Lesson 7, Volume 16—Oxygen Therapy in COPD: Persistent Controversies

By Eugene C. Fletcher, MD; and Nasser Zakieh, MD

Objectives

1. Review the mechanisms by which oxygen potentially improves survival in COPD.
2. Discuss the use of oxygen in exercise-induced hypoxemia.
3. Brief discussion about oxygen desaturation during meals.
4. Review the effects of oxygen treatment on outcome in patients with isolated nocturnal oxygen desaturation.
5. Discuss the adequacy of oxygen therapy and the need for its documentation.

Key words

COPD; nocturnal; oxygen; oxygen desaturation; rapid eye movement sleep; sleep

Abbreviations

LTOT = long-term oxygen therapy; REM = rapid eye movement

Favorable Response to Oxygen in Continuously Hypoxemic Patients

Two controlled studies have documented survival benefits of oxygen therapy in COPD patients whose PaO₂ is < 55 mm Hg: the British Medical Research Council study¹ and the Nocturnal Oxygen Therapy Trial.² In the first study, oxygen was given approximately 15 h/d and compared with air. In the second, ambulatory continuous oxygen therapy (mean, 19.4 h/d) was compared with nocturnal oxygen therapy from a stationary source (mean, 11.8 h/d). Ambulatory continuous oxygen therapy showed the most survival benefit when compared with stationary nocturnal oxygen or air alone. In patients with less severe hypoxemia (PaO₂ > 55 mm Hg), LTOT oxygen provided no survival benefit according to a 1970 study by Neff and Petty³ and more recent studies by Górecka et al⁴ and Veale et al.⁵ The investigators in the latter study found that the survival of patients with PaO₂ ranging from 50 to 59 mm Hg was similar to patients with PaO₂ < 60 mm Hg.⁵ The degree of airflow obstruction has beenfound to be the single most consistent factor predicting survival.⁶ In addition the presence of hypoxemia shifts the survival rate downward for any given FEV₁ level.

Potential Mechanisms by Which Oxygen Therapy Improves Survival

Pulmonary hypertension in COPD is associated with increased risk of hospitalization and death. Controlled and noncontrolled studies have shown that supplemental oxygen ameliorates elevated pulmonary artery pressure to a variable degree. Animal experiments showed that as little as 4 h of hypoxia per day results in pulmonary arterial hypertension and right ventricular hypertrophy after a certain number of exposures.^7,8 The pulmonary vasculature undergoes changes under the influence of chronic alveolar hypoxia, some of which are reversible but most are not. Alveolar hypoxia (along with respiratory acidosis) triggers hypoxic pulmonary vasoconstriction and its attendant increase in pulmonary vascular resistance. It also causes increased right ventricular afterload, which results in right ventricular hypertrophy and failure with its characteristic clinical features.^9-11 Erythrocytosis and respiratory acidosis add more load to the failing right ventricle. LTOT improves the former circumstance but is of unclear value in the latter.

Histopathologic studies of the pulmonary arteries of patients who died after receiving LTOT have shown persistent structural changes, especially in the intima of small pulmonary arteries and arterioles.^12,13 Hypoxic changes in the myofibroblasts of the pulmonary vessel wall and noncellular intimal fibroblastic sequelae seem to be terminal.¹³ Despite that, there is evidence that LTOT prevents the progression of hypoxic pulmonary hypertension associated with COPD.¹⁴

Improvement in pulmonary hemodynamics is believed by many investigators to be one of many other factors contributing to improved survival in COPD patients receiving LTOT. Furthermore, the degree of hemodynamic response, acute or chronic, does not consistently predict survival.^15-17 Other hemodynamic variables, such as mixed venous PaO₂ and coefficient of oxygen extraction, have been examined. Higher values were associated with better 5-year survival.¹⁸ Improved cardiac output, oxygen delivery, and improved right ventricular function were all suggestive of improved survival.^18-20

