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CLINICAL STUDIES

Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema

Ekkehard Grünig, MD^*, Derliz Mereles, MD^*, Wulf Hildebrandt, MD, Erik R. Swenson, MD, Wolfgang Kübler, MD^*, Helmut Kuecherer, MD^* and Peter Bärtsch, MD

^* Department of Cardiology, University of Heidelberg, Heidelberg, Germany
Institute of Sports Medicine, University of Heidelberg, Heidelberg, Germany

Manuscript received April 2, 1999; revised manuscript received October 15, 1999, accepted November 19, 1999.

Reprint requests and correspondence: Dr. Ekkehard Grünig, Department of Cardiology, Bergheimer Strasse 58, D-69115 Heidelberg, Germany
ekkehard_gruenig{at}med.uni-heidelberg.de

	Abstract

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OBJECTIVE

This prospective single-blinded study was performed to quantitate noninvasive pulmonary artery systolic pressure (PASP) responses to prolonged acute hypoxia and normoxic exercise.

BACKGROUND

Hypoxia-induced excessive rise in pulmonary artery pressure is a key factor in high-altitude pulmonary edema (HAPE). We hypothesized that subjects susceptible to HAPE (HAPE-S) have increased pulmonary artery pressure response not only to hypoxia but also to exercise.

METHODS

PASP was estimated at 45, 90 and 240 min of hypoxia (Fi0₂=12%) and during supine bicycle exercise in normoxia using Doppler-echocardiography in nine HAPE-S and in 11 control subjects.

RESULTS

In the control group, mean PASP increased from 26 ± 2 to 37 ± 4 mm Hg (PASP 10.3 ± 2 mm Hg) after 90 min of hypoxia and from 27 ± 4 to 36 ± 3 mm Hg (PASP 8 ± 2 mm Hg) during exercise. In contrast, all HAPE-S subjects revealed significantly greater increases (p = 0.002 vs. controls) in mean PASP both during hypoxia (from 28 ± 4 to 57 ± 10 mm Hg, PASP 28.7 ± 6 mm Hg) and during exercise (from 28 ± 4 to 55 ± 11 mm Hg, PASP 27 ± 8 mm Hg) than did control subjects. Stress echocardiography allowed discrimination between groups without overlap using a cut off PASP value of 45 mm Hg at work rates less than 150 W.

CONCLUSIONS

These data indicate that HAPE-S subjects may have abnormal pulmonary vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, Doppler echocardiography during supine bicycle exercise or after 90 min of hypoxia may be useful noninvasive screening methods to identify subjects susceptible to HAPE.

Abbreviations and Acronyms   ECG = electrocardiogram   EF = ejection fraction   HAPE = high-altitude pulmonary edema   HAPE-S = high-altitude pulmonary edema-susceptible subjects   LV = left ventricle, left ventricular   PASP = pulmonary artery systolic pressure   RV = right ventricle, right ventricular

Although pathophysiologic mechanisms leading to HAPE are not completely understood, it appears that an hypoxia-induced excessive rise in pulmonary artery pressure is a key factor as documented by invasive (5,6) and noninvasive (2,7,8) measurements during HAPE. Furthermore, invasive studies consistently showed that HAPE-susceptible (HAPE-S) subjects have an exaggerated hypoxic pulmonary vascular response during a brief hypoxic exposure at low altitude (9–11). Recent noninvasive studies using Doppler echocardiography to estimate pulmonary artery systolic pressure (PASP) during short exposure to hypoxia could, however, not sufficiently discriminate HAPE-S from nonsusceptible individuals due to a considerable overlap between groups (12,13). We hypothesized that the lack of sufficient discrimination might be due to the fact that hypoxic exposure lasted only 15 min in these studies, because it was recently shown that the maximal pulmonary artery pressure response in healthy humans requires at least 2 h of hypoxic exposure (14).

Furthermore, recent invasive studies documented that the rise of pulmonary artery pressure during exercise in normoxia is also greater in HAPE-S than in nonsusceptible individuals (10,15). Doppler echocardiography has been shown to accurately estimate PASP at rest (16), and during normoxic exercise in patients with chronic obstructive lung disease (17), mitral valve disease (18), congenital heart disease (19) and in patients with chronic congestive heart failure (20).

Therefore, the aim of this study was to examine whether HAPE-S subjects can be identified by their PASP response to normoxic supine bicycle exercise and to prolonged acute hypoxia using Doppler ultrasound.

