Abstract
Hypercapnia observed in patients with chronic respiratory failure may not be an ominous sign for prognosis when they are receiving long-term oxygen therapy (LTOT). In this study, we selected 4,552 patients with chronic obstructive pulmonary disease (COPD) and 3,028 with sequelae of pulmonary tuberculosis (TBsq) receiving LTOT from 1985 to 1993 throughout Japan and prospectively analyzed their prognoses. The hypercapnic patients (PaCO2 ⩾ 45 mm Hg) had a better prognosis than the normocapnic patients (35 ⩽ PaCO2 < 45 mm Hg) for TBsq, but no difference was found between the two groups with COPD. Furthermore, Cox's proportional hazards model revealed that in TBsq hypercapnia was an independent factor for favorable prognosis, and that the relative risk for mortality was 0.76 in patients with 45 ⩽ PaCO2 < 55 mm Hg, 0.64 for those with 55 ⩽ PaCO2 < 65 mm Hg, and 0.49 for patients with PaCO2 ⩾ 65 mm Hg against normocapnic patients. This favorable effect of hypercapnia in TBsq was particularly apparent in the patients without severe airway obstruction. Even a rise of 5 mm Hg or more in PaCO2 over the initial 6- to 18-mo follow-up period was not associated with poor prognosis in TBsq, although it was in COPD. From these findings, we conclude that hypercapnia should not be generally considered an ominous sign for prognosis in those patients who receive LTOT.
Hypercapnia is generally considered to be an ominous sign in chronic lung diseases. For example, it is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD) (1-4). However, controversy seems to exist concerning the prognostic value of hypercapnia for those patients with chronic respiratory failure who have started receiving long-term oxygen therapy (5-8). Some researchers have suggested that hypercapnia is an adaptive mechanism for some patients so that they can reduce energy for ventilatory work at the expense of high PaCO2 at rest (9-11). We thought that some uncertainty on this issue might be at least in part due to the small number of subjects analyzed in previous studies. In addition, if some favorable aspects of hypercapnia really exist in patients with chronic respiratory failure, this effect may appear differently according to the type of chronic respiratory failure.
In this study, we therefore attempted to examine the prognostic value of PaCO2 in a large population of patients with chronic respiratory failure throughout Japan who had been prescribed long-term oxygen therapy. We have data from more than 30,000 patients who were registered by the Respiratory Failure Research Group from 1985 through 1993 (12). We here report that chronic hypercapnia should not be considered an ominous sign in patients with sequelae of pulmonary tuberculosis (TBsq) or in patients with COPD during long-term oxygen therapy. In those with TBsq, particularly, chronic hypercapnia appears to be an independent factor for favorable prognosis.
We selected the patients who had been prescribed long-term oxygen therapy. The methods were described in our previous report (12). Briefly, we sent questionnaires to 1,740 medical institutions throughout Japan to register patients who had already been or would be newly prescribed long-term oxygen therapy. These medical institutions were registered to prescribe long-term oxygen therapy by the government. The guidelines for prescribing long-term oxygen therapy in Japan are issued by the Japan Thoracic Society (13). The minimal criteria are as follows: patients with chronic respiratory failure of (1) PaO2 ⩽ 55 mm Hg in room air at rest, or (2) 55 < PaO2 ⩽ 60 mm Hg in room air at rest associated with pulmonary hypertension or with severe hypoxemia (PaO2 ⩽ 55 mm Hg) during exercise or sleep. The patients must be in stable condition after more than 4 wk of optimal medical treatment, except for oxygen therapy. A total of 32,621 patients from 1,447 institutions were registered from July 1985 to June 1993. The registration card included information on sex, age, diagnosis, arterial blood gas analysis while breathing air and/or oxygen, spirometric data, oxygen sources, length of oxygen inhalation in hours per day, the date of initiation of long-term oxygen therapy and cause of death if known (respiratory failure, cancer, or others). Arterial blood gas data were collected while patients were clinically stable. Diagnosis for each patient was based on each physician's judgment. However, despite the guidelines mentioned above, prescription of long-term oxygen therapy was also dependent on each physician's judgment, so that among patients registered there were a substantial number of patients who did not fulfill the guidelines.
