ANNALS of Internal Medicine

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1 ANNALS of Internal Medicine MAY 1970 VOLUME 72 NUMBER 5 Published Monthly by the American College of Physicians Long-Term Continuous Oxygen Therapy in Chronic Airway Obstruction Mortality in Relationship to Cor Pulmonale, Hypoxia, and Hypercapnia THOMAS A. NEFF, M.D., and THOMAS L. PETTY, M.D., Denver, Colorado Thirty-three patients received continuous oxygen therapy from 7 to 41 months. The increased mortality associated with cor pulmonale and severe hypoxia was reduced 30% and 40%, respectively, by this form of therapy when contrasted to other results reported in the literature. Continuous oxygen therapy does not prevent the late development of cor pulmonale, but it does make management significantly more effective when used with an overall care program. Continuous oxygen therapy has little beneficial effect on the mortality of patients with chronic airway obstruction when severe hypoxia or cor pulmonale is not present. T HE PROGNOSIS for patients with chronic airway obstruction has been the subject of many reports (1-8). Certain clinical features and pulmonary function tests at the time of entrance into various study series have been correlated with mortality. Some authors (3, 5, 6) have shown that cor pulmonale has a very adverse From the Respiratory Care Service, Department of Medicine, University of Colorado Medical Center, Denver, Colo. effect on prognosis. Renzetti, McClement, and Litt (6) also showed that patients with chronic airway obstruction who live at moderate elevations (4,000 to 9,000 ft) developed cor pulmonale more frequently than patients at sea level, and the former group had a greater mortality. Mitchell, Webb, and Filley (3) and Boushy and Coates (4) observed that hypoxia and hypercapnia correlate with early death. Almost all authors (2-8) have shown that the greater the degree of expiratory obstruction, the greater the mortality. The majority of reports on prognosis do not stress therapy or imply that therapy does not alter the natural course of disease (8). Thus far, therapy, which is mostly designed to provide symptomatic relief, is directed at reversal of bronchospasm and management of infection (8, 9). Early results of a systematic physiologically oriented care program have demonstrated that by application of breathing training, physical reconditioning, and bronchial hygiene the expected loss of pulmonary function may be slowed (10). That study and an earlier report suggested that continuous oxygen for hypoxemic patients with cor Annals of Internal Medicine 72: ,

2 pulmonale was a practical and effective means of improving exercise tolerance and controlling heart failure (10, 11). The long-term outcome of patients receiving continuous oxygen is of great interest. This report discusses whether oxygen alters prognosis in patients with chronic airway obstruction and cor pulmonale. Materials and Methods Between August 1, 1966, and June 1, 1968, 182 patients with chronic airway obstruction were admitted to a pulmonary rehabilitation program. The detailed criteria for entrance have been previously reported (10). The patients had to have chronic airway obstruction manifested by measured "dynamic" ventilation tests as maximum voluntary ventilation (MVV) and forced expiratory volume in 1 sec (FEV a ) of 60% or less of predicted normal; clinical evidence of disability from their disease; and no other acute disease (for example, cancer, significant angina pectoris) that would interfere with the patient's ability to participate in the program. Patients were accepted in consecutive order without bias of previous forms of therapy and in spite of severe degrees of functional impairment in many cases. The therapeutic program was primarily outpatient and home based. Fifty-three of the 182 patients received supplemental oxygen on an outpatient basis. Of these, 33 received oxygen for 24 hr/day for a period of longer than 1 month (Table 1). These 33 patients are the study group for this report. The main criteria for initiating oxygen was profound disability with an inability to exercise without the aid of supplemental oxygen. All patients had at least mild hypoxemia (percent saturation of arterial hemoglobin with oxygen (Sao 2 ) less than 91% at rest). Many patients had severe hypoxemia (Sao 2 less than 80% at rest) as