Centenary of the Pike's Peak High Altitude Expedition of 1911

In the Paton Lecture at the Physiologic Society's 2011 Oxford Meeting West reviews the development of high altitude physiology beginning with Paul Bert's proof that the low partial pressure oxygen explained the physiologic and pathologic effects of high altitude. Research at several high altitude laboratories built in the late 19^th century required climbing skills, major effort and tolerance of cold and lack of adequate food. J. S. Haldane and C. G. Douglas from Oxford, not being climbers, chose to mount an altitude physiology expedition on Pike's Peak in Colorado because it had a cog railway to a comfortable hotel on the summit with fine cuisine. They made measurements first at sea level, then on the summit for five weeks, and finally over 3 weeks back at sea level. The extensive scientific program included descriptions of acute mountain sickness, many measurements of partial pressures in alveolar gas and arterial blood, changes in ventilation including periodic breathing, exercise measurements, and a large number of blood studies. Their meticulously collected data indicated that the arterial PO₂ could considerably exceed the alveolar value, supporting Haldane's belief in a lung membrane oxygen pump. This theory was later disproved by August Krogh, but the cause of the experimental error has never been discovered. West's lecture is a fascinating review of the work of a century ago (West, 2012).

Is Live High-Train Low (LHTL) Performance Improvement a Placebo Effect?

To test this possibility, Siebenmann et al (2011) designed a double blinded design. Subjects lived and slept in a room with oxygen concentration controlled to either sea level or 3000 m equivalent altitude. Sixteen endurance-cyclists trained for eight weeks at low altitude (<1,200 m). After a two weeks lead-in period, subjects spent 16h/day for the following four weeks in one of these rooms. Questionnaires revealed that subjects were unaware of group classification. Weekly training effort was similar between groups. Hemoglobin mass, maximal O₂ uptake in normoxia and at a simulated altitude of 2,500 m and mean power output in a simulated 26.15 km time-trial remained unchanged in both groups throughout the study. Exercise economy (i.e. O₂ uptake measured at 200 Watt) did not change during the LHTL-intervention and was never significantly different between groups. The authors conclude that four weeks of LHTL using 16 hours per day in 3000 m hypoxia did not improve endurance performance or any of the measured associated physiological variables.

Assessing Methods of Prediction of Risk of Altitude Illness

Richalet et al (2011) developed sophisticated methods of using physiologic tests to predict the risk of developing altitude illnesses using hypoxic exercise tests that include measurement of hypoxic ventilatory response and arterial desaturation by pulse oximetry. They now report use in 1326 subjects before a sojourn above 4000 m altitude. At altitude 314 (23.7%) developed severe high altitude illness (SHAI), 22 (1.7%) got high altitude pulmonary edema (HAPE) and 13 (0.98%) had high altitude cerebral edema (HACE). Preventive use of acetazolamide reduced the risk of SHAI by 44%. Among non acetazolamide users (n=917), main factors independently associated with SHAI were previous history of SHAI, too rapid ascent (>400m/day), history of migraine, low ventilatory response to hypoxia at exercise and >22% desaturation at exercise in hypoxia. These last two parameters were independent predictors of severe high altitude illness and improved substantially the discrimination ability of multivariate prediction model (to C-statistic=0.88).

Predicting High Altitude Pulmonary Edema Susceptibility by Hypoxic Exercise Testing

Mounier et al (2011) demonstrate that the individual rise of pulmonary arterial pressure (by Doppler echocardiography) during the standardized Richalet hypoxic exercise test procedure accurately predicted the incidence of HAPE in 8 known HAPE-susceptible subjects compared to 8 HAPE resistant mountaineers.

Predicting Acute Mountain Sickness (AMS) by Cerebral Autoregulation at Sea Level

A previous study demonstrated retrospectively a significant correlation of dynamic cerebral autoregulation index (AI) with the incidence of AMS. Cochand et al (2011) now report a significant correlation (p=0.007) between pre-altitude autoregulation tests and subsequent AMS in 18 subjects 6 hours after passive ascent to 3800 m altitude. Determination of AI is non-invasive, using Doppler untrasonography and arterial blood pressure by finger plethysmography. The authors suggest it might be useful in disclosing a risk factor and considering pharmacologic prophylaxis before ascent.

Control Expired NO Is Lower in Subjects Developing Acute Mountain Sickness in Acute Hypoxia

Nineteen normal volunteers were exposed for 6 hours to 12% O₂ by Macinnis et al (2012). The expired air fractional concentration of nitric oxide was measured hourly. Acute mountain sickness Lake Louise scores were determined hourly, and the 8 who developed scores (at any time) above 3 were termed AMS+. Mean expired NO was approximately twice as high in AMS- as in AMS+ (p=0.035) in normoxia before the study, and both groups showed about 30% gradual rise during the 6 hr exposure (p<0.001). This is the first report showing significantly lower normal control expired NO in subjects who later developed AMS than those who did not have AMS. suggesting a possibility of predicting AMS.

