Anti-Oxidant Supplementation for the Prevention of Acute Mountain Sickness

Study Overview
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Brief Summary
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Acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) are complications of rapid ascent to high altitude. Several features suggest that raised intracranial pressure (ICP) may be an important factor in the pathogenesis of AMS. Magnetic resonance imaging of HACE patients has demonstrated that the oedema in HACE is of the vasogenic, rather that cytotoxic, type. Thus it is likely that cerebrovascular permeability has an important role in the development of AMS and HACE. Reactive oxygen species (ROS) have been shown to alter the permeability of the blood-brain barrier in severe ischaemia, causing vasogenic cerebral oedema. Endogenous antioxidant systems may have some capacity to respond to oxidative stress in hypoxia. The plasma concentration of urate, a powerful endogenous antioxidant, rises on acute exposure to high altitude and may play a crucial antioxidant role in systemic hypoxia. This antioxidant prevents free-radical induced cerebral oedema in animal models. There are numerous sources of ROS in hypoxia, including the mitochondrial electron transfer chain, haemoglobin (Hb) autoxidation and xanthine oxidase activity. There have been several reports of raised markers of oxidative stress in humans at moderate altitude (<3000m). Oral antioxidant supplementation with preparations containing vitamins C and E in humans at altitude has been shown to decrease breath pentanes (a marker of oxidative stress), and improve erythrocyte filterability. In a small randomised controlled trial, Bailey and Davies demonstrated a significant reduction in symptoms of AMS in subjects taking an oral antioxidant cocktail. The antioxidants alpha-lipoic acid, vitamin C and vitamin E act synergistically to provide membrane protection from free radical damage, and may protect against hypoxia-induced vascular leakage. We hypothesised that this combination of antioxidants would reduce the severity of acute mountain sickness, and reduce pulmonary artery pressures, in healthy lowlanders acutely exposed to high altitude.

Detailed Description
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Acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) are complications of rapid ascent to high altitude. By definition, AMS is a benign condition, but it is likely that the same pathology underlies high altitude cerebral oedema (HACE). In contrast, HAPE occurs in the context of pathologically elevated pulmonary artery pressures and uneven distribution of hypoxic pulmonary vasoconstriction across the pulmonary vascular bed. Several features suggest that raised intracranial pressure (ICP) may be an important factor in the pathogenesis of AMS. Magnetic resonance imaging of HACE patients has demonstrated that the oedema in HACE is of the vasogenic, rather that cytotoxic, type. Thus it is likely that cerebrovascular permeability has an important role in the development of AMS and HACE. Reactive oxygen species (ROS) have been shown to alter the permeability of the blood-brain barrier in severe ischaemia, causing vasogenic cerebral oedema. Endogenous antioxidant systems may have some capacity to respond to oxidative stress in hypoxia. The plasma concentration of urate, a powerful endogenous antioxidant, rises on acute exposure to high altitude and may play a crucial antioxidant role in systemic hypoxia. This antioxidant prevents free-radical induced cerebral oedema in animal models. The pathogenesis of HAPE is understood to have two components: (i) increased pulmonary arterial pressures secondary to hypoxic pulmonary vasoconstriction and; (ii) an increase in endothelial permeability, possibly due to stress rupture of pulmonary capillaries. There is much debate surrounding the cellular mechanisms of hypoxic pulmonary vasoconstriction, but it is likely that ROS have an important role. There are numerous sources of ROS in hypoxia, including the mitochondrial electron transfer chain, haemoglobin (Hb) autoxidation and xanthine oxidase activity. There have been several reports of raised markers of oxidative stress in humans at moderate altitude (<3000m). Oral antioxidant supplementation with preparations containing vitamins C and E in humans at altitude has been shown to decrease breath pentanes (a marker of oxidative stress), and improve erythrocyte filterability. In a small randomised controlled trial, Bailey and Davies demonstrated a significant reduction in symptoms of AMS in subjects taking an oral antioxidant cocktail. The antioxidants alpha-lipoic acid, vitamin C and vitamin E act synergistically to provide membrane protection from free radical damage, and may protect against hypoxia-induced vascular leakage. We hypothesised that this combination of antioxidants would reduce the severity of acute mountain sickness, and reduce pulmonary artery pressures, in healthy lowlanders acutely exposed to high altitude.

Official Title
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Randomized Double-Blind Placebo-Controlled Trial of Oral Anti-Oxidant Supplementation for the Prevention of Acute Mountain Sickness.

Conditions
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Acute Mountain Sickness

Intervention / Treatment
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* Dietary Supplement: Anti-oxidant supplementation
* Dietary Supplement: Matched placebo for anti-oxidant supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants in Apex 2 trial Exclusion Criteria: High altitude pulmonary oedema (HAPE) Gasto-intestinal illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Placebo tablet | Dietary Supplement: Matched placebo for anti-oxidant supplementation<br>* Matched placebo for anti-oxidant supplementation<br>|
| Active Comparator: Intervention<br>Anti-oxidant supplementation | Dietary Supplement: Anti-oxidant supplementation<br>* Daily dose of 1g L-ascorbic acid, 400 IU of alpha-tocopherol acetate, and 600mg of alpha-lipoic acid in sealed capsules as anti-oxidant supplementation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Mountain Sickness (AMS) as assessed by Lake Louise Consensus symptom score |  | Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary artery systolic pressure |  | Day 6 |