well as cor pulmonale with recurrent congestive heart failure and secondary polycythemia. The patients received supplemental oxygen from a Linde* portable oxygen walker while ambulatory and from the liquid reservoir or conventional compressed oxygen tanks while at rest or during sleep. A patient maintained a home reservoir that contained 3 to 4 days' amount of liquid oxygen supply. A 6.5-lb cannister was filled by the patient at home from the reservoir. The cannister was portable and contained liquid oxygen * Linde Division, Union Carbide Corp., New York, N. Y. Table 1. Population Under Consideration for Continuous Oxygen Therapy Number Patients on pulmonary rehabilitation program 182 Patients on no outpatient oxygen therapy 129 Patients on outpatient oxygen therapy 53 Patients on oxygen less than 24 hr/day 14 Insufficient follow-up 3 Lost to follow-up 2 Died in less than 1 month 1 Patients on oxygen 24 hr/day longer than 1 month. = study group May 1970 Annals of Internal Medicine Volume 72 Number 5 that was constantly being converted into gaseous oxygen to supply 2 to 4 hr of oxygen at a flow rate of 2 to 4 liters/min. Careful steps were taken to maintain the patients' arterial oxygen saturation at a level of 88% to 92%, which is near normal for Denver, by adjusting the oxygen flow rate in the range of 2 to 4 liters/min. (Aspiration of tracheal air during inspiration from several patients via a cannula through the crycothyroid membrane showed that the Po 2 was 150 to 180 mm Hg at 2 liters/min oxygen flow via nasal prongs and up to 240 mm Hg at 4 liters/min oxygen flow. Normal inspired Po 2 for Denver is 120 mm Hg, and normal for sea level is 150 mm Hg. The inspired to arterial Po 2 gradient is increased in severe chronic airway obstruction at rest and widens even more during exercise.) The patients received a standard treatment regimen before and during oxygen therapy. Treatment included a bronchial hygiene program consisting of inhaled bronchodilator (isoproterenol, isoetharene with phenylephrine, or racemic epinephrine) followed by steam inhalation, which was followed by expulsive coughing maneuvers to clear the airways. All patients received breathing retraining emphasizing a diaphragmatic pattern and a controlled rate. The patients were given a physical conditioning program consisting of supervised graded exercises on a treadmill and stairs for 1 month. They were encouraged to maintain a high level of physical activity with walking at home after this 1 month of outpatient physical conditioning. All patients received an oral ephedrine containing bronchodilator regularly and cardiac glycosides and diuretics as needed. Phlebotomies were required very infrequently. Antibiotics (tetracycline and ampicillin) were given as needed for episodes of acute purulent bronchitis. Corticoids, usually prednisone, were given for acute bronchiolitis and bronchospasm. Corticoids were used in a low maintenance level in selected patients (12). All patients were living at home and were supervised by regular clinic visits to the rehabilitation program physicians. Many patients also continued to be under their private physician's care. Home supervision was provided by periodic visits from a public health nurse trained in respiratory care. Patients were hospitalized as needed for bouts of acute respiratory insufficiency and failure. They were hospitalized at Colorado General Hospital, Denver, under the supervision of the rehabilitation program doctors or at various local private hospitals under the care of their private physician. Ventilation tests were performed before and at 3- to 6-month intervals during the oxygen therapy. A liter Collins or a 9-liter Stead-Wells spirometer was used. The ventilation tests were done while the patients were in a clinical steady state and when they had not taken a bronchodilator recently. Arterial blood gas analyses were made at similar intervals. The ph was determined with a glass electrode*. The Pco 2 was measured by the Severinghaus electrode or by the Astrup tonometric method using the Siggard Anderson nomogram. Oxygen saturation was calculated from the oxygen hemoglobin dissociation curve with the Po 2 obtained from the Clark electrode in most cases or in the higher ranges of saturation by a dual-beam hemoreflecting oximeter!. * Radiometer Co., Westlake, Ohio t American Optical Co. Buffalo, N. Y.

