Climbing to high altitude within a short period of time is increasingly popular but is associated with the risk of adverse health effects. Maladaptation to acute exposure to hypobaric hypoxia at high altitude may result in discomfort, exercise intolerance, and altitude-related illness including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and pulmonary edema (HAPE) (4,15). Increases in closing volume, a measure that reflects premature closure of dependent, small airways, were found in a high proportion of mountaineers climbing from lowlands to 4559 m within 24 h (8). Whether these findings indicate subclinical extrapulmonary fluid accumulation representing hypoxia-induced early stages of HAPE, pulmonary fluid extravasation related to strenuous exercise as observed in marathon runners (25), or bronchoconstriction related to inhalation of cold air and hypocapnia (27,28) has been debated (3,32).
To investigate the changes in lung function associated with rapid ascent to high altitude in relation to pulmonary hemodynamics, we assessed spirometry, single-breath nitrogen washout, diffusing capacity, and Doppler echocardiography in unacclimatized mountaineers at the Capanna Regina Margherita hut, Monte Rosa, 4559 m, on the day of their arrival after a rapid ascent, and on the following morning after an overnight stay. We hypothesized that changes in closing volume during the stay at 4559 m would vary among subjects over time, consistent with different mechanisms underlying altered lung function during high-altitude exposure. We reasoned that increases in closing volume related to subclinical HAPE would be associated with excessive pulmonary artery pressure and persist or even progress over the night at altitude (8,10) and that transient increases in closing volume due to exercise-associated fluid extravasation or bronchial constriction would disappear over the course of several hours of rest (27,28).
METHODS
Subjects.
Twenty-six healthy, nonsmoking volunteers (13 females) gave informed written consent to participate in the study, which was approved by the ethics committee of the University Hospital of Zurich. Their mean (± SD) age was 28 ± 11 yr, height was 168 ± 35 cm, and weight was 66 ± 8 kg. All subjects were recreational mountaineers. They had not stayed above 2500 m for more than 7 d within the last month. Four males had experienced one or more previous episodes of HAPE, and 16 subjects had experienced symptoms of AMS in the past.
Clinical assessment.
A general medical history and a physical examination were performed. Symptoms of AMS were assessed by the Lake Louise questionnaire (31). The sum of the self-report and clinical score is reported (range 0-25 points; see Appendix). A score greater than 4 is considered representative of AMS (11,20). Clinically relevant HAPE was defined by the presence of typical findings such as dry cough, resting tachycardia and tachypnea, and rales on auscultation.
Pulmonary function.
Spirometry and measurement of the single-breath diffusing capacity for carbon monoxide (DLCO) were performed with a Vmax 2900 unit (SensorMedics, Yorba Linda, CA) according to standard techniques (19,26). For DLCO, the unadjusted (standard) values and the values adjusted for altitude (DLCOadj) are reported: DLCOadj = DLCO · (1 + 0.0031 · [(PB − 47) · 0.21 − 149]) (19). Calibrations of the flow meter and gas analyzers were performed several times a day. Reference values were those of the European Community for Steel and Coal (30). Using the same equipment, single-breath nitrogen washout tests were performed (2). After a full expiration, subjects inspired 100% oxygen to total lung capacity, followed by an exhalation to residual volume with a constant target flow of 0.3-0.4 L·s−1. Three repeated measurements were performed at least 2 min apart. Raw data of nitrogen washout tests were stored and processed after termination of the entire data collection, as illustrated in Figure 1. Two investigators blinded to the clinical data independently analyzed all measurements, and the means of their corresponding readings of closing volume and of the slope of phase III are reported. Arterial oxygen saturation was measured by pulse oximetry (LifeShirt, VivoMetrics, Ventura, CA).
