An observational study in Subarachnoid Hemorrhage, Aneurysmal, Intracerebral Hemorrhage and Traumatic Brain Injury, sponsored by Rigshospitalet, Denmark. Completed at 1 site in Denmark. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-12.
Sponsored by Rigshospitalet, Denmark · Observational
Acute brain injury due to traumatic brain injury (TBI), intracerebral haemorrhage (ICH), and aneurysmal subarachnoid haemorrhage (SAH) carries a high morbidity and mortality, in part due to the development of secondary brain injury. The mechanisms behind secondary brain injury are incompletely understood, but oxidative/nitrosative stress and disturbances in the metabolism of the vasodilator nitric oxide (NO) are believed to be involved. The aim of the present study is to characterise systemic changes in markers of oxidative/nitrosative stress and NO metabolism in the early phase after acute brain injury, and to examine their relationship to clinical course, neurological outcome, and mortality.
BACKGROUND:
Acute brain injury due to traumatic brain injury (TBI), intracerebral haemorrhage (ICH), and aneurysmal subarachnoid haemorrhage (SAH) is a major cause of mortality and permanent disability worldwide. Irrespective of its aetiology, acute brain injury is associated with a widespread activation of cellular and biochemical processes which can aggravate the damage after the primary injury - this is termed secondary brain injury.
Nitric oxide (NO) is a potent endogenous vasodilator produced from arginine by the enzyme nitric oxide synthase (NOS), which exists in three isoforms: endothelial, neuronal, and inducible NOS (eNOS, nNOS and iNOS). In conditions of inflammation and oxidative stress (e.g. in acute brain injury), free radicals may react with NO to form peroxynitrite (ONOO-), which is highly reactive and can directly damage biological macromolecules such as lipids and proteins. This phenomenon, i.e. an increased production of reactive nitrogen species potentially leading to cellular damage, is termed nitrosative stress.
It is widely believed that oxidative/nitrosative stress and associated disturbances in the metabolism of NO are involved in the development of secondary brain injury, but the exact role of these mechanisms remains incompletely understood. While some authors believe that NOS dysfunction and a resultant low NO bioavailability is an important cause of secondary brain injury, others argue that an overproduction of NO mediated by iNOS is maladaptive response leading to aggravated tissue injury due to nitrosative stress.
The investigators hypothesise that acute brain injury is associated with an immediate elevation in circulating biomarkers of oxidative stress and a reduction in the bioavailability of NO due to formation of peroxynitrite (nitrosative stress), and that this represents an important mechanism behind the development of secondary brain injury. This decrease in NO availability could contribute to a vicious cycle in which a resulting increase in microvascular resistance, cerebral hypoperfusion, and brain tissue hypoxia further increases free radical production. However, it is further hypothesised that the initial decrease in NO availability is followed by an iNOS-mediated increase in NO metabolites in the subsequent days after injury. The present explorative study will attempt to characterise these changes and their role in patients with acute brain injury.
HYPOTHESES:
METHODS:
The study is a single-center, prospective, explorative, observational study, which will include 50 patients with SAH, 50 patients with ICH, and 50 patients with TBI admitted to the Neurointensive Care Unit (NICU) at Rigshospitalet, Copenhagen. Patient inclusion will continue until the planned number of patients have been enrolled, or until the 1st of May 2023, at which point inclusion will be halted and data will be analysed irrespective of the number of included patients.
Arterial blood samples will be collected at 3 time points: day 0-2 (early), day 3-5 (intermediate) and day 6-8 (late) after admission. If no arterial catheter is available, central venous or peripheral venous samples may be drawn as an alternative. Blood samples will only be collected during admission to the NICU and/or intermediate care unit, and sample collection will be halted in case of discharge to another department.
Demographical, clinical and paraclinical data will be obtained from each patients' electronic medical records. Data from multimodal neuromonitoring (i.e., intracranial pressure, brain tissue oxygenation, cerebral microdialysis, and/or electrocorticography) will be collected continuously along with physiological parameters when available. Neurological outcome (as determined by the modified Rankin Scale) will be determined at 6 months in connection with an outpatient follow-up visit at the hospital or through telephone interviews.