Peripheral vascular factors that improve skeletal muscle oxygen and energy utilization on the molecular and enzymatic level suggests a contributing factor to the improved exercise tolerance and endurance that is reported in hypoxemic COPD patients receiving LTOT.²¹ Autonomic nervous system dysfunction associated with hypoxia and its partial reversibility with administration of oxygen have made some investigators suggest that autonomic dysfunction may contribute to mortality and that LTOT improves survival by ameliorating such dysfunction.²²

Neuropsychologic Benefits

LTOT has been shown in several studies to improve neuropsychologic function.^23-25 Among those cognitive functions studied, there was a significant improvement in the speed of work and recent verbal memory, a reduction in depression and anxiety score, and improvement in the psychological tension, general mood, self-esteem, and attitude toward life and therapy. This improvement in neuropsychologic status was attained despite continued deterioration in lung function. Nonspecific effects of improved mobility, reduced breathlessness, and the sense of security resulting from frequent follow-up visits were also possible contributing factors toward improved neuropsychologic function.²⁶

Quality of life, including such factors as energy, emotional liability, sleep, social life, and physical mobility, is impaired in COPD patients. Such impairment correlates with the degree of lung dysfunction. LTOT was shown to improve some of the components of quality of life including distance walked during the day, activities of daily living, and standardized scales such as St. George's Respiratory Questionnaire and Nottingham Health Profile.²⁷ It is not clear if such improvement contributes to improved longevity.

Mild Hypoxemia and Exercise Desaturation

LTOT in COPD patients with only mild hypoxemia and exercise desaturations was evaluated in one study in which patients received 6 weeks of oxygen.²⁸ There was a small but statistically significant benefit in terms of 6-min walk test and quality of life score, but not in dyspnea score or exercise testing. Exercise training was not part of this study.²⁸ In other studies, supplemental oxygen was found to facilitate exercise training and improve rehabilitation program results in COPD patients.^29,30 Some authors observed an improvement in exercise capability in COPD patients who received supplemental oxygen.³⁰ A number of studies have shown that patients with chronic lung disease who do not have exercise desaturation may also benefit from oxygen supplementation during exercise testing. The positive impact of oxygen therapy on ventilatory muscle load, degree of dyspnea, cardiac function, and wasted ventilation suggests that multiple factors are involved. More research is needed to define the patient population and the degree of exertional desaturation that will respond the most to oxygen supplementation.

Oxygen desaturation during meals and during other daily activities is well described in COPD patients with or without resting hypoxemia. The proposed etiology is a ventilation-perfusion mismatch associated with irregular breathing during chewing and swallowing. In one study, transcutaneous PCO₂ did not change significantly during episodes of desaturation associated with meals, making hypoventilation an unlikely etiology. We are unaware of any human study in the English language that has addressed the issue of oxygen supplementation or its benefits in this group of patients.^31-33

Intermittent nocturnal oxygen desaturation is common in patients with chronic lung disease. It may happen during any sleep stage but is most common during rapid eye movement (REM) sleep, when it may be frequent and severe. During REM sleep, there is inhibition of motor activity due to neuronal hyperpolarization generated in the brainstem. This results in generalized loss of skeletal muscle tone, including respiratory muscles. The respiratory outcome is a decrease in tidal volume as well as fall in functional residual capacity with worsening ventilation-perfusion mismatch. Episodic REM nocturnal oxygen desaturation occurs in about 25% of COPD patients with daytime PaO₂ > 60 mm Hg.³⁴ So far, no clinical trial has been able to document a survival benefit for nocturnal oxygen in this group of patients, despite reduction in pulmonary artery pressure.^35,36

With this in mind, it is difficult to justify the common practice of screening for desaturation or treating this group of patients with nocturnal supplemental oxygen. On the other hand, the presence of cor pulmonale, erythrocytosis, or right ventricular enlargement on ECG may warrant full nocturnal polysomnography to exclude the possibility of very severe hypoxemia or the concurrent existence of obstructive sleep apnea. Nocturnal polysomnography in the COPD patient is also recommended if the diagnosis of obstructive sleep apnea is suspected based on history and physical examination.