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FIGURE 1: Illustration of the single-breath nitrogen washout test. Raw data were exported into spreadsheet software to obtain large-scale plots of nitrogen concentration vs expired lung volume. Straight (dashed) lines were fitted by eye to the alveolar plateau (phase III), and the phase IV. The slope of phase III (in % nitrogen per liter), and the closing volume, defined by the intersection of the lines fitted to phases III and IV, were read off the plot. Closing volume was expressed in liters above residual volume (RV) and in percent of predicted inspiratory vital capacity.
Echocardiography.
Doppler echocardiography (Accuson Cypress, Siemens Medical Solutions, Erlangen, Germany) was performed with the subjects in semirecumbent position after resting at least 15 min. Systolic pulmonary artery pressure was estimated from the peak velocity of the tricuspid regurgitation jet (1). Cardiac output was derived from the systolic velocity time integral in the left ventricular outflow tract, the corresponding cross-sectional area measured from the parasternal long-axis, and the ECG-derived heart rate (23).
Protocol.
Baseline measurements were performed in Zurich (490 m) within 1 month before departure to the mountains. Subjects ascended within 24 h from Alagna (1130 m) to the Regina Margherita hut, Monte Rosa (4559m). On the first day, they were lifted by cable car to 3200 m, and they walked to the Capanna Gnifetti (3611 m) within 1-2 h. After an overnight stay, they climbed to the Regina Margherita hut within 4-6 h, arriving there around noon. Clinical assessments, pulmonary function tests, and echocardiography were performed 3 h after arrival (day 1). Subjects spent the night at 4559 m, and examinations were repeated on the following morning (day 2) before redescent. Cardiac output could not be reassessed on day 2 because of time restraints.
Statistics.
Data are presented as mean ± SD. Effects of altitude and time were evaluated by analysis of variance (6). Differences among subjects with transient versus persistent increase in closing volume during their stay at high altitude were evaluated by unpaired t-tests. Correlation and multiple regression analysis was performed between changes in closing volume and various outcomes at high altitude. Statistical significance was assumed at a two-sided P < 0.05.
RESULTS
Clinical findings.
After arrival at 4559 m, and on the following day, the subjects experienced symptoms of AMS. The mean ± SD Lake Louise score was 3.7 ± 1.9 (range 0-7) on the first day and 5.5 ± 3.5 (range 0-16) on the second day (N = 26, P < 0.01 vs day 1). On the morning of day 2, 15 (58%) of the 26 subjects suffered from AMS as defined by a Lake Louise score > 4. None of the participants, including the four subjects with previous episodes of HAPE, developed the clinical syndrome suggestive of HAPE (i.e., none of them suffered from cough, marked and disturbing resting tachycardia, and tachypnea in combination with rales on auscultation).
Pulmonary function and echocardiography.
The cardiorespiratory variables measured at low altitude and during the stay at 4559 m are summarized in Table 1. The number of valid results from repeated pulmonary function testing in the 26 subjects varied between 16 and 26 because certain results could not be obtained at all scheduled times because of technical and logistic difficulties. There was a slight but statistically significant decrease in IVC, FVC, and FEV1 already on day 1 at 4559 m, and this persisted on day 2. Because the decrease in FVC was relatively more pronounced than that of FEV1, an increase in the FEV1/FVC ratio resulted.
TABLE 1: Lung function and echocardiography at low and high altitude.
Ascent to high altitude was also associated with an increase in DLCO. Adjusting the values of DLCO for the lower estimated alveolar PO2 at 4559 m revealed a slight decrease (13,19). Arterial oxygen saturation was decreased at 4559 m, with a minimal recovery on day 2 (Table 1).
The nitrogen washout test revealed a clear increase in mean closing volume and in the slope of phase III after arrival at 4559 m (Table 1). On the following day, the slope of phase III remained elevated compared with at low altitude, whereas the changes in closing volume occurring overnight were variable. Related to the high variability in the changes of closing volume from day 1 to day 2, the mean values on day 2 did not statistically differ from baseline nor from day 1 (Fig. 2).