For this study, we selected only patients with COPD and TBsq, which are currently the two leading background diseases for long-term oxygen therapy in Japan. The following criteria were used for further selection of patients: (1) age from 40 to 80 yr, (2) PaO2 ⩽ 60 mm Hg with room air at rest, and (3) oxygen inhalation time of more than 15 h/d. Finally, there were 4,552 patients with COPD and 3,028 with TBsq who met all the criteria and whose outcomes could be annually confirmed by sending a questionnaire to the institute concerned. Additionally, since spirometric data were not available for all the patients and the diagnosis of COPD was based on each physician's judgment, we further analyzed 2,565 selected patients with COPD whose FEV1/FVC was less than 60% in order to confirm the results obtained from the analysis of all subjects. The mean follow-up period for surviving patients was 2.4 ± 1.9 (SD) yr.
We employed several statistical methods to focus on the prognostic effect of hypercapnia on survival in this study. We first compared survival between hypercapnic and normocapnic patients. Hypercapnia was defined as PaCO2 ⩾ 45 mm Hg while patients were breathing room air at rest. Normocapnia was defined as 35 ⩽ PaCO2 < 45 mm Hg. Student's unpaired t test was used for comparison of baseline data between the two groups. Survival curves were estimated by the Kaplan-Meier product limit method and compared by the log-rank test (14). Second, we evaluated prognostic factors using Cox's proportional hazards model in two ways (15). Initially, analysis was done on simultaneous effects of multiple factors. Sex, age, values of PaCO2 , PaO2 , percent of predicted vital capacity (%VC), and FEV1/FVC were used as continuous variables. Next, patients were stratified into five groups by the level of PaCO2 (< 35 mm Hg, 35 mm Hg ⩽ PaCO2 < 45 mm Hg, 45 mm Hg ⩽ PaCO2 < 55 mm Hg, 55 mm Hg ⩽ PaCO2 < 65 mm Hg, 65 mm Hg ⩽ PaCO2 ). The hazards ratio for mortality was calculated for each group in comparison with the normocapnic group (35 ⩽ PaCO2 < 45 mm Hg) with or without adjustment of other prognostic factors. A p value of less than 0.05 was considered to be significant. Values were expressed as means ± SD. Analyses were performed using the SAS statistical package (SAS Institute Inc., Cary, NC) (16).
Of the 4,552 patients with COPD, 1,611 died during the follow-up period. The causes of death were respiratory failure in 1,081 patients (67.1%), malignancy in 129 patients (8.0%), various other causes in 138 patients (8.6%), and not specified in 263 patients (16.3%). The overall survival rates after 1, 3, and 5 yr were 87.9, 62.1, and 39.5%, respectively. Baseline characteristics of the patients are shown in Table 1. The mean age of the hypercapnic patients (mean PaCO2 = 54.7 ± 7.9 mm Hg) when registered was significantly younger (by 1.3 yr) than the mean age of the normocapnic patients (mean PaCO2 = 40.5 ± 2.7 mm Hg). On the other hand, the mean %VC was 10% lower, the mean FEV1/FVC was 1.8% lower, and the mean PaO2 was 3.4 mm Hg lower in the hypercapnic than in the normocapnic patients. Despite such disadvantages in %VC, FEV1/ FVC, and PaO2 in the group of hypercapnic patients, the cumulative survival curves of both hypercapnic and normocapnic patients with COPD were quite similar (Figure 1A). The same was true when comparison was made separately in men and women (data not shown). We then analyzed only those who had spirometric data and FEV1/FVC < 60% in an attempt to eliminate those patients who had hypercapnia not caused by severe obstructive ventilatory disturbances. As is shown in Figure 2, the prognoses in the two groups with and without hypercapnia were again quite similar. Cox's proportional hazards model revealed that among the six variables used, age, sex, PaO2 , and %VC were independent predictors for survival (Table 2). However, the prognostic values of PaCO2 and FEV1/ FVC were not statistically significant.