	Methods

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Study population and design.   We investigated 21 healthy male mountaineers whose susceptibility to HAPE was known because they had participated in previous studies at the Capanna Regina Margherita, ascending from 1,120 to 4,559 m within 22 h (2). During the study, one subject of the HAPE-S group had to be excluded due to inadequate Doppler signals. Therefore, the final study group consisted of 20 subjects. The HAPE-S group consisted of nine healthy male mountaineers (mean age 45 ± 8 years, weight 82 ± 9 kg, height 182 ± 8 cm) who have had at least one episode of pulmonary edema at an altitude of 4,559 m documented by chest roentgenogram within the last four years. The control group consisted of 11 male mountaineers (mean age 37 ± 11 years, weight 76 ± 7 kg, height 179 ± 6 cm) who did not develop HAPE with the same altitude exposure. Acute or chronic pulmonary and cardiac diseases were ruled out in all subjects.

The subjects were studied in Heidelberg, Germany, at an elevation of 100 m. All subjects were nonsmokers, natives of low altitude and had not resided above 2,000 m during two weeks before the examination. None of the subjects received any medication during the study period. On the first day, we performed stress-echocardiography under normoxic conditions. On the following day, PASP was measured during 4 h of exposure to normobaric hypoxia. In one subject of the control group, the study had to be terminated after 55 min of hypoxia because of nausea and discomfort. The Ethics Committee of the Medical Faculty of the University of Heidelberg approved the protocol of this study, and the subjects gave their written, informed consent before the study.

Echocardiography.   Two-dimensional and Doppler echocardiographic recordings were obtained using 2.5-MHz duplex probes and conventional equipment (SSD-2200; Aloka, Tokyo, Japan) on two occasions: on the first day during stress-echocardiography; and on the second day during baseline in normoxia and at 45, 90 and 240 min of hypoxia (Fi0₂ = 12%). PASP was estimated from peak tricuspid regurgitation jet velocities according to the equation: PASP = 4 (V)2 + 5 mm Hg, where V is the peak velocity (in m/s) of tricuspid valve regurgitant jet, and 5 mm Hg is the estimated right atrial pressure (16). The right ventricular (RV) and atrial areas were obtained in apical four-chamber views using planimetry as described by Bommer et al. (21). Left ventricular (LV) volumes and ejection fractions (EFs) were calculated by the disc summation method (modified Simpson’s rule). Cardiac output was estimated from aortic outflow. Echocardiographic studies were performed by experienced cardiac sonographers (E.G., D.M.), who had no knowledge of the clinical data and classification of the subjects. Recordings were analyzed off-line in random order and in a blinded fashion.

Stress-echocardiography.   Patients were examined on a variable load supine bicycle ergometer (model 8420; KHL Corp., Kirkland, Washington). The exercise table was tilted laterally by 20 to 30 degrees to the left. After obtaining two-dimensional and Doppler echocardiographic images at rest, exercise was started at an initial workload of 25 W. Workload was increased by 25 W every 2 min, and blood pressure and 12-lead electrocardiogram (ECG) were recorded. A 12-lead ECG and echocardiographic examinations were continuously recorded. Exercise was discontinued because of exhaustion (n = 1, workload of 175 W), hypertensive blood pressure (n = 1, workload of 175 W) or when reaching a work load level of 200 W (n = 18). All subjects reached 80% of the age-predicted heart rate.

Measurements during hypoxia.   During the study, the subjects were supine and breathing a gas mixture of 12% oxygen and 88% nitrogen from a 30-liter reservoir bag over a face mask. This partial pressure of O₂ in the inspired air corresponds to an altitude of 4,500 m. The fraction of inspired oxygen, minute ventilation, end-tidal oxygen and carbon dioxide concentrations were measured intermittently, while oxygen saturation and heart rate were recorded continuously using a fingertip pulse oxymeter (Biox 3700; Ohmeda, Louisville, Colorado). Systemic arterial pressure and heart rate were measured with a Finapress blood pressure monitor (Ohmeda). Arterial blood was obtained before and at 90 min of hypoxic exposure by a Microsampler (Biomedical Industrade, Graz, Austria) from a radial artery and analyzed with a blood gas CO-oxymeter (model 845; Bayer Diagnostics, Fernwald, Germany). Echocardiographic variables were obtained at rest and during hypoxia at 45, 90 and 240 min.

Left ventricular diastolic filling.   Mitral inflow velocities were measured by pulsed-wave Doppler echocardiography at the tip of the mitral leaflets. Measurements were obtained at rest, at peak exercise and during prolonged hypoxia at time periods of 45, 90 and 240 min. Ratios of peak early (E) to late (A) diastolic filling velocities (E/A) were derived off-line from digitized mitral inflow tracings. An E/A ratio < 1.0 was considered abnormally low, consistent with impaired LV relaxation.

Statistical methods.   Data in figures and tables are given as mean values ± SD. All reported values of PASP represent the mean of at least three measurements. Comparisons between groups at particular examinations were performed by Mann-Whitney-Wilcoxon test. The correlation between the PASP increase with hypoxia and normoxic exercise was calculated. Differences from baseline in estimated PASP, heart rates and cardiac output between both groups were assessed using the Mann-Whitney-Wilcoxon test. In all repeated measurements, Bonferroni correction was performed by multiplication of the p value with the number of comparisons. Any p values < 0.05 were considered statistically significant.

	Results

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Blood gas analysis and pulmonary vascular responses with hypoxia.   Blood gas analysis
Arterial blood gases were not significantly different between the groups before and at 90 min of hypoxia (Table 1). There was, however, a trend to lower PaO₂ and SaO₂ values with hypoxia despite higher ventilation, as indicated by lower PaCO₂ and more pronounced alkalosis in HAPE-S as compared with control subjects. Heart rates and systemic arterial blood pressures did not change significantly in either group during hypoxia.

View larger version (19K): [in this window] [in a new window]   Figure 1 PASP response to prolonged hypoxia. Discrimination between controls and HAPE-S subjects by their PASP response to hypoxia estimated by Doppler-echocardiography. HAPE-S, subjects susceptible to high altitude pulmonary edema (n = 9); CONTROLS, control subjects (n = 11). The study was discontinued at 55 min of hypoxia in one control subject. No significant differences at rest between both groups (p = 0.36). *PASP in HAPE-S subjects compared with control subjects at 45 (p = 0.0012), 90 (p = 0.0016) and 240 (p < 0.02) min of hypoxia.

View larger version (21K): [in this window] [in a new window]   Figure 2 Time course of PASP changes during supine bicycle exercise. Discrimination between HAPE-S vs. control subjects at 50 (p = 0.24), 75 *(p = 0.03), 100 **(p = 0.06) and 125 W ***(p = 0.06).

View larger version (21K): [in this window] [in a new window]   Figure 3 PASP response to exercise. Discrimination between controls and HAPE-S subjects by their PASP response to exercise estimated by Doppler echocardiography. HAPE-S, subjects susceptible to high-altitude pulmonary edema (n = 9), CONTROLS, control subjects (n = 11). No significant differences at rest between both groups (p = 0.28). *Mean maximal PASP in controls (36 ± 3 mm Hg) vs. HAPE-S (55 ± 11 mm Hg) subjects, p < 0.002.

Changes of LV diastolic filling during hypoxia and exercise.   Six of nine HAPE-S subjects revealed dyscoordinated septal motion and mitral inflow patterns of impaired LV relaxation (E/A < 1.0) during exercise and hypoxia. Impaired relaxation was documented only in one subject of the control group, who revealed hypertensive blood pressures at rest and during exercise. Therefore, E/A ratio was significantly lower in HAPE-S than in control subjects during maximal exercise and after 45 min of hypoxia (Fig. 4).

View larger version (26K): [in this window] [in a new window]   Figure 4 Impaired LV relaxation in HAPE-S subjects during exercise and prolonged hypoxia assessed from mitral inflow velocities. Both exercise and prolonged hypoxia decreased E/A ratios to levels < 1.0 in six of nine patients susceptible to HAPE but in only one control patient; *p = 0.01 at peak exercise, and at **45, ***90 and ****240 min of hypoxia.

	Discussion

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PASP changes during prolonged hypoxia.   During hypoxia, PASP increased in all subjects. HAPE-S subjects had significantly greater increases in PASP during prolonged acute hypoxia than did controls. There was little overlap between the PASP values of the groups. The greater increase of PASP in HAPE-S subjects is consistent with measurements in previous studies using right heart catheterization (9,10,24) or Doppler echocardiography (11,12). However, there was a considerable overlap in pulmonary artery pressure between HAPE-S and control subjects when Doppler assessment was used (12,13). Hohenhaus et al. (14) did not find significant differences in PASP of seven HAPE-S and control subjects during 10 min of hypoxia. The better discrimination between groups in our study is most likely due to the longer exposure of the subjects to hypoxia. Maximal PASP values was reached in our study population after 90 min of hypoxia. Whereas previous authors have assumed that a change in pulmonary vascular resistance occurs within minutes of exposure to hypoxia (25,26), a recent study has demonstrated that PASP reaches a maximum after 2 h of isocapnic hypoxia (14). This prolonged time course is in accordance with that observed in our study.

Stress Doppler echocardiography.   To the best of our knowledge, this is the first report of stress echocardiography as a method to identify HAPE-S subjects. Our results are in accordance with previous studies that observed an increase of PASP during normoxic exercise in HAPE-S subjects assessed by right heart catheterization (10,11,15). Kawashima et al. (10) measured a greater than twofold increase in mean pulmonary artery pressure in five HAPE-S compared with five control subjects during normoxic supine low-level exercise of 25 to 50 W. Eldridge et al. (15) found a twofold greater increase of mean pulmonary artery pressure during heavy upright exercise in individuals with a history of HAPE compared with controls, similar to our findings. Janosi et al. (22) documented invasively an upper limit of PASP during supine bicycle exercise of 38 mm Hg in subjects aged 15 to 50 years. Therefore, in our study, 40 mm Hg was taken as an upper limit of normal PASP. In none of our control subjects did PASP exceed 40 mm Hg during exercise.

The fact that exercise in normoxia and supine position as well as hypoxia cause an abnormal increase in pulmonary artery pressure in HAPE-S subjects suggests that they have an intrinsic heightened vasoreactivity of the pulmonary circulation. This hypothesis is supported by the observation that there is a strong correlation between the PASP increase with 90 min of hypoxia and with normoxic exercise. Reduced vascular cross-sectional area due to smaller and less distensible lungs may also contribute to this vasoreactivity because smaller vital capacity (13,15,24,27) and lower functional residual capacity as well as lower maximal CO diffusing capacity (27) have been found in HAPE-S individuals.

Left ventricular function.   There was evidence for developing diastolic dysfunction during stress and hypoxia in subjects susceptible to HAPE. Six of the subjects in this group revealed mitral inflow patterns consistent with impaired relaxation and septal dyscoordiniation during hypoxia and exercise. In contrast, these patterns were detected in only one control subject with systemic arterial hypertension. The exact mechanism of this observation is not clear, because hemodynamic factors directly influencing mitral inflow such as left ventricular filling pressure, left atrial pressure and operating chamber compliance were not controlled in this study. However, it may be speculated that the acute rise of PASP during hypoxia, associated with dyscoordinated septal movement, mechanically impedes mitral inflow, as suggested by Ritter et al. (28). Direct alterations of active myocardial relaxation are unlikely because hypoxic conditions were similar for both groups, but reduced E/A patterns developed predominantly in the group susceptible to HAPE. Heart rate and blood pressures were similar in both groups and are unlikely to account for the observed impairment of early diastolic filling in HAPE-S.

Systolic left ventricular dysfunction has been demonstrated in chronic pulmonary hypertension secondary to chronic pulmonary diseases (29). However, in our study, the systolic LV function improved rather than decreased both during hypoxia and exercise in all subjects. This is in accordance with the findings of Suarez et al. (30), who echocardiographically documented a significant increase in LV EF in healthy subjects during exercise at a simulated altitude of 8,840 m. This improvement was associated with elevated circulating catecholamines reflecting enhanced sympathetic activity.

Study limitations.   In previous studies, the investigators could measure PASP in about 40% to 85% of subjects, although echocardiographic contrast agents were used to enhance the Doppler signal and to improve accuracy of the investigation (13,17,20). In our study, we had only a small dropout rate (5%) due to insufficient Doppler signals. This might be due to differences in study population and ultrasound equipment used in our study. Whereas others examined patients with heart disease, our study population consisted of healthy, athletic subjects. Furthermore, there exist only few data on PASP measurements on stress Doppler echocardiography, and since then, a new generation of echocardiographic machines have been developed with a marked improvement of Doppler functions. Measurements by stress echocardiography may be further limited by the fact that PASP cannot be estimated by Doppler ultrasound in all subjects, especially at high levels of exercise with heart rates >120 beats/min. In our study, PASP were obtained up to a heart rate of 120/min. Because PASP rises considerably at the beginning of exercise, a good discrimination between both groups was seen within the first stages of exercise.

Clinical implications.   HAPE-S subjects revealed a greater increase in estimated PASP during supine bicycle exercise at 50 to 125 W workload than nonsusceptible subjects without overlap of individual values. Differences of PASP during hypoxia are most prominent with minimal overlap between HAPE-S and control subjects after 90 min of exposure. Therefore, stress Doppler echocardiography during supine bicycle exercise or prolonged hypoxia may be a useful, widely available screening method for this life-threatening disorder. It needs, however, to be validated in a larger group of subjects before it can be recommended for clinical practice.

	Acknowledgments

 
We gratefully thank all the mountaineers who participated in this study. We thank M. Schuster of the Department of Sports Medicine for his excellent technical assistance, and K. Unnebrink of the Institute of Biometry, University of Heidelberg, for critical review of statistical analysis.

	References

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