Cerebral Autoregulation in Patients With Aneurysmal SubArachnoid Haemorrhage

Study Overview
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Brief Summary
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The purpose is, in patients with aneurysmal subarachnoid haemorrhage in the early phase after ictus, to examine the following: The effect of spontaneous and induced changes on the brain's static and dynamic autoregulation calculated by transcranial Doppler (TCD), ICP and MAP (primary purposes) and ICP and PbtO2; The effect of mild hyper- and hypocapnia as well as of mild hyper- and hypoxia on the brain's static and dynamic autoregulation, ICP and PbtO2; The relationship between brain autoregulation, mild hyper- and hypocapnia, as well as of mild hyper- and hypoxia and metabolism in microdialysate on the one hand and the occurrence of DCI during hospitalization and poor neurological outcome one year after ictus on the other.

Detailed Description
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Spontaneous aneurysm subarachnoid hemorrhage (SAH) occurs annually in approximately 400 people in Denmark. SAH is most commonly seen in younger (median age 56 years) and women (71%), have a high mortality (21-44%) and result in a poor neurological outcome in about 50% of patients. Due to the relatively young patient population and high mortality and morbidity, SAH in the population causes the same number of lost working years as blood clots in the brain. The occurrence of complications like hydrocephalus and re-bleeding can be minimized by rapid external ventricular drainage and aneurysm closure, and so-called delayed cerebral ischaemia (DCI) is currently considered to be the most frequent serious complication of SAH. DCI occurs in 20-30% of patients, most often within the first 14 days, is characterized by a reduction in consciousness or focal neurological deficit lasting at least one hour without any other underlying cause and is associated with a significantly increased risk of a poor outcome. The cause and treatment of DCI is controversial, and the previous hypothesis of vasospasm as the sole contributor is currently supplemented by a broader focus on several other mechanisms, including the brain's blood supply and its regulation. The brain's blood supply (CBF) is kept relatively constant in healthy by changing cardiac diameter and thus the cerebrovascular resistance (CVR) during changes in brain perfusion pressure (CPP, measured as mean arterial pressure (MAP) minus intracranial pressure (ICP)) within certain limits. This mechanism is known as cerebral autoregulation. Outside these limits, respectively. decreases and increases CBF, with the consequent risk of hypoperfusion/ischemia and hyperperfusion/vasogenic edema with prolonged changes. Weakened autoregulation, i.e. that CBF varies passively with CPP also within the normal autoregulation limits, is described in e.g. traumatic brain injury (TBI), ischemic stroke, acute liver failure and meningitis, with complete or partial restoration of autoregulation by hyperventilation (mild hypocapnia). SAH also describes impaired autoregulation with varying association with disease severity, DCI and outcome. It is not known whether mild hypocapnia restores autoregulation in patients with SAH, whereas animal experimental studies suggest this. Reduced intracerebral oxygenation (PbtO2) is associated with a worse outcome after SAH. Cerebral microdialysis measures the concentration of certain metabolites in the brain and can provide an insight into whether metabolic activity is affected by oxygen deficiency, and so-called anaerobic combustion occurs. Microdialysis measurements with elevated lactate concentration, which is a metabolic product, among other things. Anaerobic combustion appears to occur prior to clinical signs of DCI, as well as during the DCI episodes, decreasing PbtO2. It is possible that these findings could be due to a condition of impaired autoregulation and too low perfusion pressure to meet brain metabolic needs, but this has not previously been elucidated. It is also unknown if it is possible to improve brain metabolism by increasing the brain's perfusion pressure. The purpose of this study is therefore to investigate brain autoregulation in patients with SAH.

Official Title
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Cerebral Autoregulation in Patients With Aneurysmal SubArachnoid Haemorrhage

Conditions
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Subarachnoid Hemorrhage, Aneurysmal

Intervention / Treatment
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* Other: Hypertension
* Other: Hyper- and hypoxia
* Other: Hyper- and hypocapnia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria, patients: Admittance to neurointensive care unit, Rigshospitalet Age ≥ 18 years old Aneurysmal subarachnoid haemorrhage Clinical indication for placement of an external ventricular drain Measurements can be done within 3 days of ictus Closest relatives understand written and spoken danish Exclusion Criteria, patients: No aneurysm identified Conservative og failed treatment of aneurysm Pupils dilated and do not react to light Incarceration before inclusion Expected death within 48 hours Acute or chronic diseases associated with impaired autoregulation Severe chronic lung failure with a PaCO2 > 6.5 kPa or PaO2 < 8 kPa. Inclusion Criteria, healthy subjects: Age ≥ 18 years old; Understands written and spoken danish Oral and written consent No medication expect hay fever medications Alcohol consumption within the limits from the danish health care board Healthy without previous or current cerebrovascular diseases Insonation is possible from the middle cerebral artery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Sequential Assignment
Interventional Model Description: Intervention is performed once in both patients (after the aneurysm is closed and max. 5 days after ictus) and controls. The procedure consists of the following sessions: Induced hypertension; as well (Only in mechanically ventilated patients) either Mild hyper- and hypocapnia or Mild hyper- and hypoxia. In session 2 (hyper- / hypoxia or hyper- / hypocapnia), patients are randomized to order the interventions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: All patients<br>Patients included in the study. | Other: Hypertension<br>* Hypertension is induced by an infusion of noradrenaline within acceptable limits Baseline recording (10 minutes) is performed. MAP gradually increases in steps of 5-10 mmHg during ongoing TCD. When the desired maximum MAP is reached, measurement is made at steady state (10 minutes). Noradrenaline infusion is stopped. When MAP is stabilized, new baseline is measured for 10 minutes.<br>Other: Hyper- and hypoxia<br>* The mechanical ventilator is adjusted to mild hypoxia, normoxia and mild hyperoxia. Measurements are made for 10 minutes at normoxia and after steady state is reached, respectively. hyperoxia and hypoxia. Oxygenation is controlled by arterial blood gas before and during steady state.<br>Other: Hyper- and hypocapnia<br>* The mechanical ventilator is adjusted to a delta PaCO2 on the ventilator for both hypocapnia and hypercapnia. Measurements are made for 10 minutes at normocapnia and after steady state is reached, respectively. hyper- and hypocapnia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Middle cerebral artery flow velocity (MCAv) + induced hypertension | Measuring MCAv after induced hypertension | within 5 days after ictus, for 10 minutes after steady state | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial pressure (ICP) + induced hypertension | Measuring changes in ICP after induced hypertension | within 5 days after ictus | 
| Partial brain tissue oxygenation (PbtO2) + induced hypertension | Measuring changes in ICP after induced hypertension | within 5 days after ictus | 
| Intracranial pressure (ICP) + hyper- and hypocapnia | Measuring during induction of hyper- and hypocapnia | within 5 days after ictus, for 10 minutes after steady state | 
| Partial brain tissue oxygenation (PbtO2) + hyper- and hypocapnia | Measuring during induction of hyper- and hypocapnia | within 5 days after ictus, for 10 minutes after steady state | 
| Intracranial pressure (ICP) + hyper- and hypoxia | Measuring during induction of hyper- and hypoxia | within 5 days after ictus, for 10 minutes after steady state | 
| Partial brain tissue oxygenation (PbtO2) + hyper- and hypoxia | Measuring during induction of hyper- and hypoxia | within 5 days after ictus, for 10 minutes after steady state | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cerebral autoregulation