Attempts to Understand Nitric Oxide Rise With Altitude Acclimatization

The curiously increased NO levels in Tibetans and rise in sea level dwellers during altitude acclimatization and whether it has a positive or negative role is poorly understood. In connection with the Caudwell Extreme Everest Research Group, Levett et al (2011) attempt to correlate the various plasma nitrogen oxide factors with physiologic changes at altitude. They report that plasma biomarkers of NO production (nitrite, nitrate) and activity (cGMP) are elevated on acclimatization to high altitude while S-nitrosothiols are initially consumed. The authors suggest that multiple nitrogen oxides may improve hypoxia tolerance by enhancing NO availability.

Lung Membrane Diffusing Capacity at Altitude Improved by Endothelin A Receptor Blockade

Hypoxic pulmonary vasoconstriction has a primary role in high altitude lung capillary membrane damage and pulmonary edema (HAPE). Pulmonary vasodilators have been used to reduce and or treat HAPE. Endothelin A receptor blockade by sitaxsentan reduces pulmonary hypertension and vasoconstriction and increases maximum work rate and oxygen consumption. Lung diffusing capacity is decreased by exercise at altitude. In order to determine whether Endothelin A receptor blockade can improve diffusing capacity at altitude, de Bisschop et al (2011) determined diffusing capacities for nitric oxide (DL_NO) and carbon monoxide (DL_CO) using a single-breath method before and 30 minutes after maximal exercise in 22 trekkers both at sea level and at the Pyramid laboratory in the Khumbu area of Nepal at 5050 m altitude. The membrane component Dm and capillary volume Vc were calculated with corrections for hemoglobin, alveolar volume and barometric pressure. Exercise at altitude decreased DL_NO and Dm. Sitaxsentan (100 mg/day for 1 week) improved VO_{2 max} and increased resting and post-exercise DL_NO and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DL_NO. Both DL_CO and DL_NO were correlated to VO_{2 max} at sea level and altitude.

High Altitude Pulmonary Edema (HAPE) Related Oxidative Stress Genes

Mishra et al (2012) investigated polymorphisms of oxidative stress related genes CYBA and GSTP1 in 150 HAPE patients, 180 HAPE resistant lowland natives and 180 healthy highland natives. The genotype distributions differed significantly between the 3 groups. The risk alleles of CYBA and GSTP1, their haplotypes and gene-gene interactions were significantly associated with oxidative stress and high-altitude pulmonary edema.

Plasma Haptoglobin and Apolipoprotein A-I are Upregulated in HAPE

Using protein quantification based on 2D gels, Ahmad et al (2011) report expression of plasma haptoglobin and apolipoprotein and A-I showed roughly twofold increases in 20 subjects with a diagnosis of high altitude pulmonary edema (HAPE) compared with 10 normal controls, consistent with acute inflammation. The authors suggest that these two proteins might be useful biomarkers for HAPE diagnosis and prognosis.

Mitochondrial Genetic Differences Between Han and Tibetans.

Mitochondrial DNA (mtDNA) genetic haplotypes of 12 polymorphisms were determined in 72 members of a Tibetan population, 144 low altitude-Han and 227 high altitude-Han using polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-ligase detection reaction assays. The haplogroup D4, known to be common in Han, was negatively associated with high-altitude adaptation in Tibetans. The frequency of the nt3010G-nt3970C haplotype was significantly higher in Tibetans than in low and high altitude Han (Luo et al., 2011).

Do Antioxidants Facilitate Altitude Fetal Growth More in Andeans than Europeans?

Julian et al (2011) measured enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity during pregnancy and in the non-pregnant state in Andean or European residents of low (400m) or high altitude (3600-4100m). Pregnancy and altitude increased catalase and/or SOD activity to a greater extent in Andeans than Europeans. SOD was lower in mothers of small for gestational age infants at weeks 20 and 36. The authors conclude that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.

High Altitude Renal Syndrome (HARS) Proposed

A review of the problems seen in many high altitude populations has suggested to the authors, a large group of altitude physiologists, that there are specific renal problems in chronic altitude exposure. High altitude polycythemia associates with hyperuricemia, elevated systemic blood pressure and increased renal vascular resistance, microalbuminuria and increased filtration fraction. For example, in a previously reported study of Tibetans, 38% of subjects had hypertension, 29% had hyperuricemia, and 16% had albuminuria. In those with albuminuria, 51% had hypertension, 39% had hyperuricemia and 32% had high hematocrit (Arestegui et al., 2011).

