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

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Brief Title

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

Official Title

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

Brief Summary

      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

      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 Phase

Phase 1

Study Type

Interventional


Primary Outcome

Differences in oedematous changes in the brain and spinal cord

Secondary Outcome

 Primary blood brain barrier breakdown in hypoxic cytotoxic oedema

Condition

High Altitude Cerebral Edema

Intervention

Dexamethasone

Study Arms / Comparison Groups

 Dexamethasone
Description:  8ml IV 3.3mg/mL dexamethasone

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

January 14, 2019

Completion Date

March 4, 2020

Primary Completion Date

March 4, 2020

Eligibility Criteria

        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
      

Gender

All

Ages

20 Years - 50 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Christopher Imray, PhD MBBS, 024 7696 5222, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03341676

Organization ID

CI175716


Responsible Party

Sponsor

Study Sponsor

University Hospitals Coventry and Warwickshire NHS Trust


Study Sponsor

Christopher Imray, PhD MBBS, Principal Investigator, University Hospital Coventry and Warwickshire NHS Trust


Verification Date

September 2019