Cerebral Nitrosative/Oxidative Stress in Aneurysmal Subarachnoid Haemorrhage

NCT05686265 | Terminated

• 1 other identifier: H-22073181
• Study Type: observational
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Aneurysmal subarachnoid haemorrhage (SAH) carries a high morbidity and mortality, which is in part due to the development of secondary brain injury. The mechanisms behind this remain incompletely understood, but oxidative/nitrosative stress and disturbances in vasoregulatory mechanisms are believed to be involved. The present study aims to characterise the transcerebral exchange of oxidative/nitrosative stress markers and nitric oxide metabolites during the early phase after SAH compared to healthy volunteers, including the influence of induced changes in arteriel oxygen tension.

Conditions

Subarachnoid Hemorrhage, Aneurysmal

Keywords

Oxidative Stress; Nitrosative Stress; Nitric Oxide; Acute Brain Injury; Subarachnoid Hemorrhage; Secondary Brain Injury; Neuromonitoring

Outcome Measures

Primary Outcomes (3)

• Transcerebral exchange of bioactive NO, patients vs. controls

  Transcerebral exchange of bioactive NO (plasma nitrite + S-nitrosothiols) (nM) in patients vs. controls.

  At baseline

• Transcerebral exchange of oxidative stress markers, patients vs. controls

  Transcerebral exchange of the ascorbate radical (μM) in patients vs. healthy controls.

  At baseline

• Transcerebral exchange of nitrosative stress markers, patients vs. controls

  Transcerebral exchange of 3-nitrotyrosine (nM) in patients vs. healthy controls.

  At baseline

Secondary Outcomes (2)

• Transcerebral exchange of nitrosative/oxidative stress markers, effects of hypo-/hyperoxia

  Within one week

• Transcerebral exchange of nitrosative/oxidative stress markers, changes over time

  Within one week

Other Outcomes (6)

• Nitrosative/oxidative stress, relationship to disease severity

  At baseline

• Nitrosative/oxidative stress, relationship to brain oxygenation

  Within one week

• Nitrosative/oxidative stress, relationship to brain metabolism

  Within one week

Study Arms (2)

Patients

Patients with SAH (see eligibility criteria below).

Drug: Oxygen

Controls

Healthy controls (see eligibility criteria below).

Drug: Oxygen

Interventions

Oxygen DRUG

Physiological intervention consisting of 1 hour of mild hypoxia (PaO2 9-10 kPa), 1 hour of mild hyperoxia (PaO2 13-14 kPa), and in healthy subjects also 1 hour of an inspired oxygen fraction of 100%.

Also known as: Hypoxia and hyperoxia

Controls; Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Twenty patients with severe SAH and twelve pseudo-matched healthy controls.

You may qualify if:

• Age ≥ 18 years
• Admission to the NICU at Rigshospitalet
• Diagnosis of aneurysmal SAH
• Need for sedation and mechanical ventilation after the aneurysm has been secured
• Initiation of study possible ≤3 days after the ictus
• Closest relatives understand written and spoken Danish or English

You may not qualify if:

• Expected death within 24 hours
• Failed or conservative treatment of the aneurysm
• Severe acute lung failure with a PaO2/FiO2-ratio ≤16 kPa
• Severe chronic lung failure with habitual long-term oxygen therapy
• Habitual treatment with medication directly affecting NO metabolism (e.g., sildenafil)
• Age 40-60 years
• /50 sex distribution (6 men and 6 women)
• Healthy (including no prior cerebrovascular disease)
• No regular medication or recreational drug use
• Understands written and spoken Danish or English

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of South Wales: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, DK-2100, Denmark

Location

Related Publications (18)

• Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006 Jan 26;354(4):387-96. doi: 10.1056/NEJMra052732. No abstract available.

  PMID: 16436770 BACKGROUND

• van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007 Jan 27;369(9558):306-18. doi: 10.1016/S0140-6736(07)60153-6.

  PMID: 17258671 BACKGROUND

• Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014 Jan;10(1):44-58. doi: 10.1038/nrneurol.2013.246. Epub 2013 Dec 10.

  PMID: 24323051 BACKGROUND

• Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010 Oct;41(10):2391-5. doi: 10.1161/STROKEAHA.110.589275. Epub 2010 Aug 26.