Rat Lung Tolerance to Acute Hypoxia is Increased by 5 Days of 1 Hr Hyperbaric O₂ Preconditioning

Repeated exposure to short periods of hyperbaric oxygen is known to reduced subsequent ischemic damage to brain and other organs, called “preconditioning”. Li et al (2011) compared lung injury score in rats exposed 24 hr of hypobaric chamber hypoxia (6000 m altitude equivalent) with and without preconditioning by 5 days of 1 hr per day exposure to 2.0 ATA O₂. They also determined the effects of hypoxia and preconditioning on the lung expression of proteins AQP1 and AQP5, related to microvascular edema transport. Hyperbaric O₂ preconditioning significantly reduced subsequent hypoxic lung injury scores and minimized the reduction of the AQP1 & 5.

Rat Lung Tolerance to Acute Hypoxia is Increased by HSP70 Upregulated By 2 Weeks of Hypobaric Hypoxic Preconditioning

Heat shock protein HSP70 is upregulated by repeated exposure to hypobaric hypoxia. Lin et al (2011) now report that HSP70 upregulated by hypoxic preconditioning significantly attenuated pulmonary oedema, inflammation, and ischaemic and oxidative damage in the lungs in rats exposed for 24 hr to hypobaric chamber hypoxia equivalent to 6000 m altitude. Control similarly hypoxic rats without preconditioning had higher scores of alveolar oedema, neutrophil infiltration and hemorrhage, acute pleurisy (e.g. increased exudate volume, increased numbers of polymorphonuclear cells and increased lung myeloperoxidase activity), increased pro-inflammatory cytokines [e.g. TNF-alpha (tumor necrosis factor-alpha), IL (interleukin)-1beta and IL-6], and increased cellular ischemia (i.e. glutamate and lactate/pyruvate ratio) and oxidative damage [glycerol, NOx (combined nitrate+nitrite) and 2,3-dihydroxybenzoic acid] markers in the BALF (bronchoalveolar fluid).

Long Term Beneficial Effects of 2 Weeks of Normoxia in Neonatal High Altitude Rats

Mammalian birth results in profound and long-term changes in PO₂ and circulatory adjustments. Very high altitude pregnant women in the Andes often descend for delivery to offer better survival changes to the newborn. High altitude (3600 m) rat neonates were exposed to 32% O₂ from 1 day before (in utero) to 15 days after birth and studied at 2, 12 and 32 weeks age (Lumbroso et al., 2011). Compared with a control groups, the treated rats showed reduced hematocrit and hemoglobin levels at all ages (both sexes), reduced right ventricular hypertrophy (both sexes), lower airspace/tissue ratio in the lungs (males only) and higher oxygen uptake (males only). At 12 weeks, ventilation was decreased by 32% O₂ administration more than in controls. They tended to survive longer (ns).

Acetylcholinesterase Inhibitors Inhibit Hypoxic Memory Loss and Brain Injury in Rats

Using the Morris water maze task in rats exposed to hypobaric hypoxia at 6100m for 7days, Muthuraju et al (2011) report that memory was impaired along with a decrease in acetylcholine levels, increase in acetylcholinesterase activity, down regulation of choline acetyltransferase, alpha-7-nicotinic acetylcholine receptor and M₁ muscarinic acetylcholine receptor. Physostigmine or galantamine resulted in amelioration of the hypobaric hypoxia induced deleterious memory effects, improved acetylcholine level, decreased acetylcholinesterase activity, increased the synthesis of acetylcholine by increasing choline acetyltransferase activity and improved neuronal morphology, perhaps by increasing the expression of alpha-7-nicotinic acetylcholine receptor and by reducing the acetylcholinesterase level in the cortex and the hippocampus.

Brain Stem EPO is Twice Normal in High Altitude Sprague-Dawley Lab Rats

In addition to its role in erythropoesis, Epo exerts protective functions against acute and delayed degenerative diseases of the brain. In Sprague-Dawley rats living and reproducing at high altitude for longer than 19 years (3600 m in La Paz, Bolivia), Seaborn et al (2011) show that postnatal Epo concentration is two-fold higher in the brainstem than in the forebrain or in sea-level controls. The authors had reported that Epo in the central nervous system facilitates the ventilatory response and acclimatization to hypoxia. These findings strongly suggest that brainstem Epo plays an important role in tolerance to high altitude hypoxia after birth.

Insulin Pumps May Over Deliver with Ascent to Altitude by Bubble Expansion

Children and adults with type 1 diabetes using insulin pump therapy have reported hypoglycemia during air travel. King et al (2011) demonstrated that bubbles may form and trapped microbubbles will expand with falling atmospheric pressure in insulin pumps causing excess delivery.

Out of Tibet: Pliocene Woolly Rhino Suggests High-Plateau Origin of Ice Age Megaherbivores

An international paleoanthropologist group reports a new Pliocene primitive wooly rhino that evolved in Tibet before the Ice Age, being thus adapted to the oncoming chill, allowing expansion into the Eurasian lower altitude mammoth steppe (Deng et al., 2011).

—John Severinghaus