BIOCHEMICAL ANALYSES:
Blood samples will be analysed for the following markers of oxidative stress: the ascorbate radical, lipid hydroperoxides, myeloperoxidase, and the antioxidants glutathione, α/γ-tocopherol, α/β-carotene, retinol and lycopene.
The following NO metabolites will be determined: total plasma NO concentration (nitrate (NO3-) + nitrite (NO2-) + S-nitrosothiols (RSNO)) and total red blood cell bound NO (nitrite (NO2-) + nitrosyl haemoglobin (HbNO) + S-nitrosohaemoglobin (HbSNO)). In addition, 3-nitrotyrosine will be determined as a surrogate marker for peroxynitrite.
The following biomarkers of neurovascular unit injury will be determined: S100ß, glial fibrillary acidic protein, neuron-specific enolase, ubiquitin carboxy-terminal hydrolase L1, neurofilament light-chain and total tau.
509 studies on the registry are indexed under Subarachnoid Hemorrhage; 124 are open to participants now.
This study's enrollment of 150 is above the median of 117 across 226 observational studies indexed under Subarachnoid Hemorrhage.
Browse Subarachnoid Hemorrhage studies →Rigshospitalet, Denmark is the lead sponsor of 1,017 studies on the registry; 183 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Patients with acute brain injury (SAH, ICH or TBI) admitted to the NICU at Rigshospitalet - see detailed inclusion and exclusion criteria above.
Exclusion Criteria:
Patients with SAH (see eligibility criteria below). Planned enrollment: 50 patients.
Other: None (observational)
Patients with ICH (see eligibility criteria below). Planned enrollment: 50 patients.
Other: None (observational)
Patients with TBI (see eligibility criteria below). Planned enrollment: 50 patients.
Other: None (observational)
None (observational)
Neurological outcome (modified Rankin scale)
Neurological outcome as assessed using the modified Rankin Scale, which measures the degree of disability on a scale from 0 to 6 (higher score indicates a worse outcome)
Time frame: 6 months
Mortality
Mortality at 6 months
Time frame: 6 months
Neuroworsening
Neuroworsening as defined by Morris et al. \[1\]
Time frame: Within 14 days
Delayed Cerebral Ischaemia (DCI)
DCI as defined by Vergouwen et al. \[2\] (in patients with SAH)
Time frame: Within 14 days
Levels of brain injury biomarkers
Concentrations of the brain injury biomarkers S100ß (μg/L), glial fibrillary acidic protein (pg/mL), neuron-specific enolase (μg/L), ubiquitin carboxy-terminal hydrolase L1 (pg/mL), neurofilament light-chain (pg/mL) and total tau (pg/mL).
Time frame: Within 14 days
Angiographic vasospasm
Angiographic vasospasm (in patients with SAH)
Time frame: Within 14 days
Length of stay
Length of stay in the intensive care unit (ICU) and in hospital
Time frame: During hospitalisation
Systemic organ dysfunction
Systemic organ dysfunction as assessed by the Sequential Organ Failure Assessment (SOFA)-score during stay in the ICU
Time frame: During ICU stay
Brain tissue hypoxia
Brain tissue hypoxia (defined as a brain tissue oxygen tension of \<20 mmHg) as assessed by invasive brain tissue oxygen monitoring (Integra Licox®) in patients undergoing multimodal neuromonitoring
Time frame: During ICU stay
Brain metabolic crisis
Brain metabolic crisis (defined as a lactate/pyruvate ratio \>40 with a brain glucose concentration ≤0.7 mmol/L) as assessed by cerebral microdialysis in patients undergoing multimodal neuromonitoring
Time frame: During ICU stay
Cortical spreading depolarisations
The frequency (occurrence) of cortical spreading depolarisations as assessed by electrocorticography in patients undergoing multimodal neuromonitoring.
Time frame: During ICU stay
Plan to share: Yes — Data from each individual participant will be available after publication of planned manuscripts, with a valid reason, and after signing a data processing agreement.
Supporting information: Study protocol
This study is completed, as verified in Jul 2025. You cannot join it, but the record below documents what was studied.
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Rigshospitalet, Denmark