PAO₂ = (barometric pressure –47) x FIO₂ – Pa CO₂/0.8

PAO₂ Dead Sea = (800 –47) x 0.21 –PaCO₂/0.8 = 158.1 -

PaCO₂/0.8

PAO₂ Jerusalem = (696 –47) x 0.21 –PaCO₂/0.8 = 136.3 -

PaCO₂/0.8

Additional inspired PO₂ = 21.8 mm Hg – Delta PaCO₂/0.8, where PAO₂ is the partial pressure of alveolar oxygen; FIO₂ is the fractional concentration of oxygen in inspired gas; PaCO₂ is the partial pressure of arterial carbon dioxide; and PO₂ is the oxygen pressure.

We investigated the short-term effect of lowering altitude in 10 patients with various lung diseases who used oxygen on a long-term basis and compared arterial oxygenation, spirometry, exercise tolerance, and oxygen saturation values during sleep at high and low altitudes.

Methods

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We studied 10 oxygen-dependent patients attending the pulmonary clinic at Hadassah University Hospital in Jerusalem, Israel. Table 1 summarizes demographic data and diagnoses. The five males and five females, 12 to 77 years of age, had severe obstructive or restrictive lung disease, as indicated by their lung function results (Table 2).

Barometric pressure was measured daily during the study. In Jerusalem it was between 696 and 697 mm Hg and at the Dead Sea it was between 797 and 800 mm Hg.

We studied patients in Jerusalem 7 to 10 days before their descent to the Dead Sea resort area, on day 6 of their stay at the Dead Sea, and 7 to 14 days after returning to Jerusalem. The equipment and staff were the same at both locations. Each patient had the following studies on each examining day.

Blood Gas Analysis

Using radial arterial puncture and topical anesthesia, we obtained arterial blood while patients breathed room air. We used a Corning 175 gas analyzer (Corning, New York) to do blood gas analyses.

Spirometry

We measured spirometry and maximal voluntary ventilation for 12 seconds using an electronic spirometer (Vitalograph, Ltd., Buckingham, United Kingdom). The predicted values we used were European Coal Conference Standard 1983. In Jerusalem, we also measured lung volumes by whole-body plethysmography and carbon monoxide diffusion capacity by the single-breath method using MedGraphics equipment (Medical Graphics Corp., St. Paul, Minnesota). Data were corrected for body temperature and ambient pressure, saturated with water vapor (BTPS).

Exercise Testing

Patients performed incremental exercise tests using an electronically braked cycle ergometer (MedGraphics CPE 2000, Medical Graphics Corp.) and a breath-by-breath analyzing system (MedGraphics CPX, Medical Graphics Corp.). After a rest period of 2 minutes, the patients peddled at 60 rpm without added load for 2 minutes. The work load was then increased gradually in a ramp pattern at a rate calculated so each patient would complete the exercise in 6 to 10 minutes. The patients continued the test to their symptom-limited maximum capacity [12]. Data were corrected for BTPS or STPD (the gas volume at standard temperature and pressure, free of water vapor) at both locations.

Sleep Oximetric Study

Continuous nocturnal sleep oximetry was studied in Jerusalem and at the Dead Sea in six patients (patients 1, 2, 3, 4, 5, and 8). We used a Nonin 8600 finger oximeter and 8586 printer interface module (Nonin Medical, Plymouth, Minnesota). Minute-by-minute data and histograms were printed each morning after the night study was completed.

Statistical Analysis

Data are expressed as medians and observed paired differences with corresponding 95% confidence intervals of the median paired differences. We used the Wilcoxon matched-pairs signed-rank test to determine the significance of differences. Probability values less than 0.05 were considered significant.

We obtained informed consent from all patients, and the study was approved by the Helsinki Committee of Hadassah University Hospital.

Patients were interviewed before each study and were asked about their general well-being, use of oxygen, daily activities, and exercise capacity.

Results

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Spirometry

There were no significant differences in spirometry values at the two locations.