| COPD | TBsq | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PaCO2 (mm Hg) | PaCO2 (mm Hg) | |||||||||||
| Total | 35 ⩽ < 45 | 45 ⩽ | Total | 35 ⩽ < 45 | 45 ⩽ | |||||||
| Number | 4,552† | 1,364 | 2,868 | 3,028† | 556 | 2,361 | ||||||
| Male/female | 3,341/1,211 | 1,054/310 | 2,007/861 | 1,994/1,034 | 405/151 | 1,490/871 | ||||||
| Age, yr | 69.0 ± 7.7 | 69.6 ± 7.4 | 68.3 ± 7.8§ | 64.8 ± 8.0 | 66.4 ± 8.2 | 64.2 ± 7.9§ | ||||||
| PaO2, mm Hg | 50.3 ± 7.0 | 52.5 ± 5.8 | 49.1 ± 7.3§ | 49.7 ± 7.3 | 51.4 ± 6.6 | 49.3 ± 6.6§ | ||||||
| PaCO2, mm Hg | 48.8 ± 10.3 | 40.5 ± 2.7 | 54.7 ± 7.9§ | 52.8 ± 10.2 | 40.9 ± 2.6 | 56.6 ± 7.9§ | ||||||
| %VC‡ | 59.8 ± 19.3 | 65.3 ± 20.1 | 55.3 ± 17.0§ | 41.7 ± 15.0 | 49.1 ± 17.4 | 39.2 ± 13.0§ | ||||||
| FEV1/FVC, %‡ | 46.2 ± 15.3 | 46.9 ± 15.0 | 45.1 ± 15.2§ | 63.7 ± 19.7 | 60.3 ± 19.6 | 64.4 ± 19.8§ | ||||||
Fig. 1. Cumulative survival curves by the level of PaCO2 . (A) COPD. (B) Sequelae of pulmonary tuberculosis. NS = not significant.
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Fig. 2. Cumulative survival curves by the level of PaCO2 in patients with COPD whose FEV1/FVC was less than 60%. Patients' characteristics in normocapnic and hypercapnic groups are: 69.4 ± 7.0 (SD) yr versus 67.7 ± 7.6 yr for age, 53.0 ± 5.4 mm Hg versus 49.7 ± 7.0 mm Hg for PaO2 , 39.1 ± 4.3 mm Hg versus 54.0 ± 7.4 mm Hg for PaCO2 , 67.5 ± 19.4% versus 56.7 ± 16.4% for %VC, 42.0 ± 9.8% versus 40.2 ± 10.1% for FEV1/FVC, respectively. The difference between the two groups was statistically significant for all the variables (p < 0.05).
