Angiotensin Metabolite Profile After Subarachnoid Hemorrhage

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.

Study Overview

• Status: Recruiting
• Conditions: Subarachnoid Hemorrhage, Aneurysmal
• Intervention / Treatment: Other: Sampling of plasma and cerebrospinal fluid at specified time points

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.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

• Study Contact: Name: Katharina Krenn, MD, PhD; Phone Number: 41020 +43140400; Email: katharina.krenn@meduniwien.ac.at
• Study Contact Backup: Name: Roman Ullrich, MD; Email: roman.ullrich@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Katharina Krenn, MD, PhD; Phone Number: 41020 +43140400; Email: katharina.krenn@meduniwien.ac.at
    • Contact: Head of Department (Anesthesia and General Intensive Care); Email: klaus.markstaller@meduniwien.ac.at
    • Sub-Investigator: Roman Ullrich, MD
    • Sub-Investigator: Petra Höbart, MD
    • Sub-Investigator: Alessia Felli, MD
    • Sub-Investigator: Walter Plöchl, MD
    • Sub-Investigator: Paul Kraincuk, MD
    • Sub-Investigator: Nikolai Nantchev
    • Sub-Investigator: Philipp Weimann
    • Sub-Investigator: Josa Frischer, MD, PhD
    • Sub-Investigator: Andrea Reinprecht, MD
    • Sub-Investigator: Johannes Herta, MD
    • Principal Investigator: Katharina Krenn, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with a diagnosis of subarachnoid hemorrhage because of aneurysmal rupture admitted to the ICU

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients after aneurysmal subarachnoid hemorrhage; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr. Roman Ullrich
• Collaborators: Austrian Science Fund (FWF)
• Investigators: Principal Investigator: Katharina Krenn, MD, PhD, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Anticipated): February 1, 2025
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: January 11, 2022
• First Submitted That Met QC Criteria: January 24, 2022
• First Posted (Actual): February 3, 2022

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Cerebral vasospasm; Renin angiotensin system
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage
• Other Study ID Numbers: EK Nr: 1681/2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The data will be shared and made accessible after publishing of the results of the study according to the European code of conduct for research integrity - as open as possible and as closed as necessary. Results will be published in an accurate, transparent manner in an international peer reviewed journal supporting open access. As persistent identifier DOI will be used.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No