Benzolamide improves oxygenation and reduces acute mountain sickness during a high-altitude trek and has fewer side effects than acetazolamide at sea level.

Acetazolamide is the standard carbonic anhydrase (CA) inhibitor used for acute mountain sickness (AMS), however some of its undesirable effects are related to intracellular penetrance into many tissues, including across the blood-brain barrier. Benzolamide is a much more hydrophilic inhibitor, which nonetheless retains a strong renal action to engender a metabolic acidosis and ventilatory stimulus that improves oxygenation at high altitude and reduces AMS. We tested the effectiveness of benzolamide versus placebo in a first field study of the drug as prophylaxis for AMS during an ascent to the Everest Base Camp (5340 m). In two other studies performed at sea level to test side effect differences between acetazolamide and benzolamide, we assessed physiological actions and psychomotor side effects of two doses of acetazolamide (250 and 1000 mg) in one group of healthy subjects and in another group compared acetazolamide (500 mg), benzolamide (200 mg) and lorazepam (2 mg) as an active comparator for central nervous system (CNS) effects. At high altitude, benzolamide-treated subjects maintained better arterial oxygenation at all altitudes (3-6% higher at all altitudes above 4200 m) than placebo-treated subjects and reduced AMS severity by roughly 50%. We found benzolamide had fewer side effects, some of which are symptoms of AMS, than any of the acetazolamide doses in Studies 1 and 2, but equal physiological effects on renal function. The psychomotor side effects of acetazolamide were dose dependent. We conclude that benzolamide is very effective for AMS prophylaxis. With its lesser CNS effects, benzolamide may be superior to acetazolamide, in part, because some of the side effects of acetazolamide may contribute to and be mistaken for AMS.

Stanhope Speer, Physician and Alpinist: In 1853, First to Describe Mountain Sickness?

In 1853, Stanhope Templeman Speer published a two-part paper in The Association Medical Journal on Mountain Sickness. Speer was a physician who had worked at the Brompton Hospital for Chest Diseases in London and had been Professor of Medicine in Dublin. He was also an Alpine climber and had made the first ascent of one of the Wetterhorn peaks. His article ran to ten and a half pages in the Journal and to 50 pages in a reprint. It consists of anecdotal accounts of symptoms suffered at altitude from the literature and from his own experiences in the European Alps. He asks three pertinent questions. Is there a condition of mountain sickness? Are these symptoms felt by all persons alike and at the same height? What are the causes, and whence the explanation of such phenomena? In the course of the article, he answers the first two questions but, like us, 162 years later, is unable to answer the third. This article seeks to present Speer's original work and such facts about his life as I have been able to discover.

King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude.

Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.

The Silver Hut expedition, 1960-1961.

The 1960-1961 Himalayan Scientific and Mountaineering Expedition, commonly known as the Silver Hut Expedition, was a unique project to study the physiology of acclimatization in human lowlander subjects at extreme altitude over a prolonged period and also to make an attempt on Makalu, an 8470-m peak. The leader was Sir Edmund Hillary, and Dr. Griffith Pugh was the scientific leader. Studies were conducted at a Base Camp in the Everest region of Nepal at 4500 m and at the Silver Hut at 5800 m on the Mingbo Glacier. Simpler physiology was continued on Makalu, in camps at 6300 and 7400 m. The expedition left Kathmandu at the end of the monsoon in 1960 and spent the autumn setting up the Base Camp and the Silver Hut. Some members also spent time making a study of the evidence for the existence of the Yeti. The winter was spent on physiological studies at Base Camp and in the Silver Hut, and the nearby peak of Ama Dablam was climbed. In the spring the expedition moved over to Makalu and made an unsuccessful attempt to climb it without supplementary oxygen. The 9-month expedition ended at the start of the 1961 monsoon. An ambitious program of studies was successfully completed. It was a very happy and, scientifically, a successful expedition. Many of the findings were not repeated for many years, and none has been refuted. On the mountaineering side, we were unsuccessful on Makalu owing to a combination of weather and illness, but the ascent of Ama Dablam was considerable compensation.