[More] [Minimize]| Variable | b | SE | c2 | p Value | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr | 0.0442 | 0.0047 | 88.5 | < 0.0001 | ||||
| Sex, female/male | −0.4250 | 0.0766 | 30.8 | < 0.0001 | ||||
| PaO2 room air, mm Hg | −0.2234 | 0.0044 | 26.0 | < 0.0001 | ||||
| %VC | −0.0035 | 0.0017 | 4.4 | 0.02 |
Of the 3,028 patients with TBsq, 1,012 died during the follow-up period. The causes of death were respiratory failure in 733 patients (72.4%), malignancy in 47 patients (4.6%), various other causes in 82 patients (8.1%), and not specified in 150 patients (14.8%). The overall survival rates after 1, 3, and 5 yr were 86.6, 65.6, and 48.2%, respectively. The group of hypercapnic patients had some favorable background characteristics when compared with the group of normocapnic patients since the former group was 2.2 yr younger and their mean FEV1/FVC was 4.1% better than in the latter group (64.4 ± 19.8% versus 60.3 ± 19.6%) (Table 1). On the other hand, the mean PaO2 while breathing room air in the hypercapnic patients was 49.3 ± 6.6 mm Hg, which was significantly lower than the 51.4 ± 6.6 mm Hg in the normocapnic patients. In addition, the %VC in the hypercapnic patients was 39.2 ± 13.0%, which was again significantly lower than the 49.1 ± 17.4% in the normocapnic patients. Cumulative survival curves of the hypercapnic and normocapnic patients are shown in Figure 1B. The hypercapnic patients, remarkably, had a better prognosis than did the normocapnic patients. The difference in the survival rate between the two groups was 3.3% in the first year, 10.4% in the third year, and 12.3% in the fifth year (p < 0.0001). When analysis was done separately for each sex, the results were the same (data not shown). Cox's proportional hazards model revealed that the favorable prognostic value of PaCO2 was highly significant and independent of other prognostic factors such as sex, age, PaO2 , %VC, and FEV1/FVC, all of which were also shown to be significant in this analysis (Table 3). Further analysis demonstrated that the relative risk for mortality of hypercapnic patients in comparison with normocapnic patients depended on the value of PaCO2 even after adjustment by other prognostic factors (Table 4). To explore the possibility that the prognostic value of hypercapnia might be different according to the type of ventilatory impairment, we divided patients with TBsq into two groups by their severity of airway obstruction, that is, one group whose FEV1/FVC was 60% or more and another with less than 60%. The favorable prognostic effect of hypercapnia was highly significant in patients without or with mild airway obstruction, but it was not in patients with severe airway obstruction (Figure 3).
| Variable | b | SE | c2 | p Value | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr | 0.0406 | 0.0055 | 55.1 | < 0.0001 | ||||
| PaCO2 room air, mm Hg | −0.0263 | 0.0045 | 34.6 | < 0.0001 | ||||
| Sex, female/male | −0.3920 | 0.0896 | 19.1 | < 0.0001 | ||||
| FEV1/FVC, % | 0.0070 | 0.0023 | 9.6 | 0.002 | ||||
| PaO2 room air, mm Hg | −0.0242 | 0.0058 | 17.7 | < 0.0001 | ||||
| %VC | −0.0077 | 0.0033 | 5.6 | 0.02 |
| PaCO2 (mm Hg) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| < 35 | 35 ⩽ < 45 | 45 ⩽ < 55 | 55 ⩽ < 65 | 65 ⩽ | ||||||
| Number | 111 | 556 | 1,132 | 886 | 343 | |||||
| Relative risk, crude | 1.66§ | 1 | 0.75§ | 0.66§ | 0.62§ | |||||
| 95% CI | 1.23–2.25 | 0.64–0.89 | 0.55–0.79 | 0.49–0.78 | ||||||
| Relative risk, adjusted† | 1.57‡ | 1 | 0.76‡ | 0.64§ | 0.49§ | |||||
| 95% CI | 1.06–2.32 | 0.61–0.95 | 0.50–0.81 | 0.35–0.69 | ||||||
Fig. 3. Cumulative survival curves of patients with sequelae of pulmonary tuberculosis by the level of PaCO2 . (A) FEV1/FVC was 60% or more. (B) FEV1/FVC was less than 60%. NS = not significant.
[More] [Minimize]In 466 patients with COPD and in 313 patients with TBsq, the follow-up data on arterial gas analysis were available between 6 and 18 mo after the initiation of long-term oxygen therapy. The mean period between the initiation of long-term oxygen therapy and the second arterial blood gas determination was 1.18 ± 0.22 yr in COPD and 1.17 ± 0.22 yr in TBsq. The patients whose PaCO2 increased more than 5 mm Hg during this period had significantly higher mortality than did those with stable PaCO2 in COPD, but this was not the case for TBsq (Figure 4).