FIGURE 2: Changes in closing volume (upper panel) and in the slope of phase III of the nitrogen washout curve (lower panel) at 4559 m. Individual values on days 1 and 2 are represented by circles and connected by lines. Subjects with a history of previous HAPE are represented by open circles. Mean values for days 1 and 2 are shown as horizontal lines.
Consistent with the expected effect of hypoxemia, systolic pulmonary artery pressure significantly increased on ascent to high altitude and remained elevated on the following day (Table 1). This was associated with an increase in heart rate, and, at least on day 1 when this measurement was performed, with increased cardiac output.
Subjects with transient versus persistent increase in closing volume at altitude.
During the stay at 4559 m, the mean values of closing volume and of the slope of phase III of the nitrogen washout curve remained unchanged. However, there was a considerable variability in the individual trends of changes in these values (Fig. 2). Of the 21 subjects with data on closing volume after arrival, and in the following morning at high altitude, 12 (57%; six females) had a transient increase with lower values on day 2 than on day 1, and nine (43%; three females) had a persistent increase in closing volume (i.e., in these subjects, the closing volume was higher on day 2 than on day 1). To evaluate physiologic characteristics associated with transient versus persistent increases in closing volume, we compared lung function and echocardiographic data between these two groups (Table 2). They did not differ in age, weight, and height, and both groups had similar closing volumes upon arrival at 4559 m (day 1). Diffusing capacity was lower on days 1 and 2 at high altitude in the group with persistent increases in closing volume, and the difference was significant for the values of DLCO divided by alveolar volume. In addition, the group with persistent increases in closing volume had a further increase in the Lake Louise score during the stay at high altitude. There was no difference between the two groups with regard to oxygen saturation and spirometry, nor in pulmonary artery pressure. Furthermore, there was no correlation among changes in closing volume over the night with pulmonary artery pressure on days 1 and 2 (r = 0.11, P = NS, and r = 0.08, P = NS). To corroborate the observation of an uniform increase in closing volume on day 1 and a variable course thereafter, we performed a multiple regression analysis with closing volume as the dependent variable and the time of measurement (i.e., baseline, day 1 or 2 at high altitude), systolic pulmonary artery pressure, HAPE susceptibility, age, sex, height, and weight as independent variables. The model explained 55% of the variability in closing volume (R2 = 0.55, N = 46 observations). Apart from height (P = 0.001) and weight (P = 0.001), the only significant predictor (P = 0.034) of closing volume in this model was day 1 as the time of the measurement, further suggesting that the increase in closing volume was consistent at this time but more variable on day 2.
TABLE 2: Lung function, echocardiography, and symptoms in subjects with transient vs persistent increase in closing volume at high altitude.
DISCUSSION
In unacclimatized mountaineers ascending rapidly to 4559 m, closing volume and the slope of phase III of the nitrogen washout curve were consistently increased whereas FVC was reduced on the day of arrival. During the subsequent overnight stay at altitude, closing volume remained elevated in 9 of 21 mountaineers who had a lower diffusing capacity, more pronounced symptoms of AMS, but similar pulmonary artery pressures compared with the remaining 12 subjects, in whom closing volume decreased over the course of the night (Table 2). These observations and the fact that none of the mountaineers, including four susceptibles, developed clinical HAPE indicate that initial increases in closing volume after arrival at high altitude are common but cannot be explained by a single mechanism, and these changes alone do not inevitably herald an impending HAPE at an early stage.
We observed a fall in IVC and FVC of 6% and in FEV1 of 5% on the day of arrival and over time at 4559 m, resulting in a slight increase in the FEV1/FVC ratio (Table 1). This is consistent with previous studies showing a reduction of FVC and FEV1 in the initial and subsequent days after ascent to altitudes between 3800 and 5300 m (5,12,16,17,24,29). Increases in pulmonary blood volume (17) and in extravascular lung water (24) are potential explanations for a decrease in FVC at high altitude, but weakness of respiratory muscles cannot be ruled out as a contributing factor (9). The relatively minor decrease in FEV1 and the higher FEV1/FVC ratio at high altitude (Table 1) can, at least in part, be attributed to a lower airflow resistance related to reduced air density.
