Effects of Iron Supplementation and Depletion on Hypoxic Pulmonary Hypertension

Smith and colleagues (2009) report that hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. Two randomized, double-blind, placebo-controlled protocols were conducted in October–November 2008 at Cerro de Pasco, Peru (altitude 4340 m). Twenty-two healthy sea-level-resident men (aged 19 to 60) were studied over 1 week at altitude, and 11 high-altitude-resident men (aged 30 to 59) diagnosed with chronic mountain sickness (CMS, polycythemia) were studied over 1 month. On day 3 of hypoxia, sea- level subjects received intravenously Fe^III-hydroxide sucrose (200 mg) or placebo. CMS subjects underwent staged isovolemic venesection of 2 L of blood and 2 weeks later received IV Fe^III-hydroxide sucrose (400 mg) or placebo. The iron and placebo groups were reversed later. The effect of varying iron availability on pulmonary artery systolic pressure (PASP) was assessed by Doppler echocardiography. In the sea-level residents, iron reduced PASP from 37 to 31 mmHg (p = 0.01). In CMS subjects, progressive iron deficiency induced by venesection was associated with a PASP rise from 37 to 46 mmHg (p = 0.003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected.

Pulmonary Arterioles Stiffened by 8 h of Hypoxia

Pulmonary vasculature fails to dilate normally with exercise after long exposures to the hypoxia of high altitude. Herigstad and Robbins (2009) find the same effect with only 8 h of hypoxia. Ten subjects were studied on two separate days. On one day, subjects were exposed to 8 h of isocapnic hypoxia (end-tidal Peto₂ = 55 torr) and on the other day to 8 h of euoxia as a control. Before and after each exposure, subjects undertook 20 min of exercise at an intensity to elevate heart rate (HR) by approximately 30 bpm. During this period, Doppler echocardiography was used to assess the maximum pressure gradient during systole across the tricuspid valve (ΔP_max) as an index of pulmonary arterial pressure. Following 8-h hypoxia, but not control, ΔP_max increased by approximately 2 mmHg with the subjects breathing air at rest. Under control conditions, exercise at approximately 30 bpm above resting HR increased ΔP_max by 9.9 ± 1.3 mmHg (SE). Following 8-h hypoxia, but not control, this sensitivity of ΔP_max to exercise increased 35% to 13.4 ± 2.1 mmHg.

Continuous Positive Airway Pressure (CPAP) Improves Sao₂ on 2nd but Not 10th Day at High Altitude

Agostoni and colleaguees (2009) applied 7 cm H₂O CPAP for 30 min to healthy individuals 2 days after climbing to Capanna Margherita (CM, 4559 m) and 10 days after arrival at Everest Base Camp (EBC, 5350 m). At CM, CPAP reduced heart rate and systolic pulmonary artery pressure and increased Sao₂ from 80% to 91% (p < 0.001). During 10 days at EBC, Sao₂ gradually rose from 77% to 86% (p < 0.001). CPAP on day 10 did not further increase Sao₂ . The authors conclude that shortly after climbing lung has enough subclinical high altitude pulmonary edema (HAPE) to impair pulmonary gas exchange that is minimized by CPAP. After 10 days of altitude exposure, the initial alveolar fluid in subclinical HAPE is absent, so CPAP has no effect on Sao₂. The surprisingly large improvement in early HAPE suggests that significant shunting occurs from fluid-induced atelectasis even with minimal symptoms of HAPE.

Subclinical Interstitial Pulmonary Edema in Healthy Climbers During First Days at Altitude

Pellegrino and colleagues (2009) confirm that acute exposure to altitude in nonacclimatized lowlanders leads to subclinical interstitial pulmonary edema that lasts for several days after ascent. Fourteen healthy subjects were studied at 4559 and at 120 m altitude. At high altitude, both static and dynamic lung compliances and respiratory reactance at 5 Hz significantly decreased, suggestive of interstitial pulmonary edema. They show that airway responsiveness to methacholine at high altitude is well preserved despite the occurrence of interstitial pulmonary edema.

Pulmonary Function Testing Fails to Show Interstitial Edema at 4559 m Altitude During First 2 Days

Comprehensive lung function testing failed to disclose interstitial pulmonary edema in mountaineers without HAPE (Dehnert et al., 2009). In 34 mountaineers without high altitude pulmonary edema (HAPE) during the first 2 days at 4559 m altitude, there was no statistically significant difference in total lung capacity, forced vital capacity, closing volume, and lung compliance between low and high altitude, whereas diffusing capacity increased at high altitude. There was no difference in airway resistance and bronchodilator responsiveness to salbutamol. There were no significant differences in these parameters between mountaineers with and without acute mountain sickness. Mild alveolar edema on radiographs in HAPE was associated with only a minor decrease in forced vital capacity, diffusing capacity, and lung compliance and a minor increase in closing volume. Pulmonary function mechanics tests may not be sensitive enough to detect interstitial pulmonary fluid accumulation.

Ultra-Endurance Climbing at Moderate Altitude Unaffected by Dietary Protein–Carbohydrate Ratio

Bourrilhon and colleaguees (2009) investigated the effects of a 30% protein versus a 68% carbohydrate (CHO) diet on performance and physiological responses during an ultra-endurance climbing race at moderate altitude. In two different periods, in a randomized crossover design, 10 climbers (30.0 ± 0.9 yr) participated in the race. No differences in performance were found to be related to diet.

Hydration Status Affects Responses to Normobaric Hypoxic Walking Exercise

Richardson and colleagues (2009) studied 8 males who completed 2 h of intermittent walking tests under normobaric hypoxia (Fio₂ = 0.13) after controlled hyperhydration, hypohydration, and euhydration. They report that significant alterations of heart rate, core temperature, peripheral arterial oxygen saturation, and urine osmolarity were closely correlated with an environmental symptoms questionnaire, Lake Louise questionnaire, and headache scores.

Impact of Acute 4300-m Altitude Hypoxia on Performance Halved by 6-Day Staging at 2200 m

Partial acclimatization resulting from staging at moderate altitude reduces acute mountain sickness during rapid exposure to higher altitudes. In 10 healthy men during 720-kJ cycle time trials, Fulco and colleagues (2009) report that staging at 2200 m for 6 days decreased by half the decrement in time trial (TT) performance of unacclimatized sea-level residents (SLR) during rapid exposure to 4300 m (459 torr). Compared to SL TT (73 ± 6 min), performance was impaired (p < 0.01) by 38.1 ± 6 min (unstaged), but only by 18.7 ± 3 min (staged). The improvement was directly correlated with increases in exercise Sao₂ (p < 0.03), but not to changes in [Hb] or Hct.

Cause of Acute Mountain Sickness not Edema but Perhaps Free Radicals

Acute mountain sickness (AMS) is traditionally ascribed to intracranial hypertension caused by extracellular vasogenic edematous brain swelling subsequent to mechanical disruption of the blood–brain barrier in hypoxia. However, recent diffusion-weighted magnetic resonance imaging studies have identified mild astrocytic swelling caused by a net redistribution of fluid from the "hypoxia-primed" extracellular space to the intracellular space, without any evidence for further barrier disruption or additional increment in brain edema, swelling, or pressure. Minor vasogenic edema may be present in individuals without AMS. Bailey and colleagues (2009) suggest AMS may result from free radicals and their interaction with the trigeminovascular system.

No Cognitive Impairment after Gradual Ascent to 5100 m

Harris and colleagues (2009) performed a prospective, controlled, repeated-measures study of cognitive skills in 26 trekkers using written, verbal, and computerized tests at 400 m altitude and within 24 h of arrival at 5100 m after an 18-day ascent. No individual demonstrated significant cognitive impairment at 5100 m. Computerized testing produced less variable results than written testing.

Normalization of Some Antioxidants Was Delayed 14 Days after Ending Altitude Training and Sleeping

Antioxidant status has been found altered by the live high, train low (LHTL) method. Pialoux and colleagues (2009) now report that some factors of the antioxidant status remain impaired 14 days after return to normoxia following 18 days LHTL in elite athletes. Eleven elite cross-country skiers from the French Skiing Federation were studied. Six in the hypoxic group trained at 1200 m and lived in hypoxia (simulated altitudes of 2500, 3000, and 3500 m), and 5 (control group) trained and lived at 1200 m. In the hypoxic group the trolox equivalent antioxidant capacity (TEAC) lipid-soluble antioxidants (α-tocopherol, β-carotene, and lycopene) were decreased at the end of LHTL and remained low for 14 normoxic days.

Permanent Alveolar Remodeling in Canine Lung Induced by High Altitude Residence During Maturation

Prior studies showed that young canines born at sea level and raised for 5 months at 3800 m altitude, followed by return to SL before somatic maturation, had enhanced alveolar gas exchange and diffusing capacity at rest and exercise that persisted into adulthood. In male foxhounds raised similarly at 3800 m, Ravikumar and colleagues (2009) report acinar remodeling that increased lung compliance and reduced the resistance of the blood–gas diffusion barrier to diffusion that persisted into adulthood, but without permanent enhancement of alveolar tissue growth. Lung volume at a given inflation pressure was higher with enlargement of the alveolar ducts and sacs, without significant differences in the volumes of alveolar cell components or septal tissue or in alveolar-capillary surface areas. There was a shift toward a lower harmonic mean thickness of the blood–gas diffusion barrier.

Fragmentation of Human Erythrocyte Actin Following Exposure to Hypoxia

In a comparative study on erythrocytes (RBCs) drawn from mountaineers before and after a high altitude stay, Risso and colleagues (2009) observed that, upon returning to sea level, RBCs displayed a senescentlike phenotype, as indicated by their density and the partial loss of membrane proteins shed by aging RBCs. The proteins of RBC ghosts obtained before and after returning to sea level, studied by two-dimensional electrophoresis and mass spectrometry, showed lower expression and fragmentation of β-actin and cytoskeleton instability after exposure to hypoxia. Alteration in membrane skeleton structure was confirmed by β-actin release in cell lysates during ghost preparation.

