Cerebrospinal Fluid Hemoglobin to Monitor for Aneurysmal Subarachnoid Hemorrhage Related Secondary Brain Injury (HeMoVal)

Hemoglobin in the Cerebrospinal Fluid to Monitor for Secondary Brain Injury After Aneurysmal Subarachnoid Hemorrhage - a Prospective Multinational Validation Study

The primary objective of this study is to evaluate the association between hemoglobin levels in the cerebrospinal fluid (CSF-Hb) and the occurrence of secondary brain injury in patients after aneurysmal subarachnoid hemorrhage (SAH-SBI) during the first 14 days after bleeding.

Study Overview

• Status: Recruiting
• Conditions: Subarachnoid Hemorrhage, Aneurysmal; Delayed Cerebral Ischemia; Vasospasm; Delayed Ischemic Neurological Deficit

Detailed Description

This is an international multicentre observational study to validate cerebrospinal fluid hemoglobin (CSF-Hb) as a monitoring biomarker for aneurysmal subarachnoid hemorrhage related secondary brain injury (SAH-SBI). It is hypothesized that there is an association between the concentration of CSF-Hb and the occurrence of SAH-SBI during the first 14 days after the bleeding (post-SAH).

The primary objective of this study is to evaluate the association between ventricular CSF-Hb and SAH-SBI during the first 14 days post-SAH.

The secondary objectives are to investigate:

• the association between ventricular CSF-Hb and angiographic vasospasms (aVSP), delayed cerebral ischemia (DCI) and delayed ischemic neurological deficits (DIND) during the first 14 days post-SAH,
• the accuracy of ventricular CSF-Hb to monitor for aVSP, DCI and DIND during the first 14 days post-SAH,
• the association between lumbar CSF-Hb and SAH-SBI, aVSP, DCI and DIND during the first 14 days post-SAH,
• the accuracy of lumbar CSF-Hb to monitor for aVSP, DCI and DIND during the first 14 days post-SAH,
• the association between baseline measures and CSF-Hb (ventricular and lumbar during the first 14 days post-SAH),
• the association between CSF-Hb (ventricular and lumbar during the first 14 days post-SAH) and co-interventions/complications,
• the association between CSF-Hb (ventricular and lumbar during the first 14 days post-SAH) and chronic hydrocephalus at 12 weeks follow-up,
• the association between CSF-Hb (ventricular and lumbar during the first 14 days post-SAH) and functional outcome at 12 weeks follow-up,
• exploratory CSF proteome/metabolome analyses to assess Hb toxicity, inflammation, neuronal, or vascular damage.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Michael Hugelshofer, MD MSc; Phone Number: 0041432531598; Email: michael.hugelshofer@usz.ch
• Study Contact Backup: Name: Kevin Akeret, MD; Phone Number: 0041794479642; Email: kevin.akeret@usz.ch

Study Locations

• Austria
  • Linz, Austria, 4040
    • Recruiting
    • Johannes Kepler Universität Linz, Universitätsklinik für Neurochirurgie
    • Contact: Matthias Gmeiner, MD
  • Wien, Austria, 1090
    • Recruiting
    • Medizinische Universität Wien, Klinik für Neurochirurgie
    • Contact: Karl Rössler, MD
• Germany
  • Tübingen, Germany, 72076
    • Recruiting
    • Universitätsklinikum Tübingen
    • Contact: Constantin Roder, MD
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68167
      • Recruiting
      • Universitätsklinikum Mannheim
      • Contact: Nima Etminan, MD
  • Bayern
    • München, Bayern, Germany, 81675
      • Recruiting
      • Klinikum rechts der Isar TUM
      • Contact: Maria Wostrack, MD
• Switzerland
  • Zurich, Switzerland, 8091
    • Recruiting
    • University Hospital Zurich
    • Contact: Michael Hugelshofer, MD MSc; Phone Number: +41432531598; Email: michael.hugelshofer@usz.ch
    • Contact: Kevin Akeret, MD; Phone Number: +41794479642; Email: kevin.akeret@usz.ch
    • Sub-Investigator: Raphael M Buzzi, MD PhD
  • Aargau
    • Aarau, Aargau, Switzerland, CH-5001
      • Recruiting
      • Kantonsspital Aarau
      • Contact: Basil Grüter, MD
  • Saint Gallen
    • St. Gallen, Saint Gallen, Switzerland, CH-9007
      • Recruiting
      • Kantonsspital St. Gallen
      • Contact: Isabel C Hostettler, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study population consists of patients admitted to an academic tertiary care center due to an aneurysmal subarachnoid hemorrhage. The primary objective of the study focuses on patients included with EVD, while secondary objectives consider patients with both, EVD and LD as well as patients without any drainage system.

Description

Inclusion Criteria:

• age ≥ 18 years
• hospital admission due to an aneurysmal subarachnoid hemorrhage (diagnosis radiologically confirmed)

Exclusion Criteria:

• non-aneurysmal subarachnoid hemorrhage (eg. trauma, perimesencephalic subarachnoid hemorrhage).
• participation in another study with CSF sampling or an interventional medical product within the 30 days preceding and during the present study.
• previous enrolment into the current study

