Hypoxemia and acute mountain sickness: which comes first?

Hypoxemia is usually associated with acute mountain sickness (AMS), but most studies have varied in time and magnitude of altitude exposure, exercise, diet, environmental conditions, and severity of pulmonary edema. We wished to determine whether hypoxemia occurred early in subjects who developed subsequent AMS while resting at a simulated altitude of 426 mmHg (approximately 16,000 ft or 4880 m). Exposures of 51 men and women were carried out for 8 to 12 h. AMS was determined by Lake Louise (LL) and AMS-C scores near the end of exposure, with spirometry and gas exchange measured the day before (C) and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude and arterial blood at C, A1, and A12. Responses of 16 subjects having the lowest AMS scores (nonAMS: mean LL=1.0, range=0-2.5) were compared with the 16 having the highest scores (+AMS: mean LL=7.4, range=5-11). Total and alveolar ventilation responses to altitude were not different between groups. +AMS had significantly lower PaO2 (4.6 mmHg) and SaO2 (4.8%) at A1 and 3.3 mmHg and 3.1% at A12. Spirometry changes were similar at A1, but at A6 and A12 reduced vital capacity (VC) and increased breathing frequency suggested interstitial pulmonary edema in +AMS. The early hypoxemia in +AMS appears to be the result of diffusion impairment or venous admixture, perhaps due to a unique autonomic response affecting pulmonary perfusion. Early hypoxemia may be useful to predict AMS susceptibility.

Validation of a two-compartment model of ventilation/perfusion distribution.

Ventilation (V (A)) to perfusion (Q ) heterogeneity (V (A)/Q ) analyses by a two-compartment lung model (2C), utilizing routine gas exchange measurements and a computer solution to account for O(2) and CO(2) measurements, were compared with multiple inert gas elimination technique (MIGET) analyses and a multi-compartment (MC) model. The 2C and MC estimates of V (A)/Q mismatch were obtained in 10 healthy subjects, 43 patients having chronic obstructive pulmonary disease (COPD) and in 14 dog experiments where hemodynamics and acid-base status were manipulated with gas mixtures, fluid loading and tilt-table stressors. MIGET comparisons with 2C were made on 6 patients and 32 measurements in healthy subjects before and after exercise at normoxia and altitude hypoxia. Statistically significant correlations for logarithmic standard deviations of V (A)/Q distributions (SD(V (A)/Q )) were obtained for all 2C comparisons, with similar values between 2C and both other methods in the 1.1-1.5 range, compatible with mild to moderate COPD. 2C tended to overestimate MC and MIGET values at low and underestimate them at high SD(V (A)/Q ) values. SD(V (A)/Q ) weighted by Q agreed better with MC and MIGET estimates in the normal range, whereas SD(V (A)/Q ) weighted by V (A) was closer to MC at higher values because the V (A)-weighted SD(V (A)/Q ) is related to blood-to-gas PCO(2) differences that are elevated in disease, thereby allowing better discrimination. The 2C model accurately described functional V (A)/Q characteristics in 26 normal and bronchoconstricted dogs during non-steady state rebreathing and could be used to quantify the effect of reduced O(2) diffusing capacity in diseased lungs. These comparisons indicate that 2C adequately describes V (A)/Q mismatch and can be useful in clinical or experimental situations where other techniques are not feasible.

Early fluid retention and severe acute mountain sickness.

Field studies of acute mountain sickness (AMS) usually include variations in exercise, diet, and environmental conditions over days and development of clinically apparent edemas. The purpose of this study was to clarify fluid status in persons developing AMS vs. those remaining without symptoms during simulated altitude with controlled fluid intake, diet, temperature, and without exercise. Ninety-nine exposures of 51 men and women to reduced barometric pressure (426 mmHg = 16,000 ft. = 4,880 m) were carried out for 8-12 h. AMS was evaluated by Lake Louise (LL) and AMS-C scores near the end of exposure. Serial measurements included fluid balance, electrolyte excretions, and plasma concentrations, regulating hormones, and free water clearance. Comparison between 16 subjects with the lowest AMS scores near the end of exposure ("non-AMS": mean LL = 1.0, range = 0-2.5) and 16 others with the highest AMS scores ("AMS": mean LL = 7.4, range = 5-11) demonstrated significant fluid retention in AMS beginning within the first 3 h, resulting from reduced urine flow. Plasma Na+ decreased significantly after 6 h, indicating dilution throughout the total body water. Excretion of Na+ and K+ trended downward with time in both groups, being lower in AMS after 6 h, and the urine Na+-to-K+ ratio was significantly higher for AMS after 6 h. Renal compensation for respiratory alkalosis, plasma renin activity, aldosterone, and atrial natriuretic peptide were not different between groups, with the latter tending to rise and aldosterone falling with time of exposure. Antidiuretic hormone fell in non-AMS and rose in AMS within 90 min of exposure and continued to rise in AMS, closely associated with severity of symptoms and fluid retention.