Arterial Blood Gases

Results of analyses are shown in Figure 1 and Table 3. Arterial PO₂ increased from a median of 51.6 mm Hg in Jerusalem to 67.0 mm Hg at the Dead Sea, an increase of 15.2 mm Hg (CI, 4.1 to 20.4 mm Hg). The PaCO₂ values also increased but to a lesser degree. The alveolar-arterial gradient did not change substantially, and pH remained unchanged. After the return to Jerusalem, the values returned to those found before descent to the Dead Sea.

View larger version (43K): [in this window] [in a new window]   Figure 1. Blood gas analysis of 10 patients in Jerusalem (before traveling to the Dead Sea resort) and at the Dead Sea. Top left. Partial pressure of arterial oxygen (PaO2). Top right. Partial pressure of arterial carbon dioxide (PaCO2). Bottom left. Arterial oxygen saturation (SaO2). Bottom right. Alveolar-arterial (A-a) gradient.

Exercise Performance

Results of exercise testing are given in Table 4. Maximal oxygen uptake (VO_2max) increased with the descent to the Dead Sea compared with the results obtained in Jerusalem. After the return to Jerusalem, VO_2max returned to the previous level. The anaerobic threshold did not change significantly (median of 650 mL/min in Jerusalem and 710 mL/min at the Dead Sea; P = 0.5). We also found no significant differences in minute ventilation during rest and maximal exercise, although heart rate increased slightly. End tidal carbon dioxide and oxygen pulse (VO₂/heart rate) increased during rest and maximal exercise at the Dead Sea compared with the values measured in Jerusalem. At peak exercise, oxygen saturation decreased at both locations to the same degree.

Nocturnal Oximetry

Results of nocturnal oximetry are shown in Figure 2. Six patients had oximetric monitoring during the night. All reported usual sleep with a median duration of 5.5 hours in Jerusalem and 5.2 hours at the Dead Sea. Median oxygen saturation increased from 85% in Jerusalem to 90% at the Dead Sea, a change of 5% (CI, 2% to 7%; P = 0.005). The percentage of total sleep time with oxygen saturation greater than 90% increased from a median of 24% in Jerusalem to 73% at the Dead Sea, an increase of 49% (CI, 20% to 87%; P = 0.02). Median heart rate during sleep was 82 beats/min in Jerusalem and 76 beats/min at the Dead Sea (P = 0.25). When questioned, all patients reported an improvement in their general well-being, with less need for oxygen during simple daily activities compared with their usual activities in Jerusalem.

View larger version (23K): [in this window] [in a new window]   Figure 2. Sleep oximetry in six patients in Jerusalem and at the Dead Sea. Left. Mean sleep arterial oxygen saturation. Right. Percentage of sleep time with saturation greater than 90%.

Discussion

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Our study clearly shows the increase in arterial oxygen tension with the relatively mild change in altitude of 1200 m. The increase of 10 to 12 mm Hg in PaO₂ is a substantial improvement for patients with hypoxemia, which can shift their percentage saturation on the oxygen dissociation curve from the low to mid-80s to the low 90s. This may reduce pulmonary vascular resistance and pulmonary hypertension. The improvement in oxygenation caused a mild increase in arterial carbon dioxide tension, as is commonly found with the application of external oxygen in patients with chronic obstructive pulmonary disease. The addition of approximately 21 mm Hg inspired PO₂ is equivalent to about a 4% increase in FIO₂ in the Jerusalem area or to a nasal cannula with continuous oxygen flow of about 1 L per/min. The major advantage, however, is elimination of the need for external devices and tubing and assurance that the patient receives oxygen 24 hours a day, thus improving quality of life and psychological well-being and increasing independence.

Since early studies by Abraham and colleagues [13] and Petty and Finigan [14], oxygen therapy has been considered one of the basic modes of therapy in patients with chronic obstructive pulmonary disease and other end-stage lung diseases. Oxygen therapy reduced the mortality rate and increased survival in patients in several large-scale studies [2, 3]. Researchers think the mechanism by which oxygen improves survival is reduced pulmonary vascular resistance and pulmonary artery pressure [10, 13]. Exercise capacity improves after administration of oxygen in other studies [15, 16], probably by a similar mechanism.

