James S. Milledge

Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study

The aim of the study was to examine the efficacy and safety of temazepam on nocturnal oxygenation and next‐day performance at altitude. A double‐blind, randomized, cross‐over trial was performed in Thirty‐three healthy volunteers. Volunteers took 10 mg of temazepam and placebo in random order on two successive nights soon after arrival at 5000 m, following a 17‐day trek from 410 m. Overnight SaO2 and body movements, and next‐day reaction time, maintenance of wakefulness and cognition were assessed. Compared with placebo, temazepam resulted in a reduction in periodic breathing from a median (range) of 16 (0–81.3)% of the night to 9.4 (0–79.6)% (P = 0.016, Wilcoxons signed‐rank test), associated with a small but significant decrease in mean nocturnal SaO2 from 78 (65–84)% to 76 (64–83)% (P = 0.013). There was no change in sleep latency (P = 0.40) or restlessness (P = 0.30). Temazepam had no adverse effect on next‐day reaction time [241 (201–380) ms postplacebo and 242 (204–386) ms post‐temazepam], maintenance of wakefulness (seven trekkers failed to maintain 40 min of wakefulness postplacebo, and four post‐temazepam), cognition or acute mountain sickness. At high altitude temazepam reduces periodic breathing during sleep without an adverse effect on next‐day reaction time, maintenance of wakefulness or cognition. The 2% reduction in mean SaO2 post‐temazepam is likely to be predominantly because of acclimatization, as by chance more trekkers took temazepam on the first night (19 versus 14). We conclude that at high altitude temazepam is effective in reducing periodic breathing, and is safe to use, without any adverse effect upon next‐day performance.

Effect of altitude on spirometric parameters and the performance of peak flow meters.

BACKGROUND: Portable peak flow meters are used in clinical practice for measurement of peak expiratory flow (PEF) at many different altitudes throughout the world. Some PEF meters are affected by gas density. This study was undertaken to establish which type of meter is best for use above sea level and to determine changes in spirometric measurements at altitude. METHODS: The variable orifice mini-Wright peak flow meter was compared with the fixed orifice Micro Medical Microplus turbine microspirometer at sea level and at Everest Base Camp (5300 m). Fifty one members of the 1994 British Mount Everest Medical Expedition were studied (age range, 19-55). RESULTS: Mean forced vital capacity (FVC) fell by 5% and PEF rose by 25.5%. However, PEF recorded with the mini-Wright peak flow meter underestimated PEF by 31%, giving readings 6.6% below sea level values. FVC was lowest in the mornings and did not improve significantly with acclimatisation. Lower PEF values were observed on morning readings and were associated with higher acute mountain sickness scores, although the latter may reflect decreased effort in those with acute mountain sickness. There was no change in forced expiratory volume in one second (FEV1) at altitude when measured with the turbine microspirometer. CONCLUSIONS: The cause of the fall in FVC at 5300 m is unknown but may be attributed to changes in lung blood volume, interstitial lung oedema, or early airways closure. Variable orifice peak flow meters grossly underestimate PEF at altitude and fixed orifice devices are therefore preferable where accurate PEF measurements are required above sea level.

Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas.

The aims of the present study were to determine the changes in forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1) and peak expiratory flow (PEF), during an ascent to 5,300 m in the Nepalese Himalayas, and to correlate the changes with arterial oxygen saturation measured by pulse oximetry (SpO2) and symptoms of acute mountain sickness (AMS). Forty-six subjects were studied twice daily during an ascent from 2,800 m (mean barometric pressure 550.6 mmHg) to 5,300 m (mean barometric pressure 404.3 mmHg) during a period of between 10 and 16 days. Measurements of FVC, FEV1, PEF, SpO2, and AMS were recorded. AMS was assessed using a standardized scoring system. FVC fell with altitude, by a mean of 4% from sea level values [95% confidence intervals (CI) 0.9% to 7.4%] at 2,800 m, and 8.6% (95% CI 5.8 to 11.4%) at 5,300 m. FEV1 did not change with increasing altitude. PEF increased with altitude by a mean of 8.9% (95% CI 2.7 to 15.1%) at 2,800 m, and 16% (95% CI 9 to 23%) at 5,300 m. These changes were not significantly related to SpO2 or AMS scores. These results confirm a progressive fall in FVC and increase in PEF with increasing hypobaric hypoxia while FEV1 remains unchanged. The increase in PEF is less than would be predicted from the change in gas density. The fall in FVC may be due to reduced inspiratory force producing a reduction in total lung capacity; subclinical pulmonary edema; an increase in pulmonary blood volume, or changes in airway closure. The absence of a correlation between the spirometric changes and SpO2 or AMS may simply reflect that these measurements of pulmonary function are not sufficiently sensitive indicators of altitude-related disease. Further studies are required to clarify the effects of hypobaric hypoxia on lung volumes and flows in an attempt to obtain a unifying explanation for these changes.

Elevated plasma cholecystokinin at high altitude: metabolic implications for the anorexia of acute mountain sickness.

The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and subsequent cachexia at high altitude despite adequate availability of palatable foods. The metabolic implications of elevated CCK in AMS remain to be elucidated.

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.

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.

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. Pughs 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. Pughs 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.

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.

Renin-Aldosterone System

the effect of altitude and hypoxia on the renin-angiotensin-aldosterone system is interesting for many reasons. As a physician and mountaineer I have been puzzled for many years by the etiology of acute mountain sickness, especially high-altitude pulmonary edema (HAPE). A derangement of fluid homeostasis produced indirectly by hypoxia appeared to be one characteristic. The time lag of 6–24 h between exposure to hypoxia and the onset of symptoms suggests that hypoxia may stimulate a hormonal response which over this time course could upset fluid homeostasis enough to cause symptoms. For a time we considered the antidiuretic hormone, but, although levels are raised in cases of HAPE (4), this is more likely a result than a cause of the condition. Case reports of HAPE persistently stress the importance of strenuous exertion in the formation of this condition. We therefore decided to first study the effect of exercise typical of mountaineers on fluid balance.

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 Speers original work and such facts about his life as I have been able to discover.