Compliance and Adequacy of Oxygen Therapy

Oxygen desaturation has been documented in patients with or without resting daytime hypoxia receiving oxygen therapy at home. It is not clear if prolonged monitoring of arterial oxygen saturation at home and gauging O₂ to keep oxygen saturation > 88% will have any impact on the patient's morbidity or mortality. In one study, only 45% of patients receiving LTOT were found to be using their oxygen for > 15 h/d.³⁷ In selected patients with COPD receiving LTOT, oxygen prescription and usage were found to be inadequate, compared with when managed by chest physicians.³⁷

Summary

The literature on patients with continuous hypoxemia and COPD firmly supports the use of supplemental oxygen to improve survival. It appears to improve pulmonary hemodynamics and extend patient longevity. Furthermore, in patients with hypoxemia, a select group may show improvement in neuropsychologic function when provided with supplemental oxygen. In patients with borderline hypoxemia (PaO₂ > 60 mm Hg), the medical literature is much less clear in terms of improvement in function. There are studies that suggest exercise capability may be improved, especially in the setting of exercise-induced desaturation. It has also been shown, in limited studies, that supplemental oxygen during pulmonary rehabilitation programs can improve peak performance. It has not been demonstrated that oxygen saturation during eating or during coughing contributes to pulmonary hypertension or that this desaturation needs to be treated. Intermittent hypoxemia during sleep, especially associated with REM desaturation, is often associated with a severe, acute rise in pulmonary artery pressure and is frequently associated with mild, chronic pulmonary hypertension. Treatment with supplemental oxygen during sleep, however, has not been demonstrated to improve survival in either of two prospective studies published within the past 5 years. The prescription of supplemental oxygen for REM desaturation during sleep in patients whose PaO₂ is > 60 mm Hg during the day should probably be reserved for those patients with signs of right ventricular hypertrophy or cor pulmonale.