Fig. 4. Annual change in PaCO2 and prognosis in COPD and sequelae of pulmonary tuberculosis. ΔPaCO2 = PaCO2 (after 6 to 18 mo) − PaCO2 (initial). NS = not significant.
[More] [Minimize]In this study, we demonstrated that hypercapnia was an independent factor for favorable prognosis in patients with TBsq and was not a factor for either favorable or poor prognosis in patients with COPD once they started receiving long-term oxygen therapy. In TBsq, the favorable prognostic effect of hypercapnia was highly significant, particularly in those patients who did not have severe airway obstruction. Furthermore, an increase in PaCO2 of 5 mm Hg or more over the 6- to 18-mo follow-up period was not associated with poor prognosis in patients with TBsq, although it was in patients with COPD. These data indicate that chronic hypercapnia should not be generally considered an ominous sign in those patients who are receiving long-term oxygen therapy.
Because multicentric studies of the Medical Research Council (5) and the Nocturnal Oxygen Therapy Group (17) demonstrated the therapeutic efficacy of long-term oxygen therapy for hypoxic patients with COPD, several studies have investigated predictors for prognosis in patients receiving such oxygen therapy. Potential prognostic factors so far reported include age (7, 8), sex (7, 12), the level of PaO2 (18), the severity of airway obstruction (18, 19), diffusion capacity for carbon monoxide (8), and the presence of pulmonary hypertension (6, 20, 21). The effect of hypercapnia on the prognosis in patients receiving long-term oxygen therapy, however, does not seem to be clear (5-8), although hypercapnia is generally thought to be a predictor for a poor, unfavorable prognosis in patients with COPD (1-4). The uncertainty of hypercapnia as a prognostic factor in previous studies may be explained by the small numbers of subjects analyzed and also by the characteristics of the study populations because it is not easy to differentiate the prognostic effect of hypercapnia from other factors, considering the fact that hypercapnia is usually associated with variable levels of hypoxemia and airway obstruction (22).
In a recent study that found significantly high PaCO2 in the lower-mortality group receiving long-term oxygen therapy (8), the investigators suggested that a distinction should be made between progressive hypercapnia caused by terminal respiratory failure and adaptive hypercapnia, where the respiratory centers are tuned to a higher PaCO2 in order to lessen the respiratory work. Although this mechanism should naturally cause PaO2 to fall farther in turn as a consequence of decreased ventilation, such a harmful phenomenon could be prevented by long-term oxygen therapy.
The hypercapnia in patients with chronic respiratory failure can occur as a result of ineffective elimination from the lungs of carbon dioxide produced in the whole body (23). The underlying mechanisms for this may be either disturbances in gas exchange or abnormalities in the mechanical system (24). Both dead-space ventilation and ventilation-perfusion mismatch contribute to ineffective elimination of carbon dioxide from the lungs, and respiratory-muscle fatigue or weakness may cause additional reduction of ventilation in chronic respiratory failure (25-27). To whatever degree each mechanism is involved, however, the final determinant for PaCO2 must rest upon the ventilatory control system. It is well known that the responsiveness of the respiratory controller to respiratory stimuli such as hypoxia or hypercapnia varies widely even among normal subjects, and this variability in the chemical control of breathing has been explained, at least in part, by genetic factors (28-30). In fact, previous studies have shown that the offspring of hypercapnic patients with COPD have lower hypoxic ventilatory responses than do those of normocapnic patients (31-33). Thus, it is quite reasonable that there is a wide subject variation in the level of PaCO2 for a given level of mechanical disturbance in the lungs or the thorax.
