage<br>Samples (plasma, and in patients with in-dwelling cerebrospinal fluid drainages also cerebrospinal fluid) will be taken within 72 hours of subarachnoid hemorrhage and 7, 14 and 21 days following initial bleeding. Another plasma sample will be obtained if an antihypertensive therapy with a RAS modifying drug has been started. | Other: Sampling of plasma and cerebrospinal fluid at specified time points<br>* Samples (plasma, and in patients with in-dwelling cerebrospinal fluid drainages also cerebrospinal fluid) will be taken within 72 hours of subarachnoid hemorrhage and 7, 14 and 21 days following initial bleeding. Another plasma sample will be obtained if an antihypertensive therapy with a RAS modifying drug has been started.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Angiotensin metabolite concentrations within 72 hours | Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations in plasma (in pmol/L), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | within 72 hours of subarachnoid hemorrhage | 
| Angiotensin metabolite concentrations after 7 days | Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations in plasma (in pmol/L), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 7 days after subarchnoid hemorrhage | 
| Angiotensin metabolite concentrations after 14 days | Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations in plasma (in pmol/L), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 14 days after subarchnoid hemorrhage | 
| Angiotensin metabolite concentrations after 21 days | Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations in plasma (in pmol/L), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 21 days after subarchnoid hemorrhage | 
| ACE concentrations within 72 hours | active ACE concentrations in plasma and cerebrospinal fluid (in µg/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | within 72 hours of subarachnoid hemorrhage | 
| ACE concentrations after 7 days | active ACE concentrations in plasma and cerebrospinal fluid (in µg/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 7 days after subarachnoid hemorrhage | 
| ACE concentrations after 14 days | active ACE concentrations in plasma and cerebrospinal fluid (in µg/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 14 days after subarachnoid hemorrhage | 
| ACE concentrations after 21 days | active ACE concentrations in plasma and cerebrospinal fluid (in µg/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 21 days after subarachnoid hemorrhage | 
| ACE2 concentrations within 72 hours | active ACE2 concentrations in plasma and cerebrospinal fluid (in ng/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | within 72 hours of subarachnoid hemorrhage | 
| ACE2 concentrations after 7 days | active ACE2 concentrations in plasma and cerebrospinal fluid (in ng/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 7 days after subarachnoid hemorrhage | 
| ACE2 concentrations after 14 days | active ACE2 concentrations in plasma and cerebrospinal fluid (in ng/mL), comparison between patients with and without vasospasm,with and without mechanical ventilation and low versus high Hunt and Hess grade | 14 days after subarachnoid hemorrhage | 
| ACE2 concentrations after 21 days | active ACE2 concentrations in plasma and cerebrospinal fluid (in ng/mL), comparison between patients with and without vasospasm, with and without mechanical ventilation and low versus high Hunt and Hess grade | 21 days after subarachnoid hemorrhage | 
| Impact of RAS modifying drugs after subarachnoid hemorrhage | Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations in plasma (in pmol/L), comparison between sample taken after start of a RAS modifying drug and the previous sample in the study schedule | after start of a RAS modifying drug therapy for arterial hypertension in the intensive care unit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of RAS analyses with clinical parameters | Correlations of RAS parameters (Ang I, Ang II, Ang 1-7 and Ang 1-5 equilibrium concentrations and active ACE and ACE2 concentrations) and aldosterone plasma concentrations with blood pressure, blood pressure target, routine laboratory parameters and ventilator settings, and comparison of RAS parameters and aldosterone plasma concentrations between men and women | Within 72 hours, 7, 14 and 21 days following subarachnoid hemorrhage and after start of a RAS modifying drug therapy for arterial hypertension in the intensive care unit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral vasospasm, Renin angiotensin system