The Metabolic Stress of Terrestrial High Altitude
Dr Damian Miles Bailey PhD, c/o Hypoxia Research Unit, Health and Exercise Sciences Research Laboratory, University of Glamorgan, S.Wales, UK. CF37 1DL
The aims of the present investigation were to determine the physiological implications of acute mountain sickness (AMS) and establish constitutional risk factors which may be important in its pathogenesis during a mountaineering expedition to Mt Kanchenjunga (K3). We specifically concentrated on the independent roles of free radical mediated oxidative stress, branched chain amino acid (BCAA) metabolism and the hormonal regulation of satiety at high altitude. It was hypothesised that the oedema and hypoxaemia induced by AMS could be ascribed to a systemic inflammatory response secondary to an infection and/or free radical mediated vascular damage.
Nineteen apparently healthy male mountaineers aged 38 (mean) ± 12 (SD) volunteered for the study. A variety of measurements were determined at rest and following a cycling test to volitional exhaustion before (SL1) and shortly after (SL2) a 7 ± 5 days stay at K3 base-camp (BC) which was established at ~5100 m. Resting overnight fasting venous blood samples were obtained on the morning of the second day at BC. The ascent to BC lasted 20 ± 5 days and with the exception of 5 rest days, each ascent day involved 250 ± 44 min of brisk walking at 68 ± 5% of the group’s predicted maximal heart rate. All subjects refrained from taking any medication recommended for AMS prophylaxis.
The prevalence and severity of AMS quantified using established criteria increased during the ascent trek and sojourn to BC. Sixty percent of the group experienced AMS (defined as a mean symptom score ³ 2 points) during the first two days at BC and one subject was evacuated to Kathmandhu with suspected HACE. Maximal oxygen uptake (O2MAX) decreased from 3.44 ± 0.93 L.min-1 (SL1) to 1.80 ± 0.28 L.min-1 at BC (P < 0.01 v SL1) and increased to 3.05 ± 0.53 L.min-1 at SL2 (P< 0.01 v BC). Selected myofibre proteins indicative of skeletal muscle damage (total phosphocreatine activity, myoglobin), lipid peroxidation “footprints” (lipid hydroperoxide and malondialdehyde) and plasma cholecystokinin (metabolic marker of satiety) were shown to increase at altitude. There was a marked increase in the incidence and severity of infectious illnesses encountered and a subsequent decrease in the plasma concentration of glutamine and BCAA. The more physically-conditioned subjects at sea-level (presenting with the highest lactate threshold) seemed to be more prone to contracting an infection and AMS at high altitude. A relationship was observed between AMS score at BC and the following; magnitude of arterial desaturation during physical exercise (r = 0.73, P < 0.05) and the increases (BC-SL1) in total CPK (r = 0.57, P < 0.05) and lipid hydroperoxide (r = 0.61, P < 0.05). Subjects diagnosed with AMS presented with a greater increase in total serum CPK activity, myoglobin and lipid hydroperoxide concentrations and a greater decrease in BCAA concentration.
These data indicate changes in the structural integrity of skeletal or cardiac muscle cell membranes at high altitude due to physical activity and/or environmental hypoxia. We have also identified a decrease in arterial distensibility (a surrogate measure of endothelial function) shortly following return to sea-level providing further evidence of vascular dysfunction (unpublished data). The source of membrane damage, which was more pronounced in those subjects presenting with AMS, may be linked to an increased activity of oxygen free radicals (OFR). Whether increased susceptibility to membrane damage at altitude due to a deficient antioxidant defence system is the cause or consequence of AMS remains to be elucidated in future studies.
The incidence of infections, confined predominantly to the upper respiratory and gastrointestinal tracts were more prevalent at high altitude. The decrease in plasma glutamine, a conditionally essential amino acid required for optimal lymphocyte proliferation and macrophage phagocytosis, may have increased the mountaineers’ susceptibility to opportunistic infections. The subsequent release of vasoactive inflammatory mediators may be implicated in the pathogenesis of oedema which would exacerbate arterial hypoxaemia; physiological phenomena which could account for at least some of the debilitating symptoms ascribed to AMS. We are currently conducting a double-blind placebo-controlled glutamine supplementation study in the Himalayas to further explore the link between infection and susceptibility to AMS.
Two unique observations may also contribute to our understanding of the mechanisms implicated in the cachexia frequently observed during a high altitude expedition. The observed increase in the gut hormone CCK represents the first hormonal evidence for impaired satiety at altitude. Alternatively, the catabolic effects of hypoxia, previously considered a maladaptive response, may well be of functional significance, more specifically by improving immunoreactivity. The major source of nitrogen for glutamine formation are the BCAA, their metabolism being largely confined to skeletal muscle. The observed decrease in serum BCAA concentration may signal for the endogenous catabolism of skeletal muscle to provide a constant supply of BCAA and thus glutamine; the latter amino acid required as a substrate for lymphocytes and macrophages during more active immunosurveillance.The use of AMS prophylactics such as acetazolamide which functions as a respiratory stimulant by inhibiting carbonic anhydrase have become increasingly popular amongst mountaineers. Our findings also suggest a role for amino acid and antioxidant supplementation at high altitude which, via different mechanisms, may also decrease individual susceptibility to AMS.