Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE)

Study Overview
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Brief Summary
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When the brain detects a drop in oxygen levels in the blood (hypoxia) there is a compensatory increase in blood flow. Acute mountain sickness (AMS) is a cluster of symptoms which commonly occur in those ascending to high altitude and experiencing hypoxia due to increased blood flow and then swelling in the brain. Symptoms include headache, nausea, insomnia and fatigue. The exact mechanisms by which AMS develops remains poorly understood. Dexamethasone has been shown to reduce the risk of developing significant brain swelling in other settings. Therefore we hypothesise that administering low dose Dexamethasone could protect against hypoxia induced cerebral and spinal oedema.

Detailed Description
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The exact mechanisms by which AMS develops remains poorly understood. Interestingly, brain and spinal cord swelling due to low oxygen levels can also occur in the period following surgery to treat thoracic and abdominal aortic aneurysms, dangerous swellings of the major blood vessel in the body. Therefore, if we find a therapeutic benefit of receiving a dose of Dexamethasone in a controlled, reversible setting of hypoxia, it is possible that this could be useful in the treatment of post-operative hypoxia as well. Work with MRI imaging has demonstrated reduced measures of water movement in patients suffering from cerebral or spinal ischaemia, due to swelling. Specific water channels in brain cells (astrocytes) are involved in the movement of water, and Dexamethasone has been shown to reduce expression of these channels in animal models. Dexamethasone already plays a role in lowering pressure in the brain in the setting of brain tumours. Although high doses are typically used in this setting, there is evidence that lower doses may be equally effective, especially in patients with less severe swelling. Subjects will be consented and randomised in the weeks before the actual study. Before entering the tent, the following data will be collected: Lake Louise Acute Mountain Sickness self-assessment questionnaire Pulse oximetry Non-invasive cardiac monitoring (ECG) End tidal CO2 Venous blood collection (Full blood count, renal function, S100 and GFAP) Finger-prick blood collection (Purines) Magnetic Resonance Angiography Non-invasive monitoring will continue every 2 hours at the start of the study and around the time of administration of the study drug. They will continue at less frequent intervals throughout the study period. This includes ECG trace and an AMS self-assessment questionnaire. Venous sampling will be performed on 5 occasions throughout the study. Finger prick sampling will be done at the same time points Each subject will have 5 MRI scans during the course of the study. Subjects will be begin hypoxication 1 hour after entering the tent. They will be returned to normal oxygen levels after 24 hours.

Official Title
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Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE)

Conditions
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High Altitude Cerebral Edema

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent Healthy men and women aged 20-50 years Ability to fully understand the requirements of the protocol Negative pregnancy BMI <30 kg/m2 Exclusion Criteria: Recent experience of high altitude: Any subject who has visited high altitudes (defined as 8,000 - 12,000 feet above sea level) within 4 weeks of starting the study. Abnormal blood pressure: AHA guidelines state blood pressures ≥140/90 mmHg require medical management. Patients with a blood pressure above these parameters will be excluded. Any evidence of systemic infection e.g. respiratory tract infection. Any evidence of renal disease (i.e. eGFR <60, as this precludes intravenous contrast required for MRI scan) History of Tuberculosis History of heart disease Conditions including but not limited to: Glaucoma (including family history), ocular herpes simplex (risk of corneal perforation), severe affective disorders (particularly if history of steroid-induced psychosis), epilepsy, peptic ulcer, hypothyroidism, history of steroid myopathy, ulcerative colitis, diverticulitis, recent intestinal anastomoses, thromboembolic disorders or myasthenia gravis. Breastfeeding Current smoker Contraindications for MRI Known sensitivity to the study drug and / or it's excipients: History of hypersensitivity to steroids (any preparation). Taking pharmaceutical preparations or over the counter medications known to interact with intravenous Dexamethasone. Current participation in other interventional research

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomised controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone<br>8ml IV 3.3mg/mL dexamethasone | Drug: Dexamethasone<br>* Dexamethasone 3.3 mg/mL solution for injection<br>|
| Placebo Comparator: Placebo<br>8ml IV 0.9% w/v saline | Drug: Placebo<br>* Sodium Chloride 0.9% w/v solution for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in oedematous changes in the brain and spinal cord | Differences in oedematous changes in the brain and spinal cord as measured by changes in brain and spinal cord MRI imaging | 0 hour and 8, 11, 22 and 26 hours post hypoxic insult | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary blood brain barrier breakdown in hypoxic cytotoxic oedema | To assess the role of primary blood brain barrier breakdown in hypoxic cytotoxic oedema as measured by variation in serum markers | 0 hour and 8, 11, 22 and 26 hours post hypoxic insult | 
| Assessing the usefulness of biomarkers of hypoxic cerebral changes. | Change in glial specific (GFAP) and non-glial specific (purines) serum biomarkers from baseline and at 8, 11, 22 and 26 hours post hypoxic insult | 0 hour and 8, 11, 22 and 26 hours post hypoxic insult | 
| Spinal cord model | To develop a hypoxic spinal cord model for use in future research looking into complex vascular surgery. | 0 hour and 8, 11, 22 and 26 hours post hypoxic insult |