Slow Deep Breathing in Rest at Altitude Increases SpO₂ Without an Increase in Ventilation

Bilo et al (2012) investigated the ventilatory and hemodynamic effects of 15 minutes of breathing at 6 breaths/min in normal subjects at high altitude in healthy lowlanders staying either at 4559 m for 2–3 days (A, n=39) or at 5400 m for 12–16 days (B, n=28). SpO₂ rose from 80.2±7.7% to 89.5±8.2% in A and from 81.0±4.2% to 88.6±4.5 in B accompanied by significant reductions in systemic and pulmonary arterial pressure. Minute ventilation and pulmonary CO diffusion were not increased. The mechanisms are not identified by the authors, but to me suggest re-expansion by the compensating increased inspiratory volume of atelectatic areas where blood is shunting.

Acute Mountain Sickness (AMS) Probability Factors

Beidleman et al. (2012) studied the relative probabilities of developing AMS at various altitudes and other possible factors in 308 unacclimatized men and women who spent between 4–48 h at altitudes ranging from 1659–4501 m under experimentally controlled conditions (low and high activity) to determine relative contribution of altitude, time at altitude, activity level, age, body-mass index (BMI), race, sex, and smoking status. AMS severity increased nearly 2-fold for every 1000 m increase in altitude at 20 h of exposure, peaked between 18–22 h of exposure, and returned to initial levels by 48 h of exposure regardless of sex or activity level. Men were slightly but not significantly more likely to get AMS. Peak AMS severity scores were 38% higher in men than women at 20 h of exposure. High activity (>50% of maximal oxygen uptake for >45 min) increased odds of AMS by 72%. Age, BMI, race, and smoking status were not significantly associated with AMS.

Low Hypoxic Ventilatory Responses (HVR) in Subjects with History of Acute Mountain Sickness (AMS)

Nespoulet et al. (2012) compared 12 AMS-susceptible individuals with recurrent and severe symptoms (AMS+) with 12 AMS− (not susceptible) subjects, assessing HVR, pulmonary arterial pressure rise and sleep-breathing disorders in simulated acute altitude exposure. AMS+ subjects had lower isocapnic HVR (0.40±0.49 vs 0.97±0.46, Lċmin^−1.%⁻¹). SpO₂ during sleep was lower in AMS+ subjects (81.6±2.6 versus 86±4%), associated with a lower central apnoea/hypopnoea index per h (18±18 versus 33±25). In AMS+, with the lower SpO₂, pulmonary artery systolic pressure rose more in response to hypoxia. AMS+ subjects had lower lung diffusing capacity and higher endothelin-1 level at baseline. Thus while AMS+ subjects were more hypoxemic in sleep they exhibiting fewer respiratory events during sleep.

Tadalafil for the Prevention of Severe High Altitude Illness

Leshem et al. (2012) compared the effectiveness in preventing high altitude illness of tadalafil plus acetazolamide (n=24) versus acetazolamide alone (n=27) in trekkers on Mt. Kilimanjaro. The tadalafil group had lower rates of severe HAI compared with controls (4% vs 26%), mostly because of decreased high altitude pulmonary edema rates (4% vs 22%).

Ibuprofen Ineffective in Preventing Acute Mountain Sickness (AMS) in Climbers

Gertsch et al. (2012) compared 600 mg ibuprofen 3/day with placebo in a double-blinded study of 183 healthy western trekkers on the Everest approach who completed hiking from 4300 m to 4928 m. The incidence of AMS between placebo and treatment groups was not significant despite the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS.

Prophylactic Dexamethasone Improves Sleep Efficiency and Oxygen Saturation at Altitude

Dexamethasone (Dex) is the preferred treatment for severe acute mountain sickness (AMS) and high altitude cerebral edema (HACE) but is not recommended for high altitude pulmonary edema (HAPE) treatment. Nussbaumer et al. (2012) show that volunteers susceptible to HAPE experience severe sleep disturbance and nocturnal mean oxygen desaturation in the first few days altitude that can be ameliorated by pretreatment with Dex 8 mg q12h. On the first night at 4559 m, mean SpO₂ during sleep fell to 71% in 12 HAPE-s controls vs 78% in 9 pretreated with Dex. Sleeping time was 42% longer and sleeping efficiency was 95% with Dex vs 65% without. Dex given to controls before the third night at 4559 m failed to correct the sleep time and efficiency, although SpO₂ was restored to 80% and deep NREM was normalized.

