Subarachnoid Hemorrhage, Aneurysmal
Conditions
Keywords
Cerebral vasospasm, Renin angiotensin system
Brief summary
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
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.
Interventions
OTHERSampling of plasma and cerebrospinal fluid at specified time points
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.
Sponsors
Austrian Science Fund (FWF)
Dr. Roman Ullrich
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Impact of RAS modifying drugs after subarachnoid hemorrhage | after start of a RAS modifying drug therapy for arterial hypertension in the intensive care unit | 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 |
| Angiotensin metabolite concentrations within 72 hours | within 72 hours of subarachnoid hemorrhage | 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 |
| Angiotensin metabolite concentrations after 7 days | 7 days after subarchnoid hemorrhage | 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 |
| Angiotensin metabolite concentrations after 14 days | 14 days after subarchnoid hemorrhage | 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 |
| Angiotensin metabolite concentrations after 21 days | 21 days after subarchnoid hemorrhage | 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 |
| ACE concentrations within 72 hours | within 72 hours of subarachnoid hemorrhage | 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 |
| ACE concentrations after 7 days | 7 days after subarachnoid hemorrhage | 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 |
| ACE concentrations after 14 days | 14 days after subarachnoid hemorrhage | 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 |
| ACE concentrations after 21 days | 21 days after subarachnoid hemorrhage | 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 |
| ACE2 concentrations within 72 hours | within 72 hours of subarachnoid hemorrhage | 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 |
| ACE2 concentrations after 7 days | 7 days after subarachnoid hemorrhage | 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 |
| ACE2 concentrations after 14 days | 14 days after subarachnoid hemorrhage | 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 |
| ACE2 concentrations after 21 days | 21 days after subarachnoid hemorrhage | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of RAS analyses with clinical parameters | 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 | 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 |
Countries
Austria
Contacts
Primary ContactKatharina Krenn, MD, PhD
Backup ContactRoman Ullrich, MD
Outcome results
None listed