The single-breath nitrogen washout test has been employed before to investigate effects of high-altitude exposure (7,14,17,34). An increase in closing volume (by up to 0.16 L) and in the slope of phase III (by up to 0.16% per liter), along with reductions in vital capacity and thoracic electrical impedance, were noted in soldiers exercising at 3000-4300 m and taken as evidence of increased intrathoracic fluid (17). In unacclimatized mountaineers climbing to 4559 m at Mt. Rosa, an even greater increase in closing volume of 0.20 L (62%) was estimated by analysis of the intrabreath respiratory exchange ratio rather than by the standard nitrogen washout (8). The most pronounced increases (0.34 L; 122%) were found in subjects with signs of pulmonary edema in the physical or radiologic examination even in the absence of related symptoms. Accordingly, we observed a mean increase in closing volume of 0.09 L (26%) and in the slope of phase III of 0.18% per liter (21%) on the first day at 4559 m (Table 1). The data of the cited (8,17) and of the current investigations are consistent with subclinical interstitial pulmonary fluid accumulation in some subjects after rapid ascent to high altitude. Whether this represents subclinical HAPE, and therefore indicates a risk of progression to clinically relevant HAPE, has been debated (3,8,32). Strenuous exercise (25) or bronchoconstriction due to inhalation of cold air or hypocapnia (27,28) are alternative explanations for an increase in the closing volume and for an uneven distribution of ventilation reflected in the elevated slope of phase III of the nitrogen washout.
To further investigate the mechanisms of alterations in closing volume, we analyzed its changes after one night at 4559 m. Interestingly, the trends of the changes in closing volume were highly variable (Fig. 2) in contrast to the initial homogeneous increase with ascent from lowlands to high altitude. Twelve of 21 subjects (57%) revealed only a transient increase in closing volume on the first day, with a subsequent decrease on the second day at 4559 m (Table 2). This is not suggestive of HAPE, which is expected to progress during extended exposure to hypoxia. Instead, these findings would be more consistent with transient pulmonary fluid accumulation induced by a strenuous ascent (25). Even in the 9 of 21 subjects (43%) in whom closing volume remained elevated on day 2, development to HAPE would have been unlikely given the low incidence of HAPE of 6% in mountaineers studied in the same setting (3) and because excessive pulmonary artery hypertension, one of the prerequisites of HAPE (21), was absent-their systolic pulmonary artery pressure was even lower than the mean pulmonary artery pressure observed in subjects developing HAPE (21). Another potential explanation for the variable time course of closing volume at high altitude relates to individual differences in the alveolar clearance rate following a mechanical capillary leak induced by strenuous exercise in a hypoxic environment (10).
Our results do not support the alternative hypothesis that hypocapnia and cold air might have induced transient bronchoconstriction (27,28) because FEV1/FVC increased upon ascent and was similar in the two groups. If bronchoconstriction would have occurred to a significant degree, this would have resulted in a measurable decrease in the ratio.
According to the known effects of hypobaric hypoxia, which induces an increase in pulmonary capillary blood volume and enhances the rate of carbon monoxide uptake in erythrocytes (33,35), DLCO increased upon ascent to 4559 m. However, correcting DLCO for the low alveolar PO2 at 4559 m, estimated according to standard recommendations (18,19), revealed a slight decrease of the altitude-adjusted DLCO (Table 1). This may indicate a reduction in the membrane component of DLCO, possibly related to subclinical interstitial edema as suspected from the elevations in closing volume. The lower DLCO/VA in subjects with persistent increases in closing volume on day 2 would further support this hypothesis.