Acclimatization in Trekkers with and without Recent Exposure to High Altitude

MacNutt et al. (2012) demonstrate that recent altitude exposure confers an advantage in individuals who had de-acclimatized for at least 1 week before being re-exposed. 50 low-altitude natives kept a daily trekking log throughout repeated 7- to 8-day treks from Lukla (2840 m) to Gokyo Ri (5360 m). Compared to 30 trekkers with no recent altitude exposure, 20 with recent altitude exposure walked 20% faster, reported lower acute mountain sickness scores, used less medication to treat headache and at 5360 m, SpO₂ was significantly higher (85±6 vs. 78±6).

Effects of Aging on Acute Altitude Acclimatization

Lhuissier, Canoui-Poitrine, and Richalet (2012) were able to relate acclimatization problems with age using a 20-year study of 4675 subjects (2789 men, 1886 women; 14–85 years old) and a longitudinal study of 30 subjects retested after a 10 year interval. The study was based on hypoxia-induced desaturation and the ventilatory and cardiac responses to hypoxia at rest and exercise. In men, with aging ventilatory response to hypoxia increased and SpO₂ fell less. Cardiac response to hypoxia was blunted with aging in both sexes. Similar results were found in the longitudinal study. Training had a greater impact in the elderly subjects on improvement of cardiac and ventilatory responses to hypoxia. Training limited the negative effects of menopause in cardiorespiratory adaptations to hypoxia.

Acute and Chronic Effects in Lowlander Smokers on Moving to High Altitude

Two hundred healthy non-smokers and 182 cigarette smokers were recruited from Han lowland workers transported to an altitude of 4525 m. Compared with non-smokers, smokers had a lower incidence of acute mountain sickness (AMS) and lower AMS scores upon arrival. After 3 to 6 months at altitude, smokers had higher Hb and mean pulmonary arterial pressure, and lower SpO₂, 1 sec forced expiratory volume, and maximal voluntary ventilation (Wu et al., 2012).

Oxidative Stress Increased by Climbing Mt. Rainier

Nine male participants completed a 2-day climb of Mt Rainier, 4393 m. Blood samples were obtained before, at 3000 m on the way up and down and at the base. Ferric-reducing antioxidant potential was elevated 8% going up and 11% descending. Trolox equivalent antioxidant capacity was increased 10% while descending and 18% back at base, protein carbonyls were elevated 194% going up and 138% descending. Lipid hydroperoxides were increased 257% but only when back at base (Miller et al., 2012).

Correlating Mitochondrial Respiratory Capacity and Efficiency with Exercise Capacity Changes after a Month at Altitude

Muscle biopsies were obtained from 8 lowland natives at sea level and after 28 days at 3454 m altitude by Jacobs et al. (2012). High-resolution respirometry showed that mitochondrial respiratory capacity fell while efficiency rose. Respiratory capacity diminished in complex I- and complex II-specific respiration in addition to a loss of maximal state-3 oxidative phosphorylation capacity from SL to HA, all independent from alterations in mitochondrial content. Measures of mitochondrial efficiency (leak control coupling, respiratory control ratio, and oligomycin-induced leak respiration) improved. Before altitude mitochondrial respiratory capacities correlated with measures of exercise capacity, whereas following altitude mitochondrial efficiency correlated best with the expected hypoxic reduction of exercise capacity.

The Effects of Altitude Training on Hemoglobin Mass and Performance in Swimmers

Altitude training can increase body Hb mass and might thereby be useful in competitive swimming, but training at altitude reduces peak performance compared with sea level training. Wachsmuth et al (2012) examined data from 2 years of swim performances of 45 top swimmers. Twenty-five trained between one and three times for 3–4 weeks at altitude training camps. Hb mass increased by 7.2±3.3% at 2320 m and by 3.8±3.4% at 1360 m and was still elevated 4.0±2.7% 24 days after return. No increase in performance was observed until the altitude's negative effect on muscle was restored 25–35 days after return from altitude.