A study in Colorado [17] showed that survival of patients with emphysema was better at low altitudes compared with survival at high altitudes (the Denver area). Renzetti and coworkers [18] previously made a similar observation. Veterans with chronic obstructive pulmonary disease living at moderate altitudes in Utah and New Mexico had higher mortality rates than did those living at lower altitudes. Another study in Colorado [19] reported higher mortality rates from respiratory diseases in infants born at high altitudes than those living at low altitudes. Recently, Cote and associates [20] clearly showed the association between altitude and death in patients with chronic obstructive pulmonary disease in the United States. Death from chronic obstructive pulmonary disease increased by 1 per 100 000 inhabitants for each 95-m increase in resident's altitude and was independent of smoking severity. For example, death in Colorado (altitude, 1627 m; PAO₂, 134 mm Hg) was 40 per 100 000, whereas in Miami (altitude, 5 m; PAO₂, 159 mm Hg) the mortality rate was only 25 per 100 000.

Sleep hypoxemia is an important factor in the development of pulmonary hypertension, even in patients with a borderline PaO₂ of 60 mm Hg when awake [21]. Investigators noted a higher mortality rate in patients with chronic obstructive pulmonary disease and a greater degree of sleep desaturation [22-25]. Our oximetric data showed a substantial improvement in sleep oxygen saturation at low altitude such that some patients maintained saturation at more than 90% for more than 80% of their sleep time, and therefore they did not require oxygen at all.

Exercise performance is improved in patients with chronic obstructive pulmonary disease and in those with interstitial lung diseases when oxygen is supplemented [12]. Our study shows that VO_2max increased substantially by 20% after arrival at the Dead Sea. Staying longer at the low altitude and prolonging exposure to increased inspired oxygen may further improve exercise capacity.

The increase in oxygen pulse indicates that more oxygen is extracted by the contracting muscles during exercise, resulting in increased exercise performance. Heart rate did not increase at maximal exercise, although VO_2max did. Because cardiac output increases linearly with VO (₂), stroke volume probably increased during exercise at the Dead Sea as a result of decreased pulmonary vascular resistance induced by higher inspired oxygen [26].

The beneficial effect of lowering altitude noted in our patients may not be assessed in patients with intrapulmonary or intracardiac shunt. For example, patient 10, who had pulmonary thromboembolic disease with a probable intrapulmonary shunt, showed no improvement in oxygenation while at the Dead Sea (see Figure 1, top left).

The minimal descent in altitude needed for clinical improvement must still be studied. A 800- to 1200-m difference is sufficient to create a substantial effect on arterial oxygenation. A 500-m difference causes a 10 mm Hg increase of inspired oxygen pressure and a subsequent increase of 4 to 6 mm Hg in arterial oxygen tension. Although this increase seems unimportant, it can still improve arterial oxygen saturation to some extent in end-stage lung disease and may reduce pulmonary vascular resistance.

The other unanswered question is to what extent improvement in oxygenation and exercise performance lasts after leaving the area. O'Donohue [27] showed that after 6 months of oxygen therapy, arterial oxygen tension increased in about 20% of patients, probably because of improved ventilation perfusion matching. This was thought to be a result of the beneficial and perhaps therapeutic effect of oxygen on pulmonary hemodynamics and on gas transport. In our 1-week study, we noted no continuous positive effect when the patients returned to Jerusalem. However, a longer stay may produce such a positive effect, although most patients will probably need oxygen supplementation indefinitely.

We conclude that descent to an altitude below sea level can improve arterial oxygenation, exercise performance, and quality of life in patients with hypoxemia and end-stage lung disease. Our study was limited because it involved a small number of patients with various lung diseases. Further large-scale studies are needed to assess the effect of a long stay at low altitude and the minimal altitude difference required to produce a positive effect on pulmonary hypertension and survival. Based on the results of this pilot study, patients with hypoxemia who live at high altitudes can be advised to move to lower areas if feasible.