The Snow Snorkel: a proof of concept study.

OBJECTIVE: To demonstrate that the Snow Snorkel can be used safely by healthy volunteers buried in snow for up to 1 hour. METHODS: Nine healthy male volunteers were placed in a shoulder-width trench and buried with snow to a depth of 30 to 40 cm. The study was divided into 2 stages. The first stage (Stage 1) was performed with the Snow Snorkel in operation (60-minute duration) and was then followed by a second stage (Stage 2) (15-minute duration) when the device was removed. Arterial oxygen saturation (SaO2), heart rate (HR), respiratory rate (RR), axillary temperature (T), and 3-lead electrocardiography (ECG) were monitored throughout the study. RESULTS: Of the 9 volunteers who were enrolled, 7 were able to complete Stage 1, while only 3 were able to complete Stage 2. In those who completed Stage 1, the mean HR fell by 14.1 beats/min (P = .002), while RR (P = .5) and SaO2 (P = .7) remained unchanged compared to baseline measurements. There were no changes in T or ECG. CONCLUSIONS: Simple systems such as the Snow Snorkel are effective during snow burial and warrant further investigation.

Oxygen delivery at sea level and altitude (after slow ascent to 5000 meters), at rest and in mild exercise.

Oxygen delivery (DO2) calculated from cardiac output, haematocrit (Hct) and arterial oxygen saturation (SaO2), has been obtained on six subjects at sea level (London) and after slow ascent to 5000 meters (Chamlang base camp) at rest and during mild exercise (25 watts and 50 watts). Haematocrit was increased in all six subjects at 5000 m and expressed as haemoglobin (Hb) rose from a mean (+/- standard error; SEM) of 13.8 +/- 0.1 g (100 ml)(-1) to 15.8 +/-0.3 g (100 ml)(-1) (t = 6.3, p = 0.0014). SaO2 was almost constant with exercise at sea level (rest 98.5%, 25 w 98.3% and 50 w 98.3%) but declined more steeply with exercise at 5000 m (rest 88.8 +/-0.6%, 25 w 85.4 +/-0.4% and 50 w 84.4 +/- 0.5%). Arterial oxygen content (CaO2) was very similar for 25 watts exercise at altitude (5000 m, 18.1 ml per decilitre--dl) as at sea level (London, CaO2 18.2 ml dl(-1)). At rest CaO2 was higher at altitude (18.8 +/-0.2 ml dl(-1)) than at sea level (18.3 +/- 0.4 ml dl(-1)) and at 50 w CaO2 was lower at altitude (17.9 +/- 0.4 ml dl(-1)) than at sea level (18.2 +/- 0.2 ml dl(-1)). Hence, similar cardiac output values at rest (sea level, 5.0 +/- 0.4 litres min(-1) l min(-1); altitude, 5.6 +/- 0.31 min(-1)-) and at 25 w exercise (sea level, 8.2 +/-0.7 1 min(-1); altitude, 8.3 +/-0 .9 1 min'(-1) resulted in similar values for DO2 at rest (sea level, 0.9 +/-0.1 l min(-1) altitude, 1.0 +/-0.1 l min(-1) and 25 w exercise (sea level, 1.5 +/-0.1 l min(-1) altitude, 1.5 +/- 0.2 l min(-1). For 50 w exercise cardiac output and oxygen delivery were greater at altitude in one subject but were significantly reduced for the remaining five (cardiac output mean difference 3.0 +/- 0.91 min(-1), p = 0.015; DO2 mean difference, 0.56 +/- 0.21 l min(-1) p = 0.028). Acclimatization was therefore adequate to sustain a normal value for oxygen delivery for rest and 25 watts exercise (via compensatory erythropoiesis) but insufficient for 50-watt exercise in five of the six subjects.

A tribute to John Burnard West.