The present study, using statistical analysis methods for a large number of patients, has shown that chronic hypercapnia is an independent factor for favorable prognosis in patients with TBsq during long-term oxygen therapy, and that it is not a factor for either favorable or poor prognosis in patients with COPD. The independence of hypercapnia as a favorable prognostic factor in TBsq was proved by Cox's proportional hazards model. The relative risk for mortality was dependent on the level of PaCO2 . When the relative risk for mortality in normocapnic patients was assumed to have a value of one, relative risks adjusted by other prognostic factors in the three groups of hypercapnic patients (45 ⩽ PaCO2 < 55 mm Hg, 55 ⩽ PaCO2 < 65 mm Hg, and 65 mm Hg ⩽ PaCO2 ) were 0.76, 0.64, and 0.49, respectively. Interestingly enough, a favorable prognostic value for hypercapnia was prominent only in the subgroups of TBsq who showed little or only mild airway obstruction, but it was not significant in the subgroup who had severe airway obstruction. Ström and coworkers (34, 35) recently reported a favorable effect of hypercapnia on the prognosis in patients with severe thoracic deformity during long-term oxygen therapy and a similar tendency in patients with interstitial fibrosis. These data suggest that the predictive advantage of hypercapnia is more likely apparent in a particular form of chronic respiratory failure devoid of severe airway obstruction. On the other hand, in the case of chronic respiratory failure associated with severe airway obstruction, the advantage of hypercapnia would not appear or might be masked by other factors contributing to poor prognosis.
We should, however, consider another possible explanation for the favorable prognostic effect of hypercapnia observed for TBsq in this study. Hypercapnia there might simply reflect less advanced pulmonary parenchymal lesions. Those hypercapnic patients might have less severe diffusion disturbances or ventilation-perfusion mismatch because hypercapnic patients should have a smaller value for alveolar-arterial difference in oxygen tension than normocapnic patients if both groups of patients have similar levels of hypoxemia. In fact, a diagnosis of TBsq does not always represent the same pathologic state. In some patients, restrictive impairment may be caused by a parenchymal postinflammatory fibrotic change, whereas in others it may result from thoracic deformity because of thoracotomy or pleural adhesion or thickening. Airway obstructions possibly caused by smoking, tuberculosis itself, or other infections may variably contribute to chronic respiratory failure. A variety of pathologic changes involved in TBsq could somehow be related to the results of the present study. Although we cannot neglect the possibility that the favorable prognositc effect of hypercapnia seen in this study was due to the difference in parenchymal lung lesions, the 6- to 18-mo follow-up data for PaCO2 in patients with TBsq seem to support the idea that an adaptive mechanism of hypercapnia might actually be working and contribute to the favorable prognosis to some extent. Indeed, an increase in PaCO2 of 5 mm Hg or more over the follow-up period was not associated with poor prognosis in the patients with TBsq.
Finally, it must be noted that this study has some methodologic limitations. First, because of the limited information from the registration card, we could not examine the effects of smoking or medication, both of which might modify the mortality rate. Second, all causes of death were included in the analysis, although precise information was unavailable for as much as 16% of all the cases. We thus analyzed the data only from the patients who died of respiratory failure and found the same findings in both groups of patients (data not shown). In addition, when the data were separately analyzed by sex, the favorable prognostic effect was similarly apparent for both sexes in patients with TBsq. Third, the diagnosis of COPD was based on each physician's judgment in this study so that some of the patients might have been misdiagnosed. If so, the large number of patients might no longer be a strength of this study. We thus did additional analysis using selected patients with COPD who had spirometric data and whose FEV1/FVC was less than 60%, and found similar results.
In summary, we have demonstrated in this study that hypercapnia should not be considered an ominous sign in patients with chronic respiratory failure during long-term oxygen therapy. In TBsq, in particular, hypercapnia is associated with a favorable prognosis. The findings of this study may have a significant impact on the treatment policy for those patients. For instance, hypercapnic patients with chronic respiratory failure may not benefit from an attempt to reduce PaCO2 by fine adjustment of the flow rate of oxygen or by use of respiratory stimulants. One should keep in mind that hypercapnia observed in chronic respiratory failure does not necessarily need to be corrected during long-term oxygen therapy.
Supported by a Research Grant for Intractable Diseases from the Ministry of Health and Welfare, Japan.
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Dr. Kawakami is Director of the Respiratory Failure Research Group in Japan.