In conclusion, we analyzed symptoms and signs of high-altitude illness, pulmonary function, and echocardiography in unacclimatized mountaineers ascending rapidly to high altitude. We found a consistent initial increase in closing volume upon arrival at 4559 m and other cardiopulmonary effects, but the course of closing volume varied widely on the second day. Although consistent with interstitial fluid accumulation, these alterations of pulmonary function did not indicate a subsequent progression to clinical HAPE, and their extent, the time course, and the underlying mechanisms may vary according to individual susceptibility and other unknown factors.
This study was supported by grants from the Hartmann-Müller Stiftung, Zürich, Switzerland. The authors declare that they have no competing interest.
APPENDIX
* According to (22,31).
The sum of the scores of self-rating and clinical assessment is the Lake Louise Score.
A sum score greater than 5 was considered as indicating acute mountain sickness (AMS).
REFERENCES
1. Allemann, Y., C. Sartori, M. Lepori, et al. Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude.
Am. J. Physiol. Heart Circ. Physiol. 279:H2013-H2016, 2000.
2. Anthonisen, N. R., J. Danson, P. C. Robertson, and W. R. Ross. Airway closure as a function of age.
Respir. Physiol. 8:58-65, 1969.
3. Bartsch, P., M. Maggiorini, H. Mairbäurl, P. Vock, and E. R. Swenson. Pulmonary extravascular fluid accumulation in climbers.
Lancet 360:570-571, 2002.
4. Basnyat, B., and D. R. Murdoch. High-altitude illness.
Lancet 361:1967-1974, 2003.
5. Basu, C. K., W. Selvamurthy, G. Bhaumick, R. K. Gautam, and R. C. Sawhney. Respiratory changes during initial days of acclimatization to increasing altitudes.
Aviat. Space Environ. Med. 67:40-45, 1996.
6. Bland, M.
An Introduction to Medical Statistics, 3rd edition. Oxford: Oxford University Press, pp. 1-391, 2000.
7. Coates, G., G. Gray, A. Mansell, et al. Changes in lung volume, lung density, and distribution of ventilation during hypobaric decompression.
J. Appl. Physiol. 46:752-755, 1979.
8. Cremona, G., R. Asnaghi, P. Baderna, et al. Pulmonary extravascular fluid accumulation in recreational climbers: a prospective study.
Lancet 359:303-309, 2002.
9. Deboeck, G., J. J. Moraine, and R. Naeije. Respiratory muscle strength may explain hypoxia-induced decrease in vital capacity.
Med. Sci. Sports Exerc. 37:754-758, 2005.
10. Eldridge, M. W., R. K. Braun, K. Y. Yoneda, and W. F. Walby. Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.
J. Appl. Physiol. 100:972-980, 2006.
11. Erba, P., S. Anastasi, O. Senn, M. Maggiorirni, and K. E. Bloch. Acute mountain sickness is related to nocturnal hypoxemia but not to hypoventilation.
Eur. Respir. J. 24:303-308, 2004.
12. Forte, V. A. Jr., D. E. Leith, S. R. Muza, C. S. Fulco, and A. Cymerman. Ventilatory capacities at sea level and high altitude.
Aviat. Space Environ. Med. 68:488-493, 1997.
13. Gray, G., N. Zamel, and R. O. Crapo. Effect of a simulated 3,048 meter altitude on the single-breath transfer factor.
Bull. Eur. Physiopathol. Respir. 22:429-431, 1986.
14. Gray, G. W., I. D. B. Rennie, C. S. Houston, and A. C. Bryan. Phase IV of the single breath nitrogen washout curve on exposure to altitude.
J. Appl. Physiol. 35:227-230, 1973.
15. Hackett, P. H., and R. C. Roach. High-altitude illness.
N. Engl. J. Med. 345:107-114, 2001.
16. Hashimoto, F., B. McWilliams, and C. Qualls. Pulmonary ventilatory function decreases in proportion to increasing altitude.