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
Study cohort; The study population consists of patients admitted to an academic tertiary care center due to an aneurysmal subarachnoid hemorrhage. The primary objective of the study focuses on patients included with external ventricular drain (EVD), while secondary objectives consider patients with both EVD and lumbar drain (LD) as well as patients without any drainage system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aneurysmal subarachnoid hemorrhage related secondary brain injury (SAH-SBI)	Composite outcome consisting of angiographic vasospasms (aVSP), delayed cerebral ischemia (DCI), or delayed ischemic neurological deficits (DIND).	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Angiographic vasospasms (aVSP)	The definition of aVSP comprises a narrowing of cerebral arteries based on a digital subtraction angiography (DSA), CT angiography (CTA) or magnetic resonance angiography (MRA). In the absence of an appropriate imaging procedure on the respective day, this will be noted as no imaging performed.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Delayed cerebral ischemia (DCI)	DCI is defined as new ischemia or new infarction on CT/perfusion CT or MRI. In the absence of an appropriate imaging procedure on the respective day, this will be noted as no imaging performed.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Delayed ischemic neurologic deficits (DIND)	DIND is defined as a new focal neurological deficit or a decrease in Glasgow Coma Scale (GCS) of at least 2 points for at least 2 hours. In case the patient cannot be clinically assessed (e.g., sedation), this will be noted as non-assessable).	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Co-intervention 1: Nimodipine treatment	Whether the patient received preventive nimodipine treatment within the past 24 hours.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Co-intervention 2: Spasmolysis	Whether a rescue therapy with pharmacological spasmolysis or balloon angioplasty was performed within the past 24 hours.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Co-intervention 3: Intraventricular administration of rtPA (ICV-rtPA)	Whether rtPA was administered via the EVD to induce blood clot lysis within the past 24 hours.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Co-intervention 4: Triple-H-therapy	A triple-H-therapy or elements of it (hypertension, hypervolemia or hemodilution) was induced within the past 24 hours.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Co-intervention 5: Decompression	A surgical decompression (e.g. decompressive hemicraniectomy) was performed within the past 24 hours.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Complication 1: CSF infection	Differentiated between infection (Clinical symptoms and signs of CSF infection and positive CSF culture), colonization (2 positive CSF cultures without clinical symptoms and signs) and contamination (1 positive CSF culture with consecutive culture being negative).	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Complication 2: Surgical site infection	Evidence for a surgical site infection at the EVD/LD skin entrance site.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage
Chronic hydrocephalus		12 weeks follow-up visit
Functional status 1: Glasgow Outcome Scale Extended [1-8]	Death; Vegetative state (unresponsive and speechless); Lower severe disability (requires frequent help of someone to be around at home most of the time every day); Upper severe diasbility (can be left alone > 8h during the day, but unable to travel and/or go shopping without assistance); Lower moderate disability (unable to work or only in sheltered workshop); Upper moderate disability (reduced work capacity; resumes <50% of the pre-injury level of social and leisure activities); Lower good recovery (minor problems that affect daily life; resumes >50% of the pre-injury level of social and leisure activities); Upper good recovery (no current problems related to the brain injury that affect daily life)	12 weeks follow-up visit
Functional status 2: modified Rankin Scale [0-6]	0 No symptoms; No significant disability. Able to carry out all usual activities, despite some symptoms.; Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.; Moderate disability. Requires some helpt, but able to walk unassisted.; Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; Severe disability. Requires constant nursing care and attention, bedridden, incontinent.; Dead	12 weeks follow-up visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal fluid hemoglobin	CSF sampling: CSF sampling will be performed via EVD or LD, depending on the patient's access to the CSF space. The decision regarding the insertion of an EVD or LD is made independently of this study and according to the clinical standard of care. 2ml of CSF will be sampled on a daily basis at approximately the same time in the morning. CSF centrifugation and storage: Immediately after sample collection, the CSF will be centrifuged at 1500 G for 15 minutes. The cell-free CSF supernatant will be stored at -80°C until analysis. Spectrophotometric cerebrospinal fluid hemoglobin (CSF-Hb) measurements: Absorption spectra in the visual range between 350 and 650 nm of all CSF samples will be measured. Quantification of oxyhemoglobin in CSF (CSF-Hb) will be performed using spectral deconvolution.	Day 1 to day 14 after the aneurysmal subarachnoid hemorrhage

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Michael Hugelshofer, MD MSc, University Hospital and University of Zurich, Department of Neurosurgery; Study Chair: Dominik J Schaer, MD, University Hospital and University of Zurich, Department of Internal Medicine; Principal Investigator: Kevin Akeret, MD/PhD, University Hospital and University of Zurich, Department of Neurosurgery; Study Chair: Raphael M Buzzi, MD/PhD, University Hospital and University of Zurich, Department of Internal Medicine

Publications and helpful links

General Publications

• Akeret K, Buzzi RM, Saxenhofer M, Bieri K, Chiavi D, Thomson BR, Gruttner-Durmaz M, Schwendinger N, Humar R, Regli L, van Doormaal TPC, Held U, Keller E, Hugelshofer M, Schaer DJ; HeMoVal Research Group. The HeMoVal study protocol: a prospective international multicenter cohort study to validate cerebrospinal fluid hemoglobin as a monitoring biomarker for aneurysmal subarachnoid hemorrhage related secondary brain injury. BMC Neurol. 2022 Jul 18;22(1):267. doi: 10.1186/s12883-022-02789-w.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2021
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): March 30, 2024

Study Registration Dates

• First Submitted: July 19, 2021
• First Submitted That Met QC Criteria: August 1, 2021
• First Posted (Actual): August 10, 2021

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cerebrospinal Fluid; Hemoglobins
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Infarction; Stroke; Brain Infarction; Intracranial Hemorrhages; Brain Ischemia; Ischemia; Brain Injuries; Hemorrhage; Cerebral Infarction; Subarachnoid Hemorrhage
• Other Study ID Numbers: 2021-01023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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