Hypoxia Intolerance in Preterm Individuals

Study Overview
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Brief Summary
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Reduced Hypoxic Ventilatory Response (HVR) and systemic O2 saturation subsequently leading to blunted aerobic capacity as well as decreased overall physical and cognitive performance are the main physiological challenges faced by prematurely born individuals in hypobaric hypoxia (i.e. during high altitude sojourn). While these phenomena have been described previously, the underlying mechanisms are currently unresolved. Given that the reduction in altitude-performance and its underlying mechanisms are not well understood, it is currently impossible to give evidence-based recommendation for altitude sojourns in this cohort. It is also of note, that even hypobaric hypoxia exposure during long-haul flights might be detrimental to well-being of pre-term born individuals. The present project aims to comprehensively investigate physiological responses to altitude/hypoxia during rest and exercise in prematurely born, but otherwise healthy adults. Specifically, we aim to elucidate the underlying mechanisms of the altered resting and exercise cardiovascular, respiratory, cerebral and hematological responses to hypoxia in prematurely born individuals. The obtained results from this cohort will be compared to the data from a control groups consisting of healthy, age and aerobic capacity-matched individuals born at full-term. While acute hypoxic effects will be the focus of the project's first phase, we will test the effect of prolonged terrestrial (real) or simulated (normobaric hypoxia) altitude exposures in the second part. This phase will, in addition to the insight into the prolonged altitude acclimatization modulation in prematurely born individuals, also enable us to investigate the potential differences between the effects of normobaric (simulated) and hypobaric (terrestrial) hypoxia in this cohort.

Official Title
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Mechanisms of Hypoxia (in)Tolerance in Prematurely Born Individuals

Conditions
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Premature Birth, Hypoxia

