Correlation of Various Laboratory Parameters With Outcome in Patients Suffering From Acute Non-traumatic Subarachnoid Hemorrhage - Prospective Case Series

June 27, 2022 updated by: Tamas Vegh, MD, University of Debrecen

In this prospective study, the investigators aim to investigate the effect of the following three factors on the development of vasospasm and patient outcome: (1.) the role of anemia; (2.) the role of plasma fibrinolytic activity; (3.) the role of vitamin D.

The investigators include patients admitted to the Neurosurgical Intensive Care Unit of the Clinical Center of the University of Debrecen with the diagnosis of subarachnoid hemorrhage (SAH). Patients are treated according to international guidelines. As part of the study protocol the following investigations are performed: • Hemoglobin level measurement: on the day of admission and day 3-4-7 and 14 after hemorrhage •Modified clot lysis assay (mCLA): on the day of admission and day 7 after hemorrhage •25-hydroxy vitamin-D level measurement: on the day of admission •Transcranial color-coded duplex sonography (detecting vasospasm): on daily basis. •30 day follow-up: mortality, Glasgow Outcome Scale (GOS), Karnofsky score, Barthel score •90 day follow-up: mortality, Glasgow Outcome Scale , Karnofsky score, Barthel score. Laboratory test results are correlated with (a) the development of vasospasm; (b) with 30 and 90 day outcome.

Perspectives of the planned study: Considering the currently available therapeutic range for patients with SAH, results of the present study may provide a basis for designing further randomized, prospective trials to investigate the effect of treating anemia, anticoagulation and vitamin-D supplementation.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Background

The incidence of aneurysmal subarachnoid hemorrhage is 10/100000 person/year. Some epidemiological date suggest that the 30-day mortality of subarachnoid hemorrhage (SAH) is nearly 50%. (ACROSS Group. Epidemiology of aneurysmal subarachnoid hemorrhage in Australia and New Zealand: incidence and case fatality from the Australasian Cooperative Research on Sub- arachnoid Hemorrhage Study (ACROSS). Stroke. 2000;31: 1843-50 Ingall T, Asplund K, Mahonen M, Bonita R. A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke. 2000;31:1054-61.). In this relative high mortality rate the effect of delayed cerebral ischaemia (DCI) and different extracerebral complications (Takotsubo cardiomyopathy, secondary infections, etc.) have key roles. (Claassen J, Vu A, Kreiter KT, et al. Effect of acute physiologic derangements on outcome after subarachnoid hemorrhage. Crit Care Med. 2004;32:832-8.). DCI occurs in nearly third of patients and its most common cause is cerebral vasospasm (at least 70% of cases). Vasospasm usually develops on day 3 after hemorrhage, it reaches a peak on day 7-8 and solves after the day 14.

(Dorsch NWC, King MT. A review of cerebral vasospasm in aneurysmal subarachnoid hemorrhage. Part 1: Incidence and effects. J Clin Neurosci. 1994;1:19-26.).

DCI has been shown to be a multifactorial process, in which cerebral vasospasm has a remarkable part, but anemia, cortical spreading depolarization, damage of cerebral autoregulation, and activation of the inflammatory-thrombotic cascade may also play an important role. . (Chamling B, Gross S, Stoffel-Wagner B, Schubert GA, Clusmann H, Coburn M, et al. Early diagnosis of delayed cerebral ischemia: possible relevance for inflammatory biomarkers in routine clinical practice? World Neurosurg (2017) 104:152-7. McBride DW, Blackburn SL, Peeyush KT, Matsumura K, Zhang JH. The Role of Thromboinflammation in Delayed Cerebral Ischemia after Subarachnoid Hemorrhage.Front Neurol. 2017;8:555.).

In this prospective study the investigators aim to investigate the role of the following three factors on the development of vasospasm and patient outcome: (1.) anemia; (2.) plasma fibrinolytic activity; (3.) vitamin D.