Coagulation Parameters Altered During Extreme Climb

Pichler-Hefti and colleagues (2009) report significant alterations of some coagulation parameters in 34 healthy mountaineers randomized to fast or slow acclimatization protocols during an expedition on Muztagh Ata (7549 m) in China. Tests were performed at five altitudes up to 6865 m. No significant relationship between investigated parameters and AMS scores could be detected. Faster ascent increased abnormalities.

Effects of 13 Months at Altitude on Platelet Count and Fibrinogen in Sea-Level Normal Men

Vij (2009) reports significant reduction in platelet count and rise in plasma fibrinogen in 40 healthy sea-level native men following 3- and 13-month sojourns at high altitude (4100 to 4500 m). Platelet count decreased by 12% and 31% after 3- and 13-month stays. Mean platelet volume increased from 9.18 ± 0.83 fL at sea level to 10.8 ± 0.98 after 3 months and to 12.15 ± 1.18 fL at 13 months. Plasma fibrinogen concentration was 53% higher after 3 months and 61% higher after 13 months.

Human Placentas Show Less Oxidative Stress at High Altitude

Tissot van Patot and colleagues (2009) previously demonstrated that placentas from laboring deliveries at high altitude have lower binding of hypoxia-inducible transcription factor (HIF) to DNA than those at low altitude. It has recently been reported that labor causes oxidative stress in placentas, likely due to ischemic hypoxic insult. The authors now report that placentas subjected to labor from pregnancies at sea level display evidence of oxidative stress. However, equivalent placentas at 3100 m have little or no oxidative stress at the time of delivery, suggesting greater resistance to ischemia–reperfusion. Full-thickness placental tissue biopsies were collected from laboring vaginal and nonlaboring C-section term (37 to 41 weeks) deliveries from healthy pregnancies at sea level and 3100 m. After freezing in liquid nitrogen within 5 min of delivery, hydrophilic and lipid metabolites were quantified using ³¹P and ¹H magnetic resonance spectroscopy metabolomics. Metabolic markers of oxidative stress, increased glycolysis, and free amino acids were present in placentas following labor at sea level, but not at 3100 m. In contrast, at 3100 m the equivalent placentas were characterized by the presence of phosphocreatine, antioxidants, and low free amino acid concentrations. They postulate that hypoxic preconditioning might occur in placentas that develop at high altitude.

Maternal Hemoglobin Level and Fetal Outcome at Low and High Altitudes

Both low (<7 g/dL) and high (>14.5 g/dL) maternal hemoglobin [Hb] levels have been related to poor fetal outcome. Gonzales and colleagues (2009) show that this relationship exists at both high and low altitudes. They also report an adverse effect of high altitude on fetal outcome independent of the level of maternal hemoglobin, using a retrospective multicenter analysis of 35,449 pregnancies at sea level (Lima, Peru) and at six cities above 3000 m. In analyses of all women at both altitudes, those with [Hb] < 9 g/dL had increased stillbirths and preterm and small for gestational age (SGA) births compared with women with [Hb] = 11 to 12.9 g/dL, differing little with altitude. Women living at high altitude with [Hb] > 15.5 g/dL had higher risks for stillbirths and preterm and SGA births. There was also a significant adverse effect of living at high altitude, independent of hemoglobin level, for stillbirths, preterms, and SGA.

Incidence of Anemia in Pregnant Tibetan Dwellers

Hemoglobin and sociodemographic data were obtained by Xing and colleagues (2009) from the hospital-based records of 380 pregnant women in Lhasa. Sociodemographic information was related to [Hb] data by multiple linear regression and multiple logistic regression using models of the Centers for Disease Control (CDC), Dirren and colleagues, and Dallman and colleagues. The mean hemoglobin concentration was 127.6 g/L (range: 55.0 to 190.0 g/L). The prevalence rate of anemia was 70.0%, 77.9%, and 41.3%, respectively, for the three models. Gestational age, ethnicity, residence, and income were significantly associated with anemia.

Exhaled Nitric Oxide Reduced by Low Barometric Pressure, Not Low Po₂

The reduction of exhaled NO pressure at high altitude has been assumed to be due to hypoxia. Hemmingsson and Linnarsson (2009) studied exhaled NO partial pressures (PeNO) in 8 healthy subjects at 5000-m altitude (chamber) and at sea level with 11.3% O₂ equivalent hypoxia (Pio₂ = 10.7 kPa), at equal exhaled flows of 50 mL/sec. PeNO readings were corrected for gas density effects on the instrument performance. Sea-level control values for PeNO averaged 2.4 mPa and were virtually unchanged with normobaric hypoxia. At the same Pio₂, hypobaric PeNO was 1.4 mPa, a 33 ± 16% (SD) reduction. The authors propose that hypobaria permitted enhanced axial back-diffusion of NO because of the reduced gas density, with an associated increased alveolar NO uptake to the blood.