References

1. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema: report of the Medical Research Council Working Party. Lancet 1981; 1(8222):681–686
2. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial; Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 1980; 93:391–398
3. Neff TA, Petty TL. Long-term continuous oxygen therapy in chronic airway obstruction: mortality in relationship to cor pulmonale, hypoxia and hypercapnia. Ann Intern Med 1970; 72:621–626
4. Górecka D, Grzelak K, Sliwinski P, et al. Effects of long term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxemia. Thorax 1997, 52:674–679
5. Veale D, Chaileux F, Taytard A, et al. Characteristics and survival of patients prescribed long-term oxygen therapy outside prescription guidelines. Eur Respir J 1998, 12:780–784
6. Zielinski J. Effects of long-term oxygen therapy in patients with chronic obstructive pulmonary disease. Curr Opin Pulm Med 1999; 5:81–87
7. Widimsky J, Urbanowá D, Ressel J, et al. Effect of intermittent altitude hypoxia on the myocardium and lesser circulation in the rat. Cardiovasc Res 1973; 7:798–808
8. Fishman AP. State of the art: chronic cor pulmonale (review). Am Rev Respir Dis 1976; 114:775–794
9. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease (review): part one. Am J Respir Crit Care Med 1994; 150:833–852
10. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease (review): part two. Am J Respir Crit Care Med 1994; 150:1158–1168
11. Wilkinson M, Langhorne CA, Heath D, et al. A pathophysiological study of 10 cases of hypoxic cor pulmonale. Q J Med 1988; 66:65–85
12. Magee F, Wright JL, Wiggs BR, et al. Pulmonary vascular structure and function in chronic obstructive pulmonary disease. Thorax 1988; 43:183–189
13. Meyrick B, Reid L. Endothelial and subintimal changes in rat hilar pulmonary artery during recovery from hypoxia: a quantitative and ultrastructural study. Lab Invest 1980; 42:603–615
14. Kessler R, Faller M, Fourgaut G, et al. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:158–164
15. Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy: importance of pulmonary artery pressure. Chest 1995; 107:1193–1198
16. Timms RM, Khaja FU, Williams GW. Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease. Ann Intern Med 1985; 102:29–36
17. Weitzenblum E, Sategeau A, Erhart M, et al. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 131:493–498
18. Kawakami Y, Kishi F, Yamamoto H, et al. Relation of oxygen delivery, mixed venous oxygenation, and pulmonary hemodynamics to prognosis in chronic obstructive pulmonary disease. N Engl J Med 1983; 308:1045–1049
19. Bergofsky EH. Tissue oxygen delivery and cor pulmonale in chronic obstructive pulmonary disease. N Engl J Med 1983; 308:1092–1094
20. Petty TL, Bliss PL. Ambulatory oxygen therapy, exercise, and survival with advanced chronic obstructive pulmonary disease (the Nocturnal Oxygen Therapy Trial revisited). Respir Care 2000; 45:204–211
21. Payen JF, Wuyam B, Levy P, et al. Muscular metabolism during oxygen supplementation in patients with chronic hypoxemia. Am Rev Respir Dis 1993; 147:592–598
22. Scalvini S, Porta R, Zanelli E, et al. Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease. Eur Respir J 1999; 13:119–124
23. Heaton RK, Grant I, McSweeny AJ, et al. Psychologic effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med 1983; 143:1941–1947
24. Borak J, Sliwinski P, Piasecki Z, et al. Psychological status of COPD patients on long term oxygen therapy. Eur Respir J 1991; 4:59–62
25. Incalzi RA, Gemma A, Marra C, et al. Chronic obstructive pulmonary disease: an original model in cognitive decline. Am Rev Respir Dis 1993; 148:418–422
26. Cottrell JJ, Openbrier D, Lave JR, et al. Home oxygen therapy: a comparison of 2- vs 6-month patient reevaluation. Chest 1995; 107:358–361
27. Okubadejo AA, Paul EA, Jones PW, et al. Quality of life in patients with chronic obstructive pulmonary disease and severe hypoxemia. Eur Respir J 1996; 9:2335–2339
28. McDonald CF, Blyth CM, Lazarus MD, et al. Exertional oxygen of limited benefit in patients in patients with chronic obstructive pulmonary disease and mild hypoxemia. Am J Respir Crit Care Med 1995; 152(5 pt 1):1616–1619
29. Kramer MR, Springer C, Berkman N, et al. Rehabilitation of hypoxemic patients with COPD at low altitude at the Dead Sea, the lowest place on earth. Chest 1998; 113:571–575
30. Dean NC, Brown JK, Himelman RB, et al. Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. Am Rev Respir Dis 1992; 146:941–945
31. Soguel Schenkel N, Burdet L, de Muralt B, et al. Oxygen saturation during daily activities in chronic obstructive pulmonary disease. Eur Respir J 1996; 9:2584–2589
32. Brown SE, Casciri RJ, Light RW. Arterial oxygen saturation during meals in patients with severe chronic obstructive pulmonary disease. South Med J 1983; 76:194–198
33. Schols A, Mostert R, Cobben N, et al. Transcutaneous oxygen saturation and carbon dioxide tension during meals in patients with chronic obstructive pulmonary disease. Chest 1991; 100:1287–1292
34. Fletcher EC, Miller J, Divine GW, et al. Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tension above 60 mm Hg. Chest 1987; 92:604–608
35. Fletcher EC, Luckett RA, Goodnight-White S, et al. A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO₂ above 60 torr. Am Rev Respir Dis 1992; 145:1070–1076
36. Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999; 14:1002–1005
37. Kampelmacher MJ, Kesteren RGV, Alsbach GPJ, et al. Prescription and usage of long-term oxygen therapy in patients with chronic obstructive pulmonary disease in the Netherlands. Respir Med 1999; 93:46–51

Copyright ©2002 American College of Chest Physicians