The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema

High-altitude pulmonary edema (HAPE), a severe form of altitude illness that can occur in young healthy individuals, is a noncardiogenic form of edema that is associated with high concentrations of proteins and cells in bronchoalveolar lavage (BAL) fluid (Schoene et al., J. Am. Med. Assoc. 256: 63-69, 1986). We hypothesized that acute mountain sickness (AMS) in which gas exchange is impaired to a milder degree is a precursor to HAPE. We therefore performed BAL with 0.89% NaCl by fiberoptic bronchoscopy in eight subjects at 4,400 m (barometric pressure = 440 Torr) on Mt. McKinley to evaluate the cellular and biochemical responses of the lung at high altitude. The subjects included one healthy control (arterial O2 saturation = 83%), three climbers with HAPE (mean arterial O2 saturation = 55.0 +/- 5.0%), and four with AMS (arterial O2 saturation = 70.0 +/- 2.4%). Cell counts and differentials were done immediately on the BAL fluid, and the remainder was frozen for protein and biochemical analysis to be performed later. The results of this and of the earlier study mentioned above showed that the total leukocyte count (X10(5)/ml) in BAL fluid was 3.5 +/- 2.0 for HAPE, 0.9 +/- 4.0 for AMS, and 0.7 +/- 0.6 for controls, with predominantly alveolar macrophages in HAPE. The total protein concentration (mg/dl) was 616.0 +/- 3.3 for HAPE, 10.4 +/- 8.3 for AMS, and 12.0 +/- 3.4 for controls, with both large- (immunoglobulin M) and small- (albumin) molecular-weight proteins present in HAPE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise exacerbates acute mountain sickness at simulated high altitude.

We hypothesized that exercise would cause greater severity and incidence of acute mountain sickness (AMS) in the early hours of exposure to altitude. After passive ascent to simulated high altitude in a decompression chamber [barometric pressure = 429 Torr, approximately 4,800 m (J. B. West, J. Appl. Physiol. 81: 1850-1854, 1996)], seven men exercised (Ex) at 50% of their altitude-specific maximal workload four times for 30 min in the first 6 h of a 10-h exposure. On another day they completed the same protocol but were sedentary (Sed). Measurements included an AMS symptom score, resting minute ventilation (VE), pulmonary function, arterial oxygen saturation (Sa(O(2))), fluid input, and urine volume. Symptoms of AMS were worse in Ex than Sed, with peak AMS scores of 4.4 +/- 1.0 and 1.3 +/- 0.4 in Ex and Sed, respectively (P < 0.01); but resting VE and Sa(O(2)) were not different between trials. However, Sa(O(2)) during the exercise bouts in Ex was at 76.3 +/- 1.7%, lower than during either Sed or at rest in Ex (81.4 +/- 1.8 and 82.2 +/- 2.6%, respectively, P < 0.01). Fluid intake-urine volume shifted to slightly positive values in Ex at 3-6 h (P = 0.06). The mechanism(s) responsible for the rise in severity and incidence of AMS in Ex may be sought in the observed exercise-induced exaggeration of arterial hypoxemia, in the minor fluid shift, or in a combination of these factors.     

急性高原暴露后左心功能变化及与急性高原病的关系

目的：研究青年男性由平原急进高原后心脏血流动力学变化及其与急性高原病的关系。方法：分别检测218名健康青年男性在平原及急进高原24h内的血压、心卒和血氧饱和度,使用彩色多普勒超声仪检测左心功能;根据路易斯湖评分标准将受试者分为急性高原病纽（AMS组）和无急性高原病组（无AMS组）。结果：急性高原暴露后心率、舒张压、平均动脉压、左室射血分数、每搏输出量、每博指数、心输出量、心脏指数显著增加（P〈0．05）,血氧饱和度、左室收缩末容积则显著降低（P〈0．05）;急进高原后AMS组心率、收缩压、平均动脉压显著高于无AMS组（P〈0．05）,每博指数、左室舒张末容积显著低于无AMS组（P〈0．05）。结论：健康男性青年急性高原暴露后左心室收缩功能增强,左室舒张末容积、心率、每博指数可能作为预测急性高原病的参考指标。     

Effect of repeated normobaric hypoxia exposures during sleep on acute mountain sickness, exercise performance, and sleep during exposure to terrestrial altitude