Beetroot Juice Improves Skeletal Muscle Efficiency During Hypoxic Work

It has been found that dietary nitrate supplementation can reduce the oxygen cost of muscle work. This effect was investigated by Masschelein et al. (2012) in 15 young, healthy volunteers. From 6 days prior to each session, subjects received either beetroot (BR) juice delivering 0.07 mmol nitrate per kg body wt or a control drink. Subjects first cycled for 20 min at 45% of their pre-study VO_2max followed by exhaustion timing with timed step increases in work to VO_2max. Muscle oxygenation was measured by near-infrared spectroscopy. In those treated with BR, in 11% hypoxia, VO₂ was lower at rest and during 45% VO₂ max work and %SpO₂ was higher and muscle O₂ was ∼4-5% higher at rest and during both 45% and VO_2max than in controls. BR slightly increased time to exhaustion at VO_2max. BR had no effect on cerebral oxygenation status or symptoms of acute mountain sickness.

Hypoxic Exercise Limit Prolonged By Combining Theophylline with Pulmonary Vasodilator

With rapid ascent to high altitude, hypoxic pulmonary vasoconstriction (HPV) potentially limits cardiac output and systemic blood flow. Radiloff et al. (2012) report that pharmacological enhancement of the heart rate with theophylline combined with reversal of HPV via endothelin blockade by sitaxsentan or ambrisentan prolonged hypoxic run-to-fatigue time in rats. Because theophylline significantly increased muscular blood flow, and sitaxsentan increased tissue oxygenation, the combination improved both parameters but in a reduced manner. Hypoxic exercise SpO₂ was not altered by any of the drugs tested or their combinations but hind limb muscle PO₂ in hypoxic exercise was reduced 10 torr in controls but not reduced with either sitanxsentan alone or a combination. Pulmonary wet-to-dry weight ratios were unaffected by combination treatment. The authors suggest that cardiac stimulants, such as xanthene derivatives, might be used in treating high-altitude-induced decreases in physical performance and potentially other altitude-related illnesses and may have greater therapeutic potential when delivered in combination with endothelin receptor blockers.

Kenyan Champion Marathoners Do Not Have Greater Metabolic Efficiency

Maximal oxygen consumption and the energy cost of running on track was measured using a telemetric metabolic cart and lactate levels by an electro-enzymatic method during training camps at moderate altitude, to better understand the Kenyan dominance in the marathon. Ten top-level Kenyan marathon runners and 9 European marathoner controls did not have very high energetic efficiencies but both performed at extremely high sustainable fractions of VO_2max. The dominance of Kenyans over Europeans could not be explained on energetic grounds (Tam et al., 2012).

Benefit of Altitude Training Remains Unestablished

The general practice of altitude training is widely accepted as a means to enhance sport performance despite a lack of rigorous scientific studies. No double-blind, placebo-controlled, crossover trial has ever been conducted on altitude training. Lundby et al. (2012) point out weaknesses in theories and methodologies of the various altitude training paradigms. They suggest there should be more skepticism concerning the effects of altitude training methodologies, needing well-controlled studies to enhance our understanding of the mechanisms and reveal any potential benefits of altitude training.

Lack of Effects of Sympathetic and Parasympathetic Blocks on Cerebral Blood Flow at Altitude

At sea level (SL) and following 3–10 days at high altitude (HA) (5050 m), Ainslie et al. (2012) measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined alpha- and beta-adrenergic blockade. Dynamic cerebral autoregulation was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Arterial PCO₂ and ventilation and the hypercapnic ventilator response were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated but MCAv remained unchanged. Blockade reduced MAP just significantly more at HA than at SL (26 vs. 15%, P=0.048). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced it comparably at SL and HA. Blockade had little effect on cerebral autoregulation at altitude.

