Anti-Oxidant Supplementation for the Prevention of Acute Mountain Sickness
Condition: Acute Mountain Sickness
MeSH terms: Altitude Sickness
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Anti-oxidant supplementation; Matched placebo for anti-oxidant supplementation
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 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.; Matched placebo for anti-oxidant supplementation
Intervention MeSH terms: Antioxidants
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention