Cerebral Oxygen Consumption at Altitude

Several previous studies have found CMRO₂ to remain constant during acclimatization to altitude, and perhaps to be reduced in natives at high altitude. Using new MRI methodology, Smith et al (2013) measured CMRO₂ and cerebral blood flow (CBF) at sea level by MRI. CBF was determined by arterial spin labeling and CMRO₂ was calculated from venous saturation determined by MRI transverse relaxation in the superior saggital sinus. Twenty six subjects (half female) were studied before and after 40 hr at 3810 m altitude. At the end of the altitude period, each subject was kept hypoxic at his final altitude SpO₂ by mask with continuously adjusted FIO₂ during transport to sea level and in the MRI. CBF was 25% increased, but, differing from prior reports, CMRO₂ was higher than normoxic control (p=0.045). The authors suggest this was due to excitability caused by the low PCO₂ (or by wearing a mask in the MRI?)

Keratinocyte Growth Factor-2 (KGF-2) Effectively Prevents High Altitude Pulmonary Edema (HAPE) in Rats

KGF-2, also known as fibroblast growth factor (FGF)-7, reduces lung injury induced by bleomycin and prevents alveolar epithelial cell DNA damage in vitro. Jun She et al (2012) used their previously developed rat model of HAPE to evaluate the effects of intratracheal instillation of 5 mg/kg of KGF-2 72 hrs before hypoxic-exercise exposure, on mortality, lung liquid balance and lung histology They found that pre-treatment with KGF-2 (5 mg/kg) significantly decreased mortality (to zero), improved oxygenation, reduced lung wet-to-dry weight ratio and increased alveolar fluid clearance. Histological examination showed it prevented alveolar-capillary barrier disruption. It significantly reduced the hypoxically increased transendothelial permeability. Endothelial cell apoptosis was decreased due to a 10-fold increase of Akt activity. KGF-2 is a candidate for the prevention of HAPE.

History of Understanding Pulmonary Capillary Fragility

The very thin pulmonary capillary wall, measured by electron microscopy, was suspected of easy damage by pulmonary capillary hypertension. The history of discovery of evidence showing stress failure is reviewed by West (2013).

Retrospectives on Insights Gained from High Altitude Population Studies

The many investigations of human populations in the high Andes, Tibet and others have revealed both unsuspected differences and similarities in adaptation to altitude. Beall (2013) presents and illustrates major concepts and research designs in published high-altitude studies and their contributions to the improved understanding of evolution and adaptation. The discovery that Andean biological patterns were not replicated among Tibetan highlanders stimulated research on the extent and origins of the contrasts. It also shifted emphasis to a multiple population - single stress study design. The discovery of oxygen-homeostasis-associated genetic loci and traits in all multicellular animals has transformed high-altitude research.

Andean-Tibetan Genetic Differences Related to Hemoglobin Concentration

Previous studies showed that high altitude Tibetans have less polycythemia than Andeans. Bigham et al (2013) found no association in 10 Andeans between hemoglobin levels and the single nucleotide polymorphism (SNP) genotype EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1). In Tibet, these two genes are significantly correlated with hemoglobin levels. Prior studies found that both populations positively selected EGLN1.

Differences in O₂ Transport in Highland Mice Blood Are not Genetic

Some long-term high altitude mammalian populations have genetic differences from their low altitude relatives. To test whether long term dwelling at altitude has genetically altered blood O₂ transport characteristics, Tufts et al (2012) transported Rocky Mountain high altitude deer mice to low altitude for 6 weeks. All abnormalities in blood O₂ transport, higher hemoglobin concentrations, higher hematocrits, higher erythrocytic concentrations of 2,3-DPG, lower mean corpuscular hemoglobin concentrations, and smaller red cells, reverted to the normal sea level mice levels.

Anxiety Increases Acute Mountain Sickness (AMS) and Insomnia During High Altitude Acclimatization

Dong et al (2013) used Lake Louise scores for AMS and a self-rating anxiety scale (SAS) and scales for sleepiness and insomnia in 426 young males age 18–24 ascending to 3600m and after 40 days to 4400m. The 11% who reported anxiety (by SAS) had more severe physical symptoms, more severe insomnia, increased heart rate and were more likely to develop AMS.

Effectiveness of Preacclimatization Strategies Before High-Altitude Exposure

Acute mountain sickness (AMS) and large decrements in endurance exercise performance occur when unacclimatized individuals rapidly ascend to high altitudes. Six altitude and hypoxia preacclimatization strategies were evaluated to determine their effectiveness for minimizing AMS and improving performance during altitude exposures by Fulco, Beidleman and Muza (2013). They report that strategies using hypobaric chambers or true altitude were much more effective overall than those using normobaric hypoxia, either by mask or in closed space.

Is High Altitude Headache Due to Cerebral Venous Distention?

Wilson et al (2013) review studies of their postulate that high altitude headache results when hypoxia-associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. Gadolinium-enhanced magnetic resonance venography showed narrowing of one or both transverse venous sinuses in acute hypoxia. In 24 subjects ascending to 5300 m, retinal venous distension (RVD) correlated with headache severity.

Optic Nerve Sheath Diameter (ONSD) by Ultrasound at Altitude

New technology made it possible to test ONSD as an index of intracranial pressure and compare it with acute mountain sickness (AMS) in a group of 57 sea level normals after rapid ascent to 4300 m altitude (Keyes et al., 2013). Due to scatter and small changes, their data did not support a role for increased ICP in mild to moderate AMS.

Central Sleep Apnea Episode Frequency Increases with Acclimatization to High Altitude

It has been reported that sleep apnea problems increase with days and weeks of partial acclimatization. Burgess et al (2013) tested possible association of sleep apnea with the slow fall of CBF over the first weeks at altitude. 12 subjects were studied initially and after 2 weeks at 5050m. They confirmed that the apnea-hypopnea index (AHI) increased 50% over 2 weeks whereas the large cyclic rises of CBF and the associated acute changes of PCO₂ with apneic events diminished with acclimatization. The authors suggest that these early greater elevations in CBF and cyclic changes of PCO₂ have a “protective” effect during sleep. No evidence of acute mountain sickness or other undesired effects associated with sleep apnea were studied, so the word “protective” is inappropriate. I would argue that the early greater hyperventilatory response to apnea drove PCO₂ down more and raised PO₂ more in the first days, lengthening the delay before subsequent apneic awakening by hypoxemia. I also therefore suggest that this is not a finding for a role of cerebrovascular function as stated in the title.

High Blood Hemoglobin Level in Young Adults Related to Sleep Apneas and Desaturation

Chronic mountain sickness (CMS) or polycythemia occurs in many older long-term residents of high altitudes, especially in the Andes. A survey of 1149 male high altitude (3600–4100 m) residents between the ages of 18 and 25 was conducted in order to identify young males with excessive erythrocytosis (EE), termed “preclinical CMS,” and healthy controls. Julian et al (2013) compared 20 EE with mean hemoglobin 19.3 (≥18.3) g/dl with 19 controls (Hb=16.6 g/dl). The EE group had a 4-fold higher sleeping apnea-hypopnea index, a 4% lower nocturnal minimal SaO_2, and 30% more oxidative stress (8-iso-PGF2α) than controls. The authors suggest that disordered breathing may play an etiologic role for the development of CMS. Identifying and subsequently treating sleep-disordered breathing patterns in young, permanent high-altitude residents may slow or prevent the development of CMS.

Acetazolamide Improves Sleep in Acute Altitude Hypoxia in Patients with Obstructive Sleep Apnea

The improvement in sleep at altitude offered by acetazolamide (AZ) is well known. Here, Latshang et al (2012) extend this to patients with known low altitude obstructive sleep apnea problems, who spent a few nights at intermediate altitude (1630 m and 2590 m). Patients in the study continued their use of CPAP help at altitude. Use of AZ in 51 patients reduced incidence of SpO₂<90% from 57% to 13% at 2590 m.

Females are Less Affected by Periodic Breathing at Altitude

Lombardi et al (2013) compared sleep periodicity in 23 men and 14 women during the first 2 nights at high altitude. Apnea-hypopnea indices were 40 vs 2 at 3400 m and 87 vs 41 at 5400 m. A similar difference continued after 10 days at 5400 m.

Infant Carotid Body Role in Periodic Breathing

Edwards, Sands and Berger (2013) use the concept of loop gain to obtain quantitative insight into the genesis of unstable breathing patterns with a particular focus on how changes in carotid body function could underlie the age-related dependence of periodic breathing during the first year in infants.

Muscle Mitochondrial Oxidative Capacity and Efficiency at Altitude

Jacobs et al (2012) biopsied vastus muscle in 8 normal men before and after a 28 d exposure to 3454 m. Both VO_2max and mitochondrial oxidative capacity decreased without changes in mitochondrial content and with increased mitochondrial coupling efficiency. A partly different team, repeating this experiment after 9-11 days at 4559 m in 10 subjects (Jacobs et al., 2013), found that mitochondrial function was largely unaffected, because high-altitude exposure did not affect the capacity for fat oxidation or individualized respiration capacity through either complex I or complex II. Respiratory chain function remained unaltered, because neither coupling nor respiratory control changed in response to brief hypoxic exposure.

Respiratory Muscle O₂ Consumption Fraction of VO₂ max

Wilhite et al (2013) estimated the fraction of the total increase of O₂ consumption at maximum work due to respiratory muscles in runners training at altitude. Six elite male distance runners completed a 28-day “live high–train low” training intervention (living at 2150 m) and were compared retrospectively with a larger group of distance runners (n=22). They conclude that respiratory muscles contribute about 37 % of the total increase of VO₂ max at altitude. The slow decay in hyperventilation following return to sea-level may have an impact on competitive performance.

Complex Interactions of Chronic Hypoxia and Caffeine on Ventilation

The isocapnic hypoxic ventilatory response in humans doubles over 2 weeks at high altitude. Conde et al (2012) find a similar sensitization in rats. They find that chronic caffeine intake (in rats) increases the ventilatory response to acute hypoxia in normoxic rats but not in chronically hypoxic rats. Because the ventilatory changes do not correlate well with carotid chemoreceptor nerve output, they conclude that chronic caffeine ingestion alters many of the carotid body effects of chronic hypoxia, leading to a loss of acclimatization sensed as carotid body output, but, at the same time, causes at the brainstem level an increase in the gain of the carotid body input reading leading to maintenance of chronic hypoxia acclimatization in the ventilatory parameters.

Pulse Oximeter Accuracy in Military Cold Weather Altitude Training

Ross et al (2013) compared portable pulse oximeter data with blood gas analysis in 49 recruits training at high altitude in cold environments at 2100 m altitude, with all subjects showing SaO2>90%. The original Nonin “Onyx” and a variety of “PalmSat” devices averaged 2–3% higher than the ABG measurements with standard deviations of 2–3%. No data is available at extreme altitude except for David Brashears who said his finger Onyx read 75% at Everest summit. However, Grocutt found mean SaO₂=54% in 4 climber-physicians sampling arterial blood in each other while breathing ambient air at 8400 m on the Xtreme Everest trip. More data needed!

Altitude and Blood Oxygen Dissociation Changes of Affinity

The rise of pH at altitude due to hyperventilation shifts the oxygen dissociation curve left, increasing SaO₂. Balaban et al (2013) incorrectly claim that they have performed the first in-vivo study of the role of this long established effect on acclimatization.

Possible Role of VEGF and its Receptors in Modeling Hypoxic Fetal Ovine Carotid Artery Proteins

Adeoy et al (2013) support the hypothesis that in chronically hypoxic ovine fetal arteries the VEGF system contributes to hypoxic vascular remodeling through changes in the abundance, organization and function of contractile proteins. The effects were blocked by the two known VEGF receptor antagonists.

Complex l Energy for Placental Active Transport of Nutrients is 45% Low at High Altitudes

Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Colleoni et al (2013) report that placental mitochondrial respiration in cultured trophoblast-like JEG3 cells from high altitude pregnancies was reduced by about half compared with sea level pregnancies. Complex IV-supported respiration was also lower. They conclude that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.