Degradation of the Glycocalyx in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

Official title:

Degradation of the Glycocalyx in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03706768
• Other study ID #: 170016
• Status: Recruiting
• Phase: N/A
• Start date: May 1, 2018
• Est. completion date: May 1, 2020

Study information

• Verified date: April 2019
• Source: University of Virginia
• Contact: Marcia E Birk
• Phone: 434-924-2283
• Email: meb2w[@]virginia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will provide novel information to the literature base for the pathophysiology of aneurysmal subarachnoid hemorrhage. The association of breakdown products in the serum of aSAH patients were reported in a very small case series of 3 patients, as mentioned above. However, while their results are intriguing and encouraging, our study will provide more definitive information about the GC in aSAH. If there is a positive correlation, the results of this study will guide future investigations into new therapies for this devastating disease such as MMP inhibition with doxycycline.

Description:

1. The study will aim to recruit all eligible patients at UTMCK and the University of Virginia hospital over a 12 month period. Our main outcome measure is degradation of the glycocalyx in patients with aSAH. All eligible patients with confirmed aSAH admitted to the neuro-intensive care unit will be enrolled after consent is obtained from the family and/or the patient. Serum samples will be drawn from each patient on admission (day 1) and every other day until day 13 for a total of 7 samples per patient.

The following serum tests will be performed:

2. Measurement of serum syndecan-1 by ELISA

3. Measurement of serum heparan-sulfate by ELISA

4. Measurement of serum matrix metalloproteinases -9

5. Measurement of serum matrix-metalloproteinase-1

6. Measurement of urinary microalbumin-to-creatinine ratio

7. Measurement of daily TCDs (all patients currently receive daily TCDs as part of the aSAH protocol at UTMCK and UVA Hospital)

8. Outcomes:

a) Chart review: i) Incidence of DCI as defined by a consensus committee on this subject and published in the journal Stroke [29].

ii) In-hospital mortality will be recorded b) Follow-up performed by phone call or searching the Social Security Death Index [30]: i) 30-day mortality ii) 90-day mortality c) Outcomes follow-up: i) The Glasgow Outcome Scale 12 weeks post aSAH [31]

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: May 1, 2020
• Est. primary completion date: May 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• • Age 18 years of age and older

• Cerebral aneurysm on CT-angio

Exclusion Criteria:

• • comfort care only orders,

• the absence of an aneurysm on CT-angiography,

• onset of aneurysm rupture > 24 hours,

• and inability to obtain informed consent from patient or family pregnant women

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Brain Ischemia
• Cerebral Infarction
• Hemorrhage
• Ischemia
• Subarachnoid Hemorrhage

Intervention

Other:
• Glycocalyx
Measure Degradation of the Glycocalyx

Locations

Country	Name	City	State
United States	University of Virginia Health System	Charlottesville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
University of Virginia

Country where clinical trial is conducted

United States, 

References & Publications (28)

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Bell JD, Rhind SG, Di Battista AP, Macdonald RL, Baker AJ. Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis. Neurocrit Care. 2017 Jun;26(3):339-347. doi: 10.1007/s12028-016-0357-4. — View Citation

Bogason ET, Anderson B, Brandmeir NJ, Church EW, Cooke J, Davies GM, Hussain N, Patel AS, Payne R, Rohatgi P, Sieg E, Zalatimo O, Ziu E. The epidemiology of admissions of nontraumatic subarachnoid hemorrhage in the United States. Neurosurgery. 2014 Feb;74(2):227-9. doi: 10.1227/NEU.0000000000000240. — View Citation

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Chaudhry K, Rogers R, Guo M, Lai Q, Goel G, Liebelt B, Ji X, Curry A, Carranza A, Jimenez DF, Ding Y. Matrix metalloproteinase-9 (MMP-9) expression and extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation in exercise-reduced neuronal apoptosis after stroke. Neurosci Lett. 2010 Apr 26;474(2):109-14. doi: 10.1016/j.neulet.2010.03.020. Epub 2010 Mar 16. — View Citation

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Dull RO, Cluff M, Kingston J, Hill D, Chen H, Hoehne S, Malleske DT, Kaur R. Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L816-28. doi: 10.1152/ajplung.00080.2011. Epub 2011 Dec 9. — View Citation

Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, Sato H. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem. 2003 Oct 17;278(42):40764-70. Epub 2003 Aug 6. — View Citation

Fischer M, Dietmann A, Beer R, Broessner G, Helbok R, Pfausler B, Schmutzhard E, Lackner P. Differential regulation of matrix-metalloproteinases and their tissue inhibitors in patients with aneurysmal subarachnoid hemorrhage. PLoS One. 2013;8(3):e59952. doi: 10.1371/journal.pone.0059952. Epub 2013 Mar 28. — View Citation

Ince C, Mayeux PR, Nguyen T, Gomez H, Kellum JA, Ospina-Tascón GA, Hernandez G, Murray P, De Backer D; ADQI XIV Workgroup. THE ENDOTHELIUM IN SEPSIS. Shock. 2016 Mar;45(3):259-70. doi: 10.1097/SHK.0000000000000473. Review. — View Citation

Lee H, Park JW, Kim SP, Lo EH, Lee SR. Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia. Neurobiol Dis. 2009 May;34(2):189-98. doi: 10.1016/j.nbd.2008.12.012. Epub 2009 Jan 6. — View Citation

Li C, Li X, Shen Q, Li Y, He L, Li M, Tang Y, Wang Y, He Q, Peng Y. Critical role of matrix metalloproteinase-9 in acute cold exposure-induced stroke in renovascular hypertensive rats. J Stroke Cerebrovasc Dis. 2013 Nov;22(8):e477-85. doi: 10.1016/j.jstrokecerebrovasdis.2013.05.016. Epub 2013 Jun 22. — View Citation

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Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011 Jul;10(7):618-25. doi: 10.1016/S1474-4422(11)70108-9. Epub 2011 Jun 2. — View Citation

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Triglia T, Mezzapesa A, Martin JC, Verdier M, Lagier D, Dufour H, Bruder N, Alessi MC, Velly LJ. Early matrix metalloproteinase-9 concentration in the first 48 h after aneurysmal subarachnoid haemorrhage predicts delayed cerebral ischaemia: An observational study. Eur J Anaesthesiol. 2016 Sep;33(9):662-9. doi: 10.1097/EJA.0000000000000494. — View Citation

Tromp J, van der Pol A, Klip IT, de Boer RA, Jaarsma T, van Gilst WH, Voors AA, van Veldhuisen DJ, van der Meer P. Fibrosis marker syndecan-1 and outcome in patients with heart failure with reduced and preserved ejection fraction. Circ Heart Fail. 2014 May;7(3):457-62. doi: 10.1161/CIRCHEARTFAILURE.113.000846. Epub 2014 Mar 19. — View Citation

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* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Syndecan-1 and heparin sulfate	Compare the degree of glycocalyx breakdown in patients with aSAH who develop delayed cerebral ischemia (DCI) to those that do not develop DCI. This will be completed by measuring the breakdown of Syndecan-1 and heparin sulfate in the blood.	day 0 through day 13
Secondary	serum Matrix metalloproteinase-1 and Matrix metalloproteinase-9	serum MMP-9 and MMP-1 will be levels will be measured as serum MMP concentrations have been positively correlated with the incidence of delayed cerebral ishemia	day 0 through day 13
Secondary	urinary microalbumin-to-creatinine ratio (MACR)	urinary microalbumin-to-creatinine ratio (MACR) will be measured as it is marker of systemic damage to the glycocalyx	day 0 through day13