Wilderness Environ. Med. 8:214-217, 1997.
17. Jaeger, J. J., J. T. Sylvester, A. Cymerman, J. J. Berberich, J. C. Denniston, and J. T. Maher. Evidence for increased intrathoracic fluid volume in man at high altitude.
J. Appl. Physiol. 47:670-676, 1979.
18. Kanner, R. E., and R. O. Crapo. The relationship between alveolar oxygen tension and the single-breath carbon monoxide diffusing capacity.
Am. Rev. Respir. Dis. 133:676-678, 1986.
19. MacIntyre, N., R. O. Crapo, G. Viegi, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung.
Eur. Respir. J. 26:720-735, 2005.
20. Maggiorini, M., B. Buhler, M. Walter, and O. Oelz. Prevalence of acute mountain sickness in the Swiss Alps.
BMJ 301:853-855, 1990.
21. Maggiorini, M., C. Melot, S. Pierre, et al. High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
Circulation 103:2078-2083, 2001.
22. Maggiorini, M., A. Muller, D. Hofstetter, P. Bartsch, and O. Oelz. Assessment of acute mountain sickness by different score protocols in the Swiss Alps.
Aviat. Space Environ. Med. 69:1186-1192, 1998.
23. Marshall, S. A., and A. E. Weyman.
Principles and Practice of Echocardiography. Philadelphia: Lea and Febiger, pp. 955-978, 1994.
24. Mason, N. P., M. Petersen, C. Melot, et al. Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude.
J. Appl. Physiol. 94:2043-2050, 2003.
25. Miles, D. S., C. E. Doerr, S. A. Schonfeld, D. E. Sinks, and R. W. Gotshall. Changes in pulmonary diffusing capacity and closing volume after running a marathon.
Respir. Physiol. 52:349-359, 1983.
26. Miller, M. R., J. Hankinson, V. Brusasco, et al. Standardisation of spirometry.
Eur. Respir. J. 26:319-338, 2005.
27. O'Cain, C. F., N. B. Dowling, A. S. Slutsky, et al. Airway effects of respiratory heat loss in normal subjects.
J. Appl. Physiol. 49:875-880, 1980.
28. O'Cain, C. F., M. J. Hensley, E. R. McFadden, Jr., and R. H. Ingram, Jr. Pattern and mechanism of airway response to hypocapnia in normal subjects.
J. Appl. Physiol. 47:8-12, 1979.
29. Pollard, A. J., N. P. Mason, P. W. Barry, et al. Effect of altitude on spirometric parameters and the performance of peak flow meters.
Thorax 51:175-178, 1996.
30. Quanjer, P. H., G. J. Tammeling, J. E. Cotes, O. F. Pedersen, R. Peslin, and J. C. Yernault. Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European community for steel and coal. Official statement of the European Respiratory Society.
Eur. Respir. J. Suppl. 16:5-40, 1993.
31. Roach, R. C., P. Bartsch, P. H. Hackett, O. Oelz, and The Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In:
Hypoxia and Molecular Medicine: Proceedings of the 8th International Hypoxia Symposium, J. R. Sutton, G. Coates, and C. S. Huston (Eds.). Burlington, Canada: Queen City Printers, pp. 272-274, 1993.
32. Rolla, G., F. Nebiolo, and C. Bucca. Pulmonary extravascular fluid accumulation in climbers.
Lancet 360:570-571, 2002.
33. Roughton, F. J. W., and R. E. Forster. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries.
J. Appl. Physiol. 11:290-302, 1957.
34. Sutton, J. R., G. W. Gray, M. D. McFadden, A. C. Bryan, E. S. Horton, and C. S. Houston. Nitrogen washout studies in acute mountain sickness.
Aviat. Space Environ. Med. 48:108-110, 1977.
35. West, J. B. Diffusing capacity of the lung for carbon monoxide at high altitude.
J. Appl. Physiol. 17:421-426, 1962.