There is an expectation that repeated daily exposures to normobaric hypoxia (NH) will induce ventilatory acclimatization and lessen acute mountain sickness (AMS) and the exercise performance decrement during subsequent hypobaric hypoxia (HH) exposure. However, this notion has not been tested objectively. Healthy, unacclimatized sea-level (SL) residents slept for 7.5 h each night for 7 consecutive nights in hypoxia rooms under NH [n = 14, 24 ± 5 (SD) yr] or "sham" (n = 9, 25 ± 6 yr) conditions. The ambient percent O(2) for the NH group was progressively reduced by 0.3% [150 m equivalent (equiv)] each night from 16.2% (2,200 m equiv) on night 1 to 14.4% (3,100 m equiv) on night 7, while that for the ventilatory- and exercise-matched sham group remained at 20.9%. Beginning at 25 h after sham or NH treatment, all subjects ascended and lived for 5 days at HH (4,300 m). End-tidal Pco(2), O(2) saturation (Sa(O(2))), AMS, and heart rate were measured repeatedly during daytime rest, sleep, or exercise (11.3-km treadmill time trial). From pre- to posttreatment at SL, resting end-tidal Pco(2) decreased (P < 0.01) for the NH (from 39 ± 3 to 35 ± 3 mmHg), but not for the sham (from 39 ± 2 to 38 ± 3 mmHg), group. Throughout HH, only sleep Sa(O(2)) was higher (80 ± 1 vs. 76 ± 1%, P < 0.05) and only AMS upon awakening was lower (0.34 ± 0.12 vs. 0.83 ± 0.14, P < 0.02) in the NH than the sham group; no other between-group rest, sleep, or exercise differences were observed at HH. These results indicate that the ventilatory acclimatization induced by NH sleep was primarily expressed during HH sleep. Under HH conditions, the higher sleep Sa(O(2)) may have contributed to a lessening of AMS upon awakening but had no impact on AMS or exercise performance for the remainder of each day.     

Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema

To examine whether intravascular coagulation and/or decreased fibrinolysis precedes high-altitude pulmonary edema (HAPE) we examined 25 male mountaineers (median age 40 yr) at low altitude (550 m) and after 6, 18, and 42 h at an altitude of 4,559 m, which was climbed in 24 h. In 14 subjects, 2 of whom showed radiological evidence of HAPE after 42 h, symptoms of acute mountain sickness (AMS) were mild or absent. Eleven subjects suffered from AMS, six of whom developed radiologically documented HAPE after 18 or 42 h. In the absence of AMS there were no significant changes at high altitude, with the exception of a decrease in bleeding time from 246 +/- 18 to 212 +/- 13 (SE) (P less than 0.05). In AMS, partial thromboplastine time decreased from 34.2 +/- 0.8 to 31.1 +/- 0.5 s (P less than 0.001) and factor VIII procoagulant activity and von Willebrand factor antigen were increased by 57 +/- 12 and 70 +/- 13%, respectively (P less than 0.001), whereas there were no significant changes in beta-thromboglobulin (BTG), fibrinopeptide A (FPA), and fibrin fragment B beta 15-42. In subjects with HAPE, BTG, FPA, and B beta 15-42 were normal before and in beginning HAPE. Preceding HAPE, euglobulin clot lysis time declined at high compared with low altitude from 289 +/- 48 to 201 +/- 42 min without venous occlusion (VO) and from 107 +/- 36 to 86 +/- 31 min after VO (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.     

Structural and functional changes of the human macula during acute exposure to high altitude

Background

This study aimed to quantify structural and functional changes at the macula during acute exposure to high altitude and to assess their structure/function relationship. This work is related to the Tuebingen High Altitude Ophthalmology (THAO) study.

Methodology/Principal Findings

Spectral domain optical coherence tomography and microperimetry were used to quantify changes of central retinal structure and function in 14 healthy subjects during acute exposure to high altitude (4559 m). High-resolution volume scans and fundus-controlled microperimetry of the posterior pole were performed in addition to best-corrected visual acuity (BCVA) measurements and assessment of acute mountain sickness. Analysis of measurements at altitude vs. baseline revealed increased total retinal thickness (TRT) in all four outer ETDRS grid subfields during acute altitude exposure (TRT_outer = 2.80±1.00 μm; mean change±95%CI). This change was inverted towards the inner four subfields (TRT_inner = −1.89±0.97 μm) with significant reduction of TRT in the fovea (TRT_foveal = −6.62±0.90 μm) at altitude. BCVA revealed no significant difference compared to baseline (0.06±0.08 logMAR). Microperimetry showed stable mean sensitivity in all but the foveal subfield (MS_foveal = −1.12±0.68 dB). At baseline recordings before and >2 weeks after high altitude exposure, all subjects showed equal levels with no sign of persisting structural or functional sequels.

Conclusions/Significance

During acute exposure to high altitude central retinal thickness is subject to minor, yet statistically significant changes. These alterations describe a function of eccentricity with an increase in regions with relatively higher retinal nerve fiber content and vascular arcades. However, these changes did not correlate with measures of central retinal function or acute mountain sickness. For the first time a quantitative approach has been used to assess these changes during acute, non-acclimatized high altitude exposure.     

