Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE) (D4H)

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.

Study Overview

• Status: Completed
• Conditions: High Altitude Cerebral Edema
• Intervention / Treatment: Drug: Dexamethasone; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Coventry, West Midlands, United Kingdom, CV2 2DX
      • University Hospitals Coventry and Warwickshire NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 46 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospitals Coventry and Warwickshire NHS Trust
• Investigators: Principal Investigator: Christopher Imray, PhD MBBS, University Hospital Coventry and Warwickshire NHS Trust

Publications and helpful links

General Publications

• Fisher O, Benson RA, Wayte S, Kimani PK, Hutchinson C, Imray CHE. Multimodal analysis of the effects of dexamethasone on high-altitude cerebral oedema: protocol for a pilot study. Trials. 2019 Oct 24;20(1):604. doi: 10.1186/s13063-019-3681-0.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2019
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (Actual): November 14, 2017

Study Record Updates

• Last Update Posted (Actual): June 18, 2024
• Last Update Submitted That Met QC Criteria: June 17, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Altitude Sickness; Edema; Brain Edema; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: CI175716

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared with other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No