Review of related literature:

The role of anaemia in SAH: Depending on definition, anaemia develops in 40-50% of SAH patients, only 16% of patients have a hemoglobin level higher than 110g/l . According to follow-up studies anaemia appears on day 3-4 after hemorrhage (concurrently with vasospasm) and the reduction of hemoglobin concentration is 30 g/l on average. (Sampson TR, Dhar R, Diringer MN. Factors associated with the development of anemia after subarachnoid hemorrhage. Neurocrit Care. 2010;12:4-9.)

Clot lysis assay gives an opportunity to detect the plasma fibrinolytic potential. Studies from the recent years identified neutrophil extracellular trap (NET) components, releasing from activated neutrophil granulocytes and play an important role in the modulation of the fibrinolytic process. NETs are the part of the complex system of inherited immunity. A recent study has shown that parameters of the modified CLA correlate with the volume of hematoma and outcome of spontaneous intracranial hemorrhage. (Orbán-Kálmándi R, Árokszállási T, Fekete I, Fekete K, Héja M, Tóth J, Sarkady F, Csiba L, Bagoly Z. A Modified in vitro Clot Lysis Assay Predicts Outcomes in Non-traumatic Intracerebral Hemorrhage Stroke Patients-The IRONHEART Study. Front Neurol. 2021;12:613441.) No similar studies exist about SAH.

The role of vitamine D3 in SAH: In a previous pilot study vitamine D3 deficiency was identified as an independent risk factor of SAH outcome , furthermore vitamin D3 level was inversely related to the incidence and severity of vasospasm. (Kashefiolasl S, Leisegang MS, Helfinger V, Schürmann C, Pflüger-Müller B, Randriamboavonjy V, Vasconez AE, Carmeliet G, Badenhoop K, Hintereder G, Seifert V, Schröder K, Konczalla J, Brandes RP. Vitamin D-A New Perspective in Treatment of Cerebral Vasospasm. Neurosurgery. 2021;88:674-685.).

Perspectives of the planned study: Considering the currently available therapeutic range for patients with SAH, results of the present study may provide a basis for designing further randomized, prospective trials to investigate the effect of treating anemia, anticoagulation and vitamin D supplementation.

Subjects and methods

The investigators include patients admitted to the Neurosurgical Intensive Care Unit of the Clinical Center of the University of Debrecen with the diagnosis of SAH.

Inclusion criteria:

  • acut SAH
  • patients older than 18 years
  • admission within 48 hours after symptom onset

Exclusion criteria:

  • admission over 48 hours after symptom onset
  • traumatic SAH
  • Angioma
  • A-V malformation
  • Patient unable to consent and no relative available

Planned period of patient enrollment: June 1, 2022 - December 31, 2024 Planned number of patients: approx. 300 patients

Patients are treated according to local protocol based on international guidelines(Diringer MN, Bleck TP, Claude Hemphill J 3rd, Menon D, Shutter L, Vespa P, Bruder N, Connolly ES Jr, Citerio G, Gress D, Hänggi D, Hoh BL, Lanzino G, Le Roux P, Rabinstein A, Schmutzhard E, Stocchetti N, Suarez JI, Treggiari M, Tseng MY, Vergouwen MD, Wolf S, Zipfel G; Neurocritical Care Society. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15:211-240.), and neurosurgeons and interventional radiologists are involved in therapeutic decisions.

Investigations and recorded data on admission:

  • skull CT
  • angiography
  • severity classification: Fisher, Hunt-Hess, WFNS, GCS
  • medical history, especially: hypertension, diabetes mellitus, cardiovascular diseases, kidney diseases (polycystic kidney? ), previous stroke
  • laboratory investigations: blood count, blood glucose, kidney function, hemostasis + fibrinogen

Investigations associated with present study and their timing:

Hemoglobin level:

  • day of admission
  • day 3-4-7 and 14 after hemorrhage

mCLA:

  • day of admission

  • day 7 after hemorrhage

    25-hydroxy vitamin-D level:

  • day of admission

Transcranial color- coded duplex sonography:

  • daily basis

    30 day follow-up:

  • mortality
  • Glasgow Outcome Scale
  • Karnofsky score

  • Barthel score

    90 day follow-up:

  • mortality
  • Glasgow Outcome Scale
  • Karnofsky score
  • Barthel score

Transcranial color-coded duplex sonography :

Transcranial color-coded duplex (TCCD) sonography is performed by two experienced investigators (Béla Fülesdi, Péter Síró) using the 2 MHz sector transducer of the GE Venue Go (GE Healthcare 9900 Innovation Drive Wauwatosa, WI 53226 U.S.A.) ultrasound device. Regular TCCD measurements are registered in all patients between days 1 through 7. Based on previous suggestions, vasospasm is considered if mean blood flow velocity was higher than 120 cm/s and severe vasospasm is diagnosed if mean blood flow velocity exceeded 200 cm/s. If ultrasound signs of vasospasm are present in any of the cases, duplex sonographies are performed until day 21 on a daily basis.

Processing data

Correlation of all three parameters with SAV severity parameters, detected on admission: Hunt Hess score, Fischer score, WFNS score

Correlation of all three parameters with the development of vasospasm.

Definition of anemia based on hemoglobin level:

  • in males: < 120 g / l

  • in females: <110 g / l

    25-hydroxy vitamin-D level:

  • definition of low level: <50 nmol/l

Statistical analysis:

To analyse continuous variables, in the first step a normality test is performed. The t-test is used to analyse samples with a normal distribution, while non-parametric tests are used to analyse samples with non-normal distribution. Bonferroni correction is performed for multiple comparisons. To examine categorical variables, the investigators use a χ2 test with "Yates' correction for continuity" if necessary.

Study Type

Observational

Enrollment (Anticipated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Hungary
    • Hajdú-Bihar
      • Debrecen, Hajdú-Bihar, Hungary, 4032

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The study intends to include all patients over 18 years of age who were admitted to our clinic within 48 hours after the bleeding regardless of gender, neurological status or age.

Description

Inclusion Criteria:

  • acut SAH
  • patients older than 18 years
  • admission within 48 hours after symptom onset

Exclusion Criteria:

  • admission over 48 hours after symptom onset
  • traumatic SAH
  • Angioma
  • A-V malformation
  • Patient unable to consent and no relative available

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hemoglobin level
Time Frame: day of admission, day 3-4-7 and 14 after hemorrhage
correlation with the development of vasospasm
day of admission, day 3-4-7 and 14 after hemorrhage
mCLA
Time Frame: day of admission, day 7 after hemorrhage
correlation with the development of vasospasm
day of admission, day 7 after hemorrhage
25-hydroxy vitamin-D level
Time Frame: day of admission
correlation with the development of vasospasm
day of admission

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hemoglobin level
Time Frame: day 14, 30 and 90 after hemorrhage
correlation with outcome (GOS, Barthel Index, Karnofsky Index)
day 14, 30 and 90 after hemorrhage
mCLA
Time Frame: day 14, 30 and 90 after hemorrhage
correlation with outcome (GOS, Barthel Index, Karnofsky Index)
day 14, 30 and 90 after hemorrhage
25-hydroxy vitamin-D level
Time Frame: day 14, 30 and 90 after hemorrhage
correlation with outcome (GOS, Barthel Index, Karnofsky Index)
day 14, 30 and 90 after hemorrhage

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Debrecen

Investigators

  • Principal Investigator: Csilla Molnár, MD Associate professor, Department of Anesthesiology and Intensive Care, University of Debrecen, Health and Medical Science Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2022

Primary Completion (Anticipated)

December 31, 2024

Study Completion (Anticipated)

December 31, 2024

Study Registration Dates

First Submitted

May 31, 2022

First Submitted That Met QC Criteria

May 31, 2022

First Posted (Actual)

June 3, 2022

Study Record Updates

Last Update Posted (Actual)

July 1, 2022

Last Update Submitted That Met QC Criteria

June 27, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DE KK RKEB/IKEB 5924-2021

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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