Acute mountain sickness: increased severity during simulated altitude compared with normobaric hypoxia

Roach, Robert C., Jack A. Loeppky, and Milton V. Icenogle.Acute mountain sickness: increased severity during simulated altitude compared with normobaric hypoxia. J. Appl.Physiol. 81(5): 1908-1910, 1996.Acute mountainsickness (AMS) strikes those in the mountains who go too high too fast.Although AMS has been long assumed to be due solely to the hypoxia ofhigh altitude, recent evidence suggests that hypobaria may also make asignificant contribution to the pathophysiology of AMS. We studied ninehealthy men exposed to simulated altitude, normobaric hypoxia, andnormoxic hypobaria in an environmental chamber for 9 h on separateoccasions. To simulate altitude, the barometric pressure was lowered to432 ± 2 (SE) mmHg (simulated terrestrial altitude 4,564 m).Normobaric hypoxia resulted from adding nitrogen to the chamber(maintained near normobaric conditions) to match the inspiredPO₂ of the altitude exposure. Bylowering the barometric pressure and adding oxygen, we achievednormoxic hypobaria with the same inspiredPO₂ as in our laboratory at normalpressure. AMS symptom scores (average scores from 6 and 9 h ofexposure) were higher during simulated altitude (3.7 ± 0.8)compared with either normobaric hypoxia (2.0 ± 0.8;P < 0.01) or normoxic hypobaria (0.4 ± 0.2; P < 0.01). In conclusion,simulated altitude induces AMS to a greater extent than does eithernormobaric hypoxia or normoxic hypobaria, although normobaric hypoxiainduced some AMS.

     

Plasma cytokine profiling to predict susceptibility to acute mountain sickness

Extensive studies have been performed on acute mountain sickness (AMS), but biomarkers predicting AMS are lacking. Presently, the mainstay methods to identify AMS biomarkers include proteomic and genetic methods at high altitudes or in hypoxic simulated chambers. In the present study, we compared plasma cytokine profiles between AMS-susceptible individuals and AMS-resistant individuals at low altitude by cytokine array analysis. In total, 75 differentially expressed cytokines were identified between AMS-susceptible individuals and AMS-resistant individuals, most involved in inflammation. A quantifiable human custom cytokine antibody array was then used to further test results of cytokine array analysis. Compared to AMS-resistant individuals, the level of insulin-like growth factor binding protein 6 (IGFBP-6) was significantly lower in AMS-susceptible individuals (37,318.99 ± 23,493.11 pg/mL and 25,665.38 ± 25,691.29 pg/mL, respectively; P = 0.04). Conversely, the levels of serum amyloid A1 (SAA1), dickkopf WNT signaling pathway inhibitor 4 (Dkk4), and interleukin 17 receptor A (IL-17RA) were significantly higher in AMS-susceptible individuals than in AMS-resistant individuals (SAA1: 4,069.69 ± 2,502.93 pg/mL vs. 2,994.98 ± 2,295.91 pg/mL, P = 0.05; Dkk4: 2,090.00 ± 2,094.89 pg/mL vs. 1,049.88 ± 1,690.93 pg/mL, P = 0.07; IL-17RA: 11.52 ± 8.33 pg/mL vs. 8.67 ± 6.22 pg/mL, P = 0.08). Although further in-depth research is required to examine the possible role of these cytokines in the development of AMS, these four cytokines may be of use in predicting AMS-susceptibility in a low-altitude environment.     

Effects of acute exposure to high altitude on ventilatory drive and respiratory pattern

To assess changes in ventilatory regulation in terms of central drive and timing, on exposure to high altitude, and the effects of induced hyperoxia at high altitude, six healthy normal lowland subjects (mean age 19.5 +/- 1.64 yr) were studied at low altitude (518 m) and on the first 4 days at high altitude (3,940 m). The progressive increase in resting expired minute ventilation (VE; control mean 9.94 +/- 1.78 to 14.25 +/- 2.67 l/min on day 3, P less than 0.005) on exposure to high altitude was primarily due to a significant increase in respiratory frequency (f; control mean 15.6 +/- 3.5 breaths/min to 23.8 +/- 6.2 breaths/min on day 3, P less than 0.01) with no significant change in tidal volume (VT). The increase in f was due to significant decreases in both inspiratory (TI) and expiratory (TE) time per breath; the ratio of TI to TE increased significantly (control mean 0.40 +/- 0.08 to 0.57 +/- 0.14, P less than 0.025). Mouth occlusion pressure did not change significantly, nor did the ratio of VE to mouth occlusion pressure. The acute induction of hyperoxia for 10 min at high altitude did not significantly alter VE or the ventilatory pattern. These results indicate that acute exposure to high altitude in normal lowlanders causes an increase in VE primarily by an alteration in central breath timing, with no change in respiratory drive. The acute relief of high altitude hypoxia for 10 min has no effect on the increased VE or ventilatory pattern.