Studying Physiological and Anatomical Cerebral Effects of Carbon Dioxide and Tilt

Study Overview
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Brief Summary
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The purpose of this study is to study the effects of carbon dioxide combined with head down tilt on cerebral physiology and anatomy. This paradigm will help establish a ground-based analog for spaceflight, and also evaluate the ability of non-invasive devices to monitor brain physiology.

Detailed Description
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Many of the long duration astronauts develop visual changes, associated with neuroophthalmological abnormalities suggesting elevated intracranial pressure. There is currently no suitable ground based analog to simulate these changes on Earth, or a standard methodological approach to monitoring the combined effects of head down tilt and atmospheric carbon dioxide. Given that carbon dioxide and cephalad fluid shifting are known factors in spaceflight, we sought to evaluate an approach to monitoring these effects in healthy subject in a ground based analog on Earth.

Official Title
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Studying Physiological and Anatomical Cerebral Effects of Carbon Dioxide and Tilt

Conditions
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Healthy

Intervention / Treatment
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* Other: 0.5% CO2
* Other: ambient air


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Ages between 30 to 55 years old Body Mass Index (BMI) of 20-26 kg/m2 Weight between 65-85 kg Height between 158-190 cm Non-smoker, for at least six months before the start of the study VO2 max of at least 30ml/kg/min Exclusion Criteria: History of intracranial pressure elevation History of abnormal intraocular pressure Ophthalmological conditions: glaucoma, retinopathy, severe cataracts, eye trauma or implants. History of diseases of the optic nerve Pre-existing corneal injury History of these eye surgeries: implanted lens, corneal transplant, recent (less than 6 months) LASIK surgery Congenital abnormalities of the anterior chamber Active eye infections, recent corneal abrasions, inflammation Intraocular pressure greater than 20 mm Hg Viral or bacterial eye infection Severe dry eye syndrome Retinal or choroidal detachment More than -6,0 dpr (high myopia) More than +5,0 dpr Arm or shoulder injury in the past year Psychiatric conditions including major depression, bipolar disorder or severe anxiety History of cerebrovascular disease including brain aneurysms, stroke, transient ischemic attack, brain hemorrhage, arteriovenous malformations History of brain tumor, congenital cysts, hydrocephalus, brain injury (requiring hospitalization) Meningitis/encephalitis Epilepsy History of severe hypertension (> 160/90 mmHg), Diabetes mellitus Coronary artery disease Congestive heart failure Ventricular or atrial arrhythmias Autonomic disorders (syncope, autoimmune neuropathy) Hepatic disease Renal disease Chronic infections including HIV, Hepatitis B or C, Lyme disease History of hematological disease including hemophilia, leukemia, thrombocytosis, thrombocytopenia, myelodysplastic syndrome, autoimmune disease (lupus, rheumatoid arthritis, Sjogren's syndrome) History of malignancy except for basal cell carcinoma Chronic back pain (inability to lay in bed for long periods of time) Conditions that would preclude MRI including severe claustrophobia, pace maker or other metallic implants or devices Sleep disturbances including: obstructive sleep apnea, narcolepsy, insomnia - Medications that exert cardiovascular, cerebrovascular or psychiatric function (i.e. beta blockers, calcium channel blockers, diuretics, diamox, sedatives) Drug, medication or alcohol abuse (regular consumption of more than 20-30 g alcohol/day)* Smoking VO2 max less than 30 ml/kg/min or greater than 60 ml/kg/min Vegetarian, vegan Migraine Previous psychiatric illness Hiatus hernia Gastro-esophageal reflux Diabetes mellitus Rheumatic illness Muscle or joint disorder Pronounced orthostatic intolerance (< 10 min standing) Hyperlipidaemia Thyroid gland disorder: deviations from normal values for TSH in plasma Hyper-homocysteinaemia Hyperuricaemia or hypouricaemia: deviations from normal values for uric acid in plasma. Hypercalcaemia or hypocalcaemia: deviations from normal values for calcium in plasma. Iron deficiency Vitamin D deficiency Baseline blood gas values deviating from the normal reference values Elevated risk of venous thromboembolism including deep venous thrombosis, pulmonary embolism Chronic back complaints Participation in another clinical study within the last 3 months before start of this study Criminal record Stomach sleepers Any other medical condition that the investigators consider a contraindication to the study procedures that would make it unsafe or confound the measurements.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Atmosphere 1 - Ambient air<br>First, the subjects will have 1 baseline day in the upright body position. This will be followed by 28 hours of head down tilt body position and ambient air at sea level, followed by 2 hour exposure of 3% carbon dioxide inhalation. | Other: ambient air<br>* The subjects will be randomized to breath ambient air during one of the -12 degree head down tilt body position periods in crossover design<br>|
| Experimental: Atmosphere 2 - 0.5% CO2<br>First, the subjects will have 1 baseline day in the upright body position. This will be followed by 28 hours of head down tilt body position and air with 0.5% carbon dioxide, followed by 2 hour exposure of 3% carbon dioxide inhalation. | Other: 0.5% CO2<br>* The subjects will be randomized to breath 0.5% carbon dioxide during one of the -12 degree head down tilt body position periods in crossover design<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cerebral blood flow: Transcranial doppler | Transcranial Doppler derived measurements of mean cerebral blood flow velocity | 24 and 48 hours from baseline measurements | 
| Changes in intracranial volume | Cerebrotech monitor derived intracranial fluid volume changes (percentage change) | 24 and 48 hours from baseline measurements | 
| Changes in intracranial pressure | Vittamed ICP meter derived intracranial pressure (mmHg) | 24 and 48 hours from baseline measurements | 
| Changes in cognitive function | Cognition battery score (max 1000): tests multiple cognitive domains including spatial memory, psychomotor processing speed, facial emotional recognition | 24 and 48 hours from baseline measurements | 
| Changes in cerebral blood flow: cFLOW | cFLOW derived changes in cerebral blood flow index | 24 and 48 hours from baseline measurements | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of combined -12 head down tilt and 0.5% carbon dioxide | Assess safety outcomes: tolerance of condition through duration of study and number of adverse events | Within 48 hours from baseline | 
| Changes in intraocular pressure | iCare derived intraocular pressure measurements from both eyes (mmHg) | 24 and 48 hours from baseline measurements | 
| Changes in pulmonary mechanics | minute ventilation, respiratory rate and vital capacity | 24 and 48 hours from baseline measurements | 
| Changes in internal jugular vein volumes | Ultrasound derived measure of right internal jugular vein cross sectional areas | 48 hours from baseline measurements | 
| Changes in peripheral arterial vasoreactivity | Ultrasound Doppler Measurement of arterial diameter and flow (cm/sec) after transient cuff occlusion of brachial artery | 48 hours from baseline measurements | 
| Changes in cardiac hemodynamics | Assessment of cardiac output, stroke volume, heart rate, blood pressure | 48 hours from baseline measurements | 
| Changes in olfactory threshold | Sniffin' sticks threshold testing for phenyethyl alcohol | 24 and 48 hours from baseline measurement | 
| Changes in pulmonary gas exchange | changes in arterial pH and partial pressure CO2 | 24 and 48 hours from baseline measurements | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain physiology, Intracranial pressure, Cognition, Cerebrovascular, Head down tilt, Space flight