Role of hypobaria in fluid balance response to hypoxia.

To estimate the separate and combined effects of reduced P(B) and O2 levels on body fluid balance and regulating hormones, measurements were made during reduced PB (altitude, ALT; P(B) = 432 mm Hg, F(I(O2)) = 0.207), reduced inspired O2 concentration (normobaric hypoxia, HYX; P(B) = 614 mm Hg, F(I(O2)) = 0.142), and lowered ambient pressure without hypoxia (normoxic hypobaria HYB; P(B) = 434 mm Hg, F(I(O2)) = 0.296). Nine fit and healthy young men were exposed to these conditions for 10 h in a decompression chamber. Lake Louise AMS scores, urine collections, and blood samples were obtained every 3 h, with recovery measurements 2 h after exposure. AMS was significantly greater during ALT than HYX, as previously reported (J. Appl. Physiol. 81:1908-1910. 1996), because the combination of reduced P(B) and P(O2) over the 10 h favored fluid retention by reducing urine volume, while plasma volume (PV) remained higher than during HYX. At ALT the plasma Na+ fell significantly at 6 h, probably from dilution of extracellular fluid, and antidiuretic hormone (ADH) was highest (p = 0.006 versus HYB). The PV, urine flow, free water clearance, and plasma renin activity (PRA) rose significantly during recovery from ALT as AMS symptoms subsided, suggesting increased intravascular fluid and reduced adrenergic tone. During HYB, the plasma aldosterone (ALDO) and K+ levels were significantly elevated, and PRA was highest and ADH lowest, without fluid retention. During HYX, fluid balance was similar to HYB, but PV and ALDO were significantly lower, and ALDO increased significantly in recovery from HYX. The fluid retention at ALT in AMS-susceptible subjects appears related to a synergistic interaction involving reduced P(B) and ADH and ALDO.

Body temperature, autonomic responses, and acute mountain sickness.

A few studies have reported increased body temperature (T(o)) associated with acute mountain sickness (AMS), but these usually include exercise, varying environmental conditions over days, and pulmonary edema. We wished to determine whether T(o) would increase with AMS during early exposure to simulated altitude at rest. Ninety-four exposures of 51 men and women to reduced P(B) (423 mmHg = 16,000 ft = 4850 m) were carried out for 8 to 12 h. AMS was evaluated by LL and AMS-C scores near end of exposure, and T(o) was measured by oral digital thermometer before altitude and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude. Other measurements included ventilation, O(2) consumption and autonomic indicators of plasma catecholamines, HR, and HR variability. Average T(o) increased by 0.5 degrees F from A1 to A12 in all subjects (p < 0.001). Comparison between 16 subjects with lowest AMS scores (mean LL = 1.0, range = 0 to 2.5) and 16 other subjects with highest AMS scores (mean LL = 7.4, range = 5 to 11) demonstrated a transient decline in T(o) from A1 to A6 in AMS, in contrast to a rise in non-AMS (p = 0.001). Catecholamines, HR, and HR variability (increased low F/high F ratio) indicated significant elevation of sympathetic activity in AMS, where T(o) fell, but no change in metabolic rate. The apparently greater heat loss during early AMS suggests increased hypoxic vasodilation in spite of enhanced sympathetic drive. Greater hypoxic vasodilation and elevated HR in AMS in the absence of other changes suggest that augmentation of beta-adrenergic tone may be involved in early AMS pathophysiology.

Plasma volume by Evans blue: effects of eating and comparison with other methods at altitude.

HYPOTHESIS: Measurements of plasma volume (PV) and its changes (delta%PV) by Evans blue (EB) dye are presumed to be valid only in fasting subjects. In addition, delta%PVEB with acute altitude exposure has not been compared with other methods employing the concentration or dilution of naturally occurring blood (hematocrit (Hct), hemoglobin (Hb)) and plasma (density, proteins) components, but should be similar if capillary permeability and the sampled vein/whole body Hct ratio remain unchanged. METHODS: PVEB was determined in six subjects while fasting or eating on different days, with injection and sampling in the same arm, 4-h extrapolation to time zero and correcting readings with the 620-740 A method. For 93 experiments at altitude, delta%PVEB was obtained similarly from a 3-h extrapolation near the end of a 12-h chamber exposure to 426 mm Hg (-4,880 m =16,000 ft) and at the same time on the preceding control day. RESULTS: Mean PVEB with and without eating was not significantly different (SE of absolute difference = +/- 2.8%). The EB decay curves had significantly more scatter with eating than fasting. The fasting vs. non-fasting values for the single 20-min post-injection point also gave a close comparison (r = +0.97). At altitude the loss in PV measured with EB was significantly greater (delta%PVEB = -6.3%) than losses estimated from Hct-Hb (-2.9%), plasma protein (-3.7%), and plasma density (-3.9%). The expected larger PV loss in subjects tolerant to altitude sickness compared with intolerant ones was most clearly shown by delta%PVEB (8.8%). CONCLUSIONS: Obtaining more samples can offset reproducibility lost by eating. The delta%PVEB were largest and nearest to values previously reported at altitude, perhaps because the single baseline and altitude samples utilized by the other methods are more sensitive to subtle, transient fluctuations in body water and vasomotor tone associated with apprehension, vomiting, fluid intake, and regional vasodilation and constriction.