Intervention / Treatment
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* Other: Normoxia
* Other: Normobaric hypoxia
* Other: Hypobaric hypoxia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: prematurely born (gestational age: ≤ 32 weeks; gestational weight ≤ 1500g) full-term born healthy individuals male Exclusion Criteria: presence of any medical risk factors to exercise and/or exposure to altitude presence of any medical condition that would make the protocol unreasonably hazardous for the patient smokers exposure to altitude above 1000m in the last 2 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Preterm born<br>Premature born but otherwise healthy adults exposed to normoxic, normobaric hypoxic and hypobaric hypoxic interventions. | Other: Normoxia<br>* 48 hours experimental protocol conducted at sea level<br>* Other names: Sea level;Other: Normobaric hypoxia<br>* 24 hours experimental protocol conducted in a normobaric hypoxic facility<br>* Other names: Simulated altitude;Other: Hypobaric hypoxia<br>* 72 hours experimental protocol conducted at terrestrial altitude<br>* Other names: Terrestrial altitude;|
| Full-term control<br>Full-term born healthy adults exposed to normoxic, normobaric hypoxic and hypobaric hypoxic interventions. | Other: Normoxia<br>* 48 hours experimental protocol conducted at sea level<br>* Other names: Sea level;Other: Normobaric hypoxia<br>* 24 hours experimental protocol conducted in a normobaric hypoxic facility<br>* Other names: Simulated altitude;Other: Hypobaric hypoxia<br>* 72 hours experimental protocol conducted at terrestrial altitude<br>* Other names: Terrestrial altitude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebrovascular reactivity to carbon dioxide (CO2) | Subjects will breath 4 min 3% CO2 and 4 min 6% CO2 separated by 4 min of breathing ambient air. Gas exchange, blood flow in the middle cerebral artery and peripheral oxygen saturation will be continuously recorded by metabolic cart, transcranial doppler, and finger pulse oximeter, respectively. | 48 hours after exposure to normoxia and hypobaric hypoxia, respectively. | 
| Cognitive function | Cognitive function will be assessed by a computerized psychometric test battery previously used by our research group. These will assess working memory and visuo-motor coordination. | 24 hours after exposure to normoxia, hypobaric hypoxia, and normobaric hypoxia, respectively | 
| Acute Mountain Sickness (AMS) | AMS will be assessed by Lake Louise scale. AMS will be diagnosed if the Lake Louise score is 3 or higher. | 8 hours (prior to sleep) and 16 hours (upon waking) after exposure to hypobaric and normobaric hypoxia | 
| Change in respiratory function | Respiratory function will be assessed by spirometry. | Immediately after exposure to hypobaric and normobaric hypoxia, relative to baseline. | 
| Lung comets | Lung comets will be assessed by counting the number of B-lines present, which will be measured using Doppler ultrasound. | Every day before and immediately after each exercise bout. | 
| Heart rate response to exercise | Heart rate (HR, bpm) will be continuously monitored during different exercise bouts of variety intensities (moderate and heavy intensities will be used). | Every day during each exercise bout. | 
| Respiratory response to exercise | Oxygen consumption (VO2, L/min and mL/min/kg) will be continuously monitored during different exercise bouts of variety intensities (moderate and heavy intensities will be used). | Every day during each exercise bout. | 
| Changes in muscular oxygenation during exercise | Muscle oxygenation/deoxygenation will be continuously recorded during each exercise bout by Near Infra-Red Spectroscopy (NIRS) placed on the vastus lateralis. NIRS measure the quantity of oxygenated and deoxygenated haemoglobin and myoglobin (microM) in the investigated areas (vastus lateralis). | Every day during each exercise bout. | 
| Changes in cerebral oxygenation during exercise | Brain oxygenation/deoxygenation will be continuously recorded during each exercise bout by Near Infra-Red Spectroscopy (NIRS) placed at the frontal levels. NIRS measure the quantity of oxygenated and deoxygenated haemoglobin (microM) in the investigated areas (prefrontal cortex). | Every day during each exercise bout. | 
| Changes in the rate of muscular oxygen consumption (mV̇O2) | Muscle oxygen consumption will be assessed using a previously validated protocol. Briefly, a Near Infra-Red Spectroscopy (NIRS) optode will be placed on the vastus lateralis muscle. Before the protocol, an ischemic calibration will be performed to normalize the NIRS signals by inflating the blood pressure cuff to 250-300 mmHg for a maximum of 5 min. Resting mV̇O2 will be assessed from the decrease in muscle oxygenation which accompanies the arterial occlusion. Four resting measurements will be performed using 10 sec of arterial occlusion. Then, each subject will perform a voluntary knee extension exercise for 15 sec. To measure the recovery of oxygen consumption after exercise, subject will have a series of arterial occlusion as follows: 5 occlusions 5sec on-5sec off, 5 occlusions 5sec on-5sec off, and 8 occlusions 10 sec on-20 sec off. | Before each exercise bouts. | 
| Acute change in sleep quality | Polysomnography will be used to assess sleep quality. Measurements will include electroencephalography (EEG), electrooculography (EOG), chin and tibial surface electromyography (EMG), electrocardiography (ECG), nasal pressure (nasal pressure cannula), respiratory movements (chest and abdominal belts) as well as capillary oxygenated haemoglobin saturation measurement. | On the first night in normoxia, normobaric hypoxia and hypobaric hypoxia. | 
| Change in sleep quality after prolonged exposure to hypobaric hypoxia | Polysomnography will be used to assess sleep quality. Measurements will include electroencephalography (EEG), electrooculography (EOG), chin and tibial surface electromyography (EMG), electrocardiography (ECG), nasal pressure (nasal pressure cannula), respiratory movements (chest and abdominal belts) as well as capillary oxygenated haemoglobin saturation measurement. | On the third night after exposure to terrestrial altitude. | 
| Changes in endothelial capacity to flow-mediated dilation (FMD) | A pneumatic cuff is positioned distal to the ultrasound probe in order to avoid ischemia of the artery studied. Radial artery diameter is measured at rest, during inflation of the distal cuff to suprasystolic pressure (5 min) and for the 5 min following deflation. The subsequent decrease in local blood flow in response to ischemia causes a progressive decrease in the radial artery diameter until a plateau (L-FMC). Upon cuff deflation, the increased blood flow causes radial artery dilatation. L-FMC is calculated as the percentage decrease in arterial diameter in the last 30 s of cuff occlusion as compared with resting diameter. FMD is calculated as the maximum percentage increase in arterial diameter following cuff deflation. | 24 hours after exposure to normoxia and hypobaric hypoxia. | 
| Changes in orthostatic tolerance | Orthostatic tolerance will be assessed by measuring heart rate variability. This will involve an app-validated 10-min protocol, which will use a chest-band to monitor heart rate changes from 5 minutes of supine position followed by 5 minutes of standing. | At 6am on every trial day (upon waking). | 
| Changes in oxidative stress markers in the blood | Oxidative stress markers concentration will be measured on collected venous blood sample. | Blood samples will be collected at 6am (upon waking). | 
| Change in salivary cortisol concentration | Cortisol concentration will be measured on collected saliva samples. | Saliva samples will be collected at 6am (upon waking). | 
| Change in hydration status | Urine samples will be assessed using urine specific gravity. | Urine samples will be collected at 6am (upon waking). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebral blood flow in the internal carotid artery | Cerebral blood flow in the internal will be assessed every morning by doppler ultrasound. | Cerebral blood flow will be measured at 10am. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acclimatization, Altitude, Preterm birth, Cardiorespiratory, Cerebrovascular, Exercise