3 Results The ages and ventilatory and blood gas status of the 33 patients before and after oxygen therapy are summarized in Table 2. These 33 patients have been followed for 24.3 months (mean) with the range being 7 to 41 months. Three patients died within the first year of observation (two at 7 and one at 9 months), but the remaining 30 have been followed for more than 1 year. The mean follow-up observation was 16.9 months for blood gas analysis and 16.4 months on ventilation testing. All tests showed statistically significant worsening, except Po 2 and oxygen saturation, which, of course, improved by virtue of supplemental oxygen. MORTALITY AND COR PULMONALE Nineteen of the 33 patients had cor pulmonale (defined as the presence of the history of right heart failure with no demonstrable cause for right heart failure other than chronic airway obstruction) before beginning oxygen therapy*. The cumulative mortality of these patients has been calculated by the life table method and is compared to the data from Renzetti, McClement, and Litt (6) who used the same definition for cor pulmonale (Figure 1). A significant reduction in mortality is noted (P < 0.01). The cumulative mortality by the life table method for the 14 patients without cor pulmonale is recorded in Figure 2. These data are compared to closest comparable group of Renzetti and co-workers (6), although the blood gases of the 14 patients in our group were measured while the patients were at rest. No significant difference in survival is noted (P < 0.10). MORTALITY AND HYPOXIA The 33 patients have also been grouped according to their blood gas measurements, before oxygen, similar to the method of Boushy and Coates (4). The * Mortality figures presented below for cor pulmonale patients are from the time they entered the observation series (Neff, Petty, and Renzetti) and not from the time of first development of cor pulmonale. Figure 1. Cumulative mortality in chronic airway obstruction for patients with cor pulmonale (life table method). Both groups (Renzetti and associates, and Neff and Petty) used same definitions for cor pulmonale (see text). Mean forced expiratory volume in 1 sec (FEVj), 0.84 liters; Sao 2F 88%; Pco 2l 53 mm Hg for Renzetti group. Mean FEV lf 0.71 liters; Sao 2f 78%; Pco 2, 45 mm Hg for Neff and Petty group. cumulative mortality of the patients so grouped has been calculated by the life table method for total patient years*. These data, with a comparison of the data of Boushy and associates are presented in Table 3. Mortality is significantly less (P < 0.01) in severely hypoxic patients Sa 02 < 80%) but is not significantly changed (P > 0.05) in mild to moderate hypoxia (Sa to 90%). With moderate carbon dioxide retention (Pa C o 2 45 to 54 mm Hg) again mortality in our series is significantly less (P < 0.01) than in Boushy and associates' comparable group. * Most bio statisticians do not feel this method is as valid as the more conventional life table method (22) but was done here so a comparison could be made. See Appendix for the mortality figures by the more acceptable method. Table 2. Objective Changes in Patients on Oxygen 1.4 Years (Mean) Before Oxygen After Oxygen P Difference Number Mean SD Number Mean SD Age, yr Vital capacity, liters Forced expiratory volume in 1 sec Maximum mid-expiratory flow, liters/sec Maximum voluntary ventilation, liters/sec PH Paco 2, mm Hg Pao2, mm Hg Sao 2, % Neff and Petty Chronic Airway Obstruction 623

4 Figure 2. Cumulative mortality rate in chronic airway obstruction for patients without cor pulmonale (life table method). Sao 2 < 92% and Pco 2 > 48 mm Hg after exercise for Renzetti group. Sao 2 < 91% for Neff and Petty group. DEVELOPMENT OF COR PULMONALE Six of the 14 patients who were started on oxygen without cor pulmonale developed cor pulmonale while receiving oxygen, and one developed combined right and left heart failure during oxygen therapy. Seven have remained without heart failure during oxygen therapy. Three of these seven patients are still living and may yet develop cor pulmonale while on oxygen. Three of the four patients who died while on oxygen without ever developing cor pulmonale may have had a "shortened course on oxygen" because of death from nonpulmonary causes (that is, suicide, cancer, and acute myocardial infarction). Only one patient in this series has died of respiratory failure without having developed cor pulmonale (right heart failure) at some time during the course of his disease^ Cause of Death Fifteen of the 33 patients have died (Table 4). Eleven died of progressive respiratory failure and one each from cancer, acute myocardial infarct, necrotizing pneumonia, and suicide (with cancer). While on oxygen, no patient of this series had more than mild edema (trace, +1) even during the terminal phase of illness. Discussion 624 May 1970 Annals of Internal Medicine Volume 72 Number 5 The causes of pulmonary emphysema and bronchitis, the two major diseases manifesting chronic airway obstruction, remain unknown; therefore, the treatment of these conditions remains largely empirical and symptomatic. Since a lack of oxygen certainly is not the primary cause of emphysema and bronchitis, its use in treating these diseases must be classified as symptomatic rather than specific. The appropriate use of oxygen in treatment of acute respiratory failure has adequately been described by others and will not be further discussed here (11,13-15). The use of chronic continuous oxygen is still controversial and expensive ($100 to $200 per month). The application of sound physiologic principles and objective criteria for its use on a continuous basis is therefore of paramount importance. Hypoxemia and hypercarbia are intrinsic objective manifestations of disease processes that affect the lung to a moderate or more severe degree. On the other hand, cor pulmonale is by definition a pathologic condition dependent upon and secondary to the primary pulmonary disease. The role of chronic hypoxia in development of cor pulmonale with congestive heart failure is certainly important. The relationship between hypoxia and increased pulmonary resistance and pulmonary hypertension, myocardial dysfunction, decreased renal clearance of-inulin and water, and secondary polycythemia is well established (16-20). The short-term reversal of many of the previous pathophysiologic processes by the use of oxygen has also been demonstrated (16, 17, 20). Since many patients have increased morbidity and Table 3. Cumulative Mortality Rate in Chronic Airway Obstruction with Blood Gas Abnormalities: Life Table Method in Patient Years Years Neff and Petty Boushy an d Associates Af ter ^est T~ Patients ^ Death TT Rate Patients Death Rate Followed (Percent Followed (Percent This Cumulative) This Cumulative) Period Period Arterial blood < 80% saturation P <0.01 Arterial blood 81% to 90% saturation P = N* Arterial blood carbon dioxide 45 to 54 mm Hg P <0.01 Arterial blood carbon dioxide <45 mm Hg P = N* * N = not significant (P > 0.05).

5 Table 4. Cause of Death Progressive respiratory failure Acute myocardial infarct Necrotizing pneumonia Cancer Suicide Total mortality from cor pulmonale, effective treatment of this condition might change the natural course of chronic airway obstruction. Our study shows that results of the mean measurements of ventilatory function became significantly and progressively worse while the patient was on oxygen. The rate of worsening was severe. The mean forced expiratory volume in 1 sec (FEVi) decrease was 170 ml/1.4 years or 120 ml/year. This shortterm rate of decline is even greater than the mean 75 to 80 ml/year in other series (8). Does this severe rate of progressive obstruction represent the selection of a group of patients with the most severe type of chronic airway obstruction that is, patients being selected because of hypoxia and disability or does chronic oxygen therapy actually accelerate the terminal obstructive rate in patients with chronic airway obstruction? An attempt to answer this question was made by analyzing the rate of expiratory worsening for a period of time before oxygen therapy when possible. Since many patients were started on oxygen shortly after entering the study, only 9 out of 33 patients had reliable ventilation tests for a calculable time before oxygen was started. The mean decrease in FEVi for these nine patients before starting oxygen was 80 ml/3.6 months or 233 ml/year. Therefore, there is no convincing evidence that oxygen accelerated the progress of chronic airway obstruction. Actually, airway obstruction is worsened by hypoxemia and airway resistance reduced with oxygen (21). Table 2 also shows progressive alveolar hypoventilation with the Pco 2 increasing from 45.6 mm Hg to 61.2 mm Hg in 1.4 years. This 15.6-mm Hg rise in carbon dioxide is most likely a result of both progressive obstruction to expiratory flow and some suppression of the respiratory drive from the degree of severe hypoxia that was present before oxygen therapy. Since the Pco 2 was already significantly elevated (45.6 mm Hg) before oxygen therapy, the severe progressive obstruction seems to be the more important factor causing alveolar hypoventilation. In no case in this series did oxygen have to be stopped because it caused an intolerable increase in carbon dioxide retention. By comparing the cumulative mortality rate in cor pulmonale of patients with airway obstruction in our series with that of Renzetti and co-workers (Figure 1), we see a marked decrease in mortality on a shortterm (IVi year) basis. Our experience showed that continuous oxygen was extremely important and effective in treating cor pulmonale of airway obstruction. In a number of cases cardiac compensation was accomplished with oxygen and salt restriction without the use of digitalis or diuretics. Also, many of the patients' congestive heart failure could not be satisfactorily controlled without oxygen therapy. When digitalis and diuretic therapy are "pushed" in severely hypoxic patients in an attempt to achieve an edemafree state, the end result is too frequently electrolyte imbalance and digitalis toxicity and not cardiac compensation. However, our experience also showed that continuous oxygen therapy is not the panacea or the definitive solution in these patients. Indeed, decompensated cor pulmonale that is, so-called right congestive heart failure has been present or has developed in every patient in this series except one who died from respiratory failure. Continuous oxygen therapy did make the overall management of these patients much more effective, and in no case was intractable or severe edema a problem while the patients were on oxygen therapy. Comparison of our 14 patients without cor pulmonale before oxygen therapy to those 19 with cor pulmonale (Figures 1 and 2) shows a 57% and 28% cumulative mortality for each group, respectively, after 2Vi years. The fact that the patient group without cor pulmonale had a mortality rate twice that of the patient group with cor pulmonale is paradoxical at first glance but is probably explained as follows. Our group of patients without cor pulmonale and treated with oxygen, although perhaps not exactly comparable to Renzetti and associates' group (Figure 2) in the usual "controlled" fashion, is very similar nonetheless. Our group had a slightly smaller mortality at 1 year (7% to 22%) but a slightly larger mortality at V/i years (57% to 47%). We conclude from this comparison of rather small numbers of patients that oxygen therapy does not essentially change the natural course of severe airway obstruction when cor pulmonale, or severe hypoxia, or both, do not exist. We also have shown that effective treatment of a known adverse complication of chronic airway obstruction, that is, cor pulmonale, lowers the mortality significantly. Although again the studies are not "controlled" the selection of patients and their residence at altitude are very similar, {see footnote, Figure 1). In Table 2 blood gas abnormalities are used to classify patients with chronic airway obstruction, and oxygen therapy appears to decrease mortality in severely hypoxic patients (less than 80% oxygen Neff and Petty Chronic Airway Obstruction 625

6 saturation). The oxygen-treated patients in the present study had only a 31% overall mortality when contrasted with those in the series by Boushy and associates, who had a 71% mortality at the end of 2 years (Table 3). In contrast, no appreciable effect on the mortality of moderately hypoxic patients (80% to 90% oxygen saturation) was observed from continuous oxygen therapy (Table 3). These statistics support our clinical opinion that oxygen does not prolong life of the severely dyspneic patient as long as the dyspneic patient maintains relatively normal oxygen saturation and no clinical right heart failure. We believe that we must qualify the above tentative conclusions concerning continuous oxygen therapy. Many of our arguments are supported by contrasting our series with two well-noted and accepted series in the literature. Indeed, the physiologic indicators in our series have been matched closely with those of other authors. However, no investigators' series can be identical to others. Although the use of continuous oxygen versus the apparent lack of its use is one of the major differences between our series and those of Renzetti and Boushy and their associates, its use is assuredly not the only variable. The field of intensive respiratory care is probably now more developed and more aggressively utilized in our smaller current series than in the earlier series of other authors, where therapy is not specifically reported. Therefore, the decreased mortality in our series as contrasted to the earlier reports should be considered a result of continuous oxygen therapy used in conjunction with modern systematic intensive and rehabilitative care. ACKNOWLEDGMENTS: The authors thank Tracey Spencer, M.D., for his help in the collection of the data and Myron Miller, B.A., and Philip Archer, Sc.D., for their help in statistical analysis of the data. Supported in part by contract , Chronic Respiratory Disease Control Program, U. S. Public Health Service, Washington, D.C. Findings and conclusions do not necessarily represent the views of the U. S. Public Health Service. Received November 14, 1969; revision accepted January 27, Requests for reprints should be addressed to Thomas L. Petty, M.D., Department of Medicine, University of Colorado Medical Center, Denver, Colo References 1. BALDIN EDEF, COURNAND A, RICHARDS DW JR: Pulmonary insufficiency. III. A study of 122 cases of chronic pulmonary emphysema. Medicine (Bait) 28: , BATES DV, KNOTT JMS, CHRISTIE RV: Respiratory function in emphysema in relation to prognosis. Quart J Med 25: , MITCHELL RS, WEBB NC, FILLEY GF: Chronic obstructive bronchopulmonary disease. III. Factors influencing prognosis. Amer Rev Resp Dis 89: , BOUSHY SF, COATES EO JR: Prognostic value of pulmonary function tests in emphysema: with special reference to arterial blood studies. Amer Rev Resp Dis 90: , BOUSHY SF, ADHIKARI PK, SAKAMOTO A, et al: Factors affecting prognosis in emphysema. Dis Chest 45: , RENZETTI AD JR, MCCLEMENT JH, LITT BD: Veterans Administration cooperative study of pulmonary function. III. 626 May 1970 Annals of Internal Medicine Volume 72 Number 5 Mortality in relation to respiratory function in chronic obstructive pulmonary disease. Amer J Med 41: , SIMPSON T: Chronic bronchitis and emphysema with special reference to prognosis. Brit J Dis Chest 62:57-69, BURROWS B, EARLE RH: Course and prognosis of chronic obstructive lung disease. New Eng J Med 280: , MEDICAL RESEARCH COUNCIL: Papers and original value of chemoprophylaxis and chemotherapy in early chronic bronchitis: report to Medical Research Council by their Working Party on Trials of Chemotherapy in Early Chronic Bronchitis. Brit Med J 1: , PETTY TL, NETT LM, FINIGAN MM, et al: A comprehensive ' care program for chronic airway obstruction. Ann Intern Med 70: , PETTY TL, FINIGAN MM: Clinical evaluation of prolonged ambulatory oxygen therapy in chronic airway obstruction. Amer J Med 45: , PETTY TL, BRINK GA, MILLER MW, et al: Objective functional improvement in chronic airway obstruction. Dis Chest In press. 13. CHERNIACK RM, HAKIMPOUR K: The rational use of oxygen in respiratory insufficiency. JAMA 199: , FLENLEY DC: The rationale of oxygen therapy. Lancet 1: , PETTY TL: Misunderstanding concerning the proper clinical use of oxygen (editorial). Ann Intern Med 70: , LEVINE BL, BIGELOW DB, HAMSTRA RD, et al: The role of long-term continuous oxygen administration in patients with chronic airway obstruction with hypoxemia. Ann Intern Med 66: , ABRAHAM AS, COLE RB, BISHOP JM: Reversal of pulmonary hypertension by prolonged oxygen administration to patients with chronic bronchitis. Circ Res 23: , DUNER H, GRANBERG P: Effect of induced hypoxia in renal function in man. Acta Chir Scand 125: , KAHLER RL, GOLDBLATT A, BRAUNWALD E: The effects of acute hypoxia on the systematic venous and arterial systems and on myocardial contractile force. / Clin Invest 41: , CHAMBERLAIN DA, MILLARD FJC: The treatment of polycythemia secondary to hypoxic lung disease by continuous oxygen administration. Quart J Med 32: , ASTIN TW, PENMAN WB: Airway obstruction due to hypoxemia in patients with chronic lung disease. Amer Rev Resp Dis 95: , CUTLER SJ, EDERER F: Maximum utilization of life table method in analyzing survival. / Chron Dis 8: , 1958 APPENDIX. Cumulative Mortality Rate in Chronic Airway Obstruction with Blood Gas Abnormalities: Data by Life Table Method* Interval Alive Died Not Yet Cumulative in Years Beginning During Reached Mortality of Interval Interval Next Interval in Percent Arterial blood < 80% saturation Arterial blood 81% to 90% saturation Arterial blood carbon dioxide 45 to 54 mm Hg Arterial blood carbon dioxide < 45 mm Hg * Data for 33 patients receiving continuous oxygen.