John West is well known to the "Hypoxia" community for his many contributions to the physiology and Pathophysiology of high altitude and for his leadership of the 1981 American Medical Research Expedition to Everest. He is known to the wider medical world for his researches into respiratory physiology especially gas exchange in the lung and perhaps even more for his numerous books on these topics. His publication list numbers over 400 original papers. His research career started in the UK but since 1969 he has been Professor of Medicine at UCSD, leading a very productive team at La Jolla. He has been honoured by numerous prizes and named lectureships, the latest honour being to be elected to the Institute of Medicine, National Academies (USA).

Altitude medicine and physiology including heat and cold: a review.

With increasing numbers of people travelling to high altitude destinations for recreation or work, there is a need for practitioners of Travel Medicine to be familiar with altitude illnesses and the physiology of altitude. In mountainous areas travellers may also be exposed to problems of heat and cold. This article reviews these topics and gives practical advice on the management of the clinical problems involved, together with a discussion of underlying mechanisms, as far as they are understood at present.

Symptoms of infection and acute mountain sickness; associated metabolic sequelae and problems in differential diagnosis.

Infections and acute mountain sickness (AMS) are common at high altitude, yet their precise etiologies remain elusive and the potential for differential diagnosis is considerable. The present study was therefore designed to compare clinical nonspecific symptoms associated with these pathologies and basic changes in free radical and amino-acid metabolism. Nineteen males were examined at rest and after maximal exercise at sea level before (SL(1)/SL(2)) and following a 20 +/- 5 day ascent to Kanchenjunga base camp located at 5100 m (HA). Four subjects with symptoms consistent with an ongoing respiratory and recent gastrointestinal infection were also diagnosed with clinical AMS on the evening of day 1 at HA. These and six other subjects recovering from symptoms consistent with a respiratory infection presented with a greater increase (HA minus SL(1)) in AMS scores and resting venous concentration of lipid hydroperoxides (LH) and in total creatine phosphokinase and ratio of free tryptophan/branched chain amino acids, and greater decrease in glutamine (Gln) compared to healthy controls (n = 9, p < 0.05). The decrease in Gln was consistently related to the altitude/exercise-induced increase in LH (r = -0.69/r = -0.45; p < 0.05) and altitude-induced increase in myoglobin (r = -0.73, p < 0.05). These findings highlight the potential for the misdiagnosis of altitude illness due to the similarity of nonspecific constitutional symptoms associated with infection and AMS. Both conditions were characterized by parallel changes in peripheral biomarkers related to free-radical, skeletal muscle damage and amino acid metabolism. While clearly not establishing cause and effect, free radical-mediated changes in peripheral amino acid metabolism known to influence immune and cerebral serotoninergic function may enhance susceptibility to and/or delay recovery from altitude illness.

Griffith Pugh, pioneer Everest physiologist.

Lewis Griffith Cresswell Evans Pugh (1909-1994), best known as the physiologist on the successful 1953 British Everest Expedition, inspired a generation of scientists in the field of altitude medicine and physiology in the decades after World War II. This paper details his early life, his introduction to exercise physiology during the war, and his crucially important work in preparation for the Everest expedition on Cho Oyu in 1952. Pugh's other great contribution to altitude physiology was as scientific leader of the 1960-1961 Himalayan Scientific and Mountaineering Expedition (the Silver Hut), and the origins and results of this important expedition are discussed. He had a major and continuing interest in the physiology of cold, especially in real-life situations in Antarctica, exposure to cold wet conditions on hills in Britain, and in long distance swimming. He also extended his interest to Olympic athletes at moderate altitude (Mexico City) and to heat stress in athletes. Pugh's strength as a physiologist was his readiness to move from laboratory to fieldwork with ease and his rigor in applying the highest standards in both situations. He led by example in both his willingness to act as a subject for experiments and in his attention to detail. He was not an establishment figure; he was critical of authority and well known for his eccentricity, but he inspired great loyalty in those who worked with him.