Effects of acute leg ischemia during cycling on oxygen and carbon dioxide stores.

This study estimated changes in whole body oxygen stores (O(2)s) and carbon dioxide stores (CO(2)s) during steady state exercise with leg ischemia induced by leg cuff inflation. Six physically fit subjects performed 75 W steady state exercise for 15 min on a cycle ergometer. After 5 min of exercise, cuffs on the upper and lower legs were inflated to 140 mmHg. Cuffs were deflated after 5 min and exercise continued for another 5 min. O(2 )uptake (VO(2)) and CO(2) output (VCO(2)) significantly increased during the first 30 s after inflation, significantly decreased between 60 and 90 s, and then rose linearly until deflation. VO(2) and VCO(2) significantly increased further after cuff deflation, peaking between 30 and 60 s and then returned to near baseline exercise levels. Model-estimated changes in total O(2)s and CO(2)s were compared with time-integrated store changes from VO(2) and VCO(2). During 5 min after cuff deflation, VO(2) and VCO(2) exceeded the model-estimated change in stores by 273 and 697 mL, respectively. These results reflect the O(2) cost repayment of the anaerobic component and lactate buffering to neutralize circulating metabolites caused by the preceding ischemia.

CO2 rebreathing model in COPD: blood-to-gas equilibration.

Rebreathing in a closed system can be used to estimate mixed venous PCO2 (PvCO2) and cardiac output, but these estimates are affected by VA/Q heterogeneity. The purpose of this study was to validate a mathematical model of CO2 exchange during CO2 rebreathing in 29 patients with chronic obstructive pulmonary disease (COPD), with baseline arterial PCO2 (PaCO2) ranging from 28 to 60 mmHg. Rebreathing increased end-tidal PCO2 (PETCO2) by 20 mmHg over 2.2 min. This model employed baseline values for inspired (bag) PCO2, estimated PvCO2, distribution of ventilation and blood flow in one high VA/Q and one low VA/Q compartment, the ventilation increase and conservation of mass equations to simulate time courses of PICO2, PETCO2, PvCO2, and PaCO2. Measured PICO2 and PETCO2 during rebreathing differed by an average (SEM) of 1.4 (0.4) mmHg from simulated values. By end of rebreathing, predicted PvCO2 was lower than measured and predicted PaCO2, indicating gas to blood CO2 flux. Estimates of the ventilatory response to CO2, quantified as the slope (S) of the ventilation increase versus PETCO2, were inversely related to gas-to-blood PCO2 disequilibria due to VA/Q heterogeneity and buffer capacity (BC), but not airflow limitation. S may be corrected for these artifacts to restore S as a more valid noninvasive index of central CO2 responsiveness. We conclude that a rebreathing model incorporating baseline VA/Q heterogeneity and BC can simulate gas and blood PCO2 in patients with COPD, where VA/Q variations are large and variable.

Effects of ischemic training on leg exercise endurance.

This study tested whether ischemic exercise training (Tr(IS+EX)) would increase endurance of ischemic (Ex(IS)) and ramp exercise (Ex(RA)) knee-extension tests more than exercise training (Tr(EX)) alone. Ten healthy subjects performed pre- and posttraining tests with each leg. For Ex(RA), after subjects warmed up, a weight was added each minute until they were exhausted. Ex(IS) was similar, but after warm-up, we inflated a thigh cuff to 150 mmHg instead of adding weights. One leg was chosen for Tr(IS+EX) (cuff inflated to 150 mmHg during exercise) and the other for Tr(EX), both with a small weight on each leg, four to six times per daily session for 3 to 5 min each, 5 days per week for 6 weeks. Ex(IS) duration increased 120% more (p = 0.002) in the Tr(IS+EX) leg than in the contralateral Tr(EX) leg, whereas Ex(RA) duration increased only 16% (nonsignificant). Tr(IS+EX )and Tr(EX) significantly attenuated the ventilation increase (ergoreflex) during Ex(IS). TheO(2) debt for Ex(IS )was significantly lower and systolic blood pressure recovery was faster after Tr(IS+EX) than after Tr(EX). Heart rate recovery after Ex(RA )andEx(IS )was faster after Tr(IS+EX). Apparently, Tr(IS+EX) with low-intensity resistance increases exercise endurance and attenuates the ergoreflex and therefore may be a useful tool to increase regional muscle endurance to improve systemic exercise capacity in patients.