Possible Effect of High Altitude on Cerebral Metabolic Rate (CMRO₂)

In an effort to identify the causes of acute mountain sickness (AMS), Smith et al. (2012) studied 26 normal human subjects divided into 2 clearly different groups, AMS− and AMS +, based on Lake Louise AMS scores <2 and >5 (not including those between 2 and 5). CMRO₂ was calculated from cerebral blood flow (CBF) and arterial-venous difference in O₂ content. CBF was measured using arterial spin labeling MRI, venous O₂ saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Measurements were made during normoxia and on the second day at 3800 m. No differences were found between AMS− and AMS+ groups. However, surprisingly, in all subjects CMRO₂ was increased at 3800 m from 1.54±0.37 to 1.82±0.49 μmol/g/min (n=26, P=0.045). The authors hypothesize that the low P_ETCO₂ of 32±2.5 torr, (normal at this altitude on day 2) may have increased CMRO₂. Most former work has not supported such an effect.

Detecting Cognitive Decline in Long Term Dwelling Above 4300 m Altitude

High altitude has been associated with hippocampal atrophy and cognitive impairment in mountaineers. Hota et al. (2012) validated a new multi-domain cognitive screening test (MDCST) by comparing it in a group of 28 individuals with two older standard tests: Mini Mental State Examination (MMSE) and Clinical Dementia Rating. The MDCST battery with EEG was then validated on 843 lowlanders staying at high altitudes >4300 m for over a year and 862 subjects sea level. The new MDCST test found mild cognitive impairment in 12.4% of altitude dwellers vs 1.2% in lowlanders. The MDCST was 3 times more sensitive than MMSE in detecting decline in immediate recall, procedural memory and mind body coordination at altitude, changes that were negligible in lowlanders.

Genetic Differences in Subjects with History of High Altitude Pulmonary Edema (HAPE)

Mishra et al. (2012) report an extensive genetic study of hypoxia related genes in 250 HAPE-s (susceptible) subjects (history of HAPE), compared with 210 HAPE-n (non-susceptible) and 430 normal high altitude natives in Ladakh. The master hypoxia response gene HIF-prolyl hydroxylase 2 (EGLN1), an oxygen sensor, has a major role in hypoxia response. The authors screened 30 polymorphisms of EGLN1, evaluated its gene expression and performed association analyses. In addition, the role of allelic variants in altering transcription factor (TF)-binding sites and consequently the replacement of TFs at these loci was also investigated. The genotypes of seven polymorphisms, rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736 and rs973252 differed significantly between HAPE-s and HAPE-n. These were identified as risk genotypes and their counterpart homozygotes, prevalent in the HAPE-n group, were identified as protective. The authors conclude that the upregulation of EGLN1 expression in HAPE-s is significantly associated with the risk genotypes and their haplotypes and interacted-genotypes.

Mitochondrial Haplotypes Correlated with High Altitude Pulmonary Edema (HAPE) in Han Chinese

Luo et al. (2012) recruited 204 HAPE patients and 174 healthy controls in Tibet (3658 m above sea level), all Han Chinese. They report that mtDNA haplogroup D4 is associated with resistance to HAPE, while haplogroup B4c is a genetic risk factor.

How Does Altitude Cause Fetal Pulmonary Arterial Thickening?

The high altitude lamb fetus pulmonary arteries were found by Yang et al. (2012) to have reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of cyclin-dependent kinase inhibitor p21. Treatment with histone deacetylase (HDAC) inhibitor trichostatin A decreased the smooth muscle cellular proliferation rate, in part, due to altered expression of p21, decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. The authors propose that in chronic hypoxia, loss of p21 leads to epigenetic reduction of histone acetylation and DNA methylation leading to fetal pulmonary hypertension.

Three Reviews of Altitude and Pulmonary Physiologic Historical Interest

Readers may be interested in John West's clinical review of high altitude medicine (2012a), his essay on the physiological legacy of the Fenn, Rahn, and Otis school (2012b), and the role of the fragility of the pulmonary blood-gas barrier in the evolution of the pulmonary circulation (2012c).