Effect of Natural Oxygen Enrichment at Low Altitude on Oxygen-Dependent Patients with End-Stage Lung Disease

  1. Mordechai R. Kramer, MD;
  2. Chaim Springer, MD;
  3. Neville Berkman, MBBCh;
  4. Ephraim Bar-Yishay, PhD;
  5. Avraham Avital, MD;
  6. Avigdor Mandelberg, MD;
  7. Dov Effron, MD; and
  8. Simon Godfrey, MD, PhD, FRCP
  1. From the Institute of Pulmonology, Hadassah University Hospital, Jerusalem, Israel. Requests for Reprints: Mordechai R. Kramer, MD, Institute of Pulmonology, Hadassah University Hospital, P.O. Box 12000, Jerusalem, Israel.
     
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    Abstract

    Objective: To assess the effect of lowering altitude to that of the lowest place on earth (Dead Sea) on arterial oxygenation and exercise performance in patients with hypoxemia and end-stage lung disease.

    Design: A cohort of 10 patients.

    Setting: Pulmonary function laboratories in Jerusalem, Israel, and at the Dead Sea.

    Patients: 10 patients with end-stage lung disease who were receiving long-term oxygen therapy. The 4 males and 6 females were 12 to 77 years old. Four patients had chronic obstructive pulmonary disease; 2 had cystic fibrosis; 3 had pulmonary fibrosis; and 1 had pulmonary hypertension (thromboembolic). Mean forced vital capacity was 1.54 L (54% of predicted value) and mean forced expiratory volume in 1 second was 0.85 L (35% of predicted value).

    Measurements: Spirometry, blood gas analysis, progressive exercise testing, and sleep oximetry were done in Jerusalem (altitude, 800 m above sea level; barometric pressure, 696 mm Hg); the same measurements were done 6 days after arrival at the Dead Sea (altitude, 402 m below sea level; barometric pressure, 800 mm Hg) and then 7 to 14 days later in Jerusalem.

    Results: Arterial oxygenation increased from a median partial pressure of arterial oxygen of 51.6 mm Hg in Jerusalem to 67.0 mm Hg at the Dead Sea, an increase of 15.2 mm Hg (95% CI of paired difference, 4.1 to 20.4 mm Hg; P = 0.001). Partial pressure of arterial carbon dioxide increased from a median of 43.2 to 45.9 mm Hg, an increase of 2.7 mm Hg (CI, 0.5 to 6.4 mm Hg; P = 0.004), with a borderline significant change in the alveolar-arterial gradient. Arterial oxygen saturation increased from a median of 87.7% to 92.8%, a change of 4.8% (CI, 1.9% to 9.8%; P = 0.003). Exercise performance also improved as maximum oxygen uptake increased from a median of 827 mL/min to 1056 mL/min, an increase of 203 mL/min (CI, 54 to 388 mL/min; P = 0.006). Sleep oximetry also improved as median arterial oxygen saturation measured during sleep increased from 85% to 90%, a change of 5% (CI, 2% to 7%; P = 0.005), and percentage of sleep time with an oxygen saturation rate of 90% or more increased from a median of 24% to 73%, a change of 49% (CI, 20% to 87%; P = 0.02). No change in spirometry was noted. All patients felt less dyspneic and reported improved functional capacity with reduced need for oxygen.

    Conclusion: Descent to low altitude can improve arterial oxygenation, exercise performance, and sleep oximetry and consequently the quality of life in patients with hypoxemia and advanced lung disease.

    Long-term home oxygen therapy is the standard of care for patients with chronic obstructive pulmonary disease and end-stage lung disease with chronic hypoxemia [1-6]. Oxygen therapy improves functional and exercise capacity [4-7], reduces pulmonary hypertension, and improves right ventricular function [8, 9] and survival [10, 11]. This important tool in pulmonary medicine involves substantial cost and requires continuous maintenance of equipment and patient cooperation. Further, despite the major advances in portable oxygen devices, quality of life for patients receiving long-term oxygen therapy is substantially impaired because of the constant dependence on an oxygen source and equipment. An alternative to portable oxygen therapy is the natural oxygen enrichment resulting from high barometric pressure at altitudes below sea level, but this has not been investigated and is not routinely recommended by pulmonary physicians or in any major textbook in pulmonary medicine. To assess this therapeutic option, we took advantage of the natural topography of the Dead Sea and its holiday resorts that lie at the lowest natural altitude on earth (402 m below sea level), a short distance (40 km) from Jerusalem, which lies 800 m above sea level. This yields a 1200-m difference in altitude between the two locations. The alveolar oxygen concentration can be calculated using the following equations:

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

    PAO2 Dead Sea = (800 −47) × 0.21 −PaCO2/0.8 = 158.1 -

    PaCO2/0.8

    PAO2 Jerusalem = (696 −47) × 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.

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    Methods

    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).

    View this table:
    Table 1. Demographic Data of Patients with End-Stage Lung Disease*
    View this table:
    Table 2. Pulmonary Function of Patients*

    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.

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    Results

    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 this table:
    Table 3. Blood Gas Analysis in Jerusalem and at the Dead Sea*
    Figure 1. Partial pressure of arterial oxygen (Pa ). Partial pressure of arterial carbon dioxide (Pa ). Arterial oxygen saturation (Sa ). Alveolar-arterial (A-a) gradient.
    View larger version:
      Figure 1. Partial pressure of arterial oxygen (Pa ). Partial pressure of arterial carbon dioxide (Pa ). Arterial oxygen saturation (Sa ). Alveolar-arterial (A-a) gradient. Blood gas analysis of 10 patients in Jerusalem (before traveling to the Dead Sea resort) and at the Dead Sea.Top left.O2Top right.CO2Bottom left.O2Bottom right.

      Exercise Performance

      Results of exercise testing are given in Table 4. Maximal oxygen uptake (VO2max) increased with the descent to the Dead Sea compared with the results obtained in Jerusalem. After the return to Jerusalem, VO2max 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.

      View this table:
      Table 4. Progressive Exercise Testing in Jerusalem and at the Dead Sea*

      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.

      Figure 2. Mean sleep arterial oxygen saturation. Percentage of sleep time with saturation greater than 90%.
      View larger version:
        Figure 2. Mean sleep arterial oxygen saturation. Percentage of sleep time with saturation greater than 90%. Sleep oximetry in six patients in Jerusalem and at the Dead Sea.Left.Right.
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        Discussion

        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 VO2max 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 VO2max did. Because cardiac output increases linearly with VO2, 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.

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        1. Ann Intern Med November 1, 1994 vol. 121 no. 9 658-662
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