  PMID: 20798370 BACKGROUND

• Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, Menon DK, Pickard JD, Kirkpatrick PJ. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1343-53. doi: 10.1136/jnnp-2014-307711. Epub 2014 May 20.

  PMID: 24847164 BACKGROUND

• Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007 Jan;87(1):315-424. doi: 10.1152/physrev.00029.2006.

  PMID: 17237348 BACKGROUND

• Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT. The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol. 2015 Jan;263:235-43. doi: 10.1016/j.expneurol.2014.10.017. Epub 2014 Oct 29.

  PMID: 25447937 BACKGROUND

• Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther. 2005 Jan;105(1):23-56. doi: 10.1016/j.pharmthera.2004.10.002.

  PMID: 15626454 BACKGROUND

• Pluta RM. Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl. 2008;104:139-47. doi: 10.1007/978-3-211-75718-5_28.

  PMID: 18456999 BACKGROUND

• Sehba FA, Schwartz AY, Chereshnev I, Bederson JB. Acute decrease in cerebral nitric oxide levels after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2000 Mar;20(3):604-11. doi: 10.1097/00004647-200003000-00018.

  PMID: 10724124 BACKGROUND

• Sobey CG, Faraci FM. Subarachnoid haemorrhage: what happens to the cerebral arteries? Clin Exp Pharmacol Physiol. 1998 Nov;25(11):867-76. doi: 10.1111/j.1440-1681.1998.tb02337.x.

  PMID: 9807657 BACKGROUND

• Sehba FA, Bederson JB. Nitric oxide in early brain injury after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110(Pt 1):99-103. doi: 10.1007/978-3-7091-0353-1_18.

  PMID: 21116923 BACKGROUND

• Sehba FA, Chereshnev I, Maayani S, Friedrich V Jr, Bederson JB. Nitric oxide synthase in acute alteration of nitric oxide levels after subarachnoid hemorrhage. Neurosurgery. 2004 Sep;55(3):671-7; discussion 677-8. doi: 10.1227/01.neu.0000134557.82423.b2.

  PMID: 15335435 BACKGROUND

• Hino A, Tokuyama Y, Weir B, Takeda J, Yano H, Bell GI, Macdonald RL. Changes in endothelial nitric oxide synthase mRNA during vasospasm after subarachnoid hemorrhage in monkeys. Neurosurgery. 1996 Sep;39(3):562-7; discussion 567-8. doi: 10.1097/00006123-199609000-00026.

  PMID: 8875487 BACKGROUND

• Jung CS, Oldfield EH, Harvey-White J, Espey MG, Zimmermann M, Seifert V, Pluta RM. Association of an endogenous inhibitor of nitric oxide synthase with cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2007 Nov;107(5):945-50. doi: 10.3171/JNS-07/11/0945.

  PMID: 17977265 BACKGROUND

• Iqbal S, Hayman EG, Hong C, Stokum JA, Kurland DB, Gerzanich V, Simard JM. Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain Circ. 2016;2(1):8-19. doi: 10.4103/2394-8108.178541.

  PMID: 27774520 BACKGROUND

• Macmillan CS, Andrews PJ. Cerebrovenous oxygen saturation monitoring: practical considerations and clinical relevance. Intensive Care Med. 2000 Aug;26(8):1028-36. doi: 10.1007/s001340051315.

  PMID: 11030158 BACKGROUND

• Bailey DM, Taudorf S, Berg RM, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol. 2009 Nov;297(5):R1283-92. doi: 10.1152/ajpregu.00366.2009. Epub 2009 Sep 2.

  PMID: 19726713 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood (whole blood, serum, plasma, and red blood cells), cerebrospinal fluid, and cerebral microdialysate.

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Brain Injuries

Interventions

Oxygen

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Chalcogens; Elements; Inorganic Chemicals; Gases

Study Officials

• Anton Lund, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 9, 2023
• First Posted: January 17, 2023
• Study Start: May 11, 2023
• Primary Completion: March 15, 2024
• Study Completion: March 15, 2024
• Last Updated: March 19, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The approved study protocol will be available upon request until publication of the study results.
• Access Criteria: Valid reason